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Sample records for gene transposition causing

  1. Gene transposition causing natural variation for growth in Arabidopsis thaliana.

    Science.gov (United States)

    Vlad, Daniela; Rappaport, Fabrice; Simon, Matthieu; Loudet, Olivier

    2010-05-13

    A major challenge in biology is to identify molecular polymorphisms responsible for variation in complex traits of evolutionary and agricultural interest. Using the advantages of Arabidopsis thaliana as a model species, we sought to identify new genes and genetic mechanisms underlying natural variation for shoot growth using quantitative genetic strategies. More quantitative trait loci (QTL) still need be resolved to draw a general picture as to how and where in the pathways adaptation is shaping natural variation and the type of molecular variation involved. Phenotypic variation for shoot growth in the Bur-0 x Col-0 recombinant inbred line set was decomposed into several QTLs. Nearly-isogenic lines generated from the residual heterozygosity segregating among lines revealed an even more complex picture, with major variation controlled by opposite linked loci and masked by the segregation bias due to the defective phenotype of SG3 (Shoot Growth-3), as well as epistasis with SG3i (SG3-interactor). Using principally a fine-mapping strategy, we have identified the underlying gene causing phenotypic variation at SG3: At4g30720 codes for a new chloroplast-located protein essential to ensure a correct electron flow through the photosynthetic chain and, hence, photosynthesis efficiency and normal growth. The SG3/SG3i interaction is the result of a structural polymorphism originating from the duplication of the gene followed by divergent paralogue's loss between parental accessions. Species-wide, our results illustrate the very dynamic rate of duplication/transposition, even over short periods of time, resulting in several divergent--but still functional-combinations of alleles fixed in different backgrounds. In predominantly selfing species like Arabidopsis, this variation remains hidden in wild populations but is potentially revealed when divergent individuals outcross. This work highlights the need for improved tools and algorithms to resolve structural variation

  2. Single-copy genes define a conserved order between rice and wheat for understanding differences caused by duplication, deletion, and transposition of genes.

    Science.gov (United States)

    Singh, Nagendra K; Dalal, Vivek; Batra, Kamlesh; Singh, Binay K; Chitra, G; Singh, Archana; Ghazi, Irfan A; Yadav, Mahavir; Pandit, Awadhesh; Dixit, Rekha; Singh, Pradeep K; Singh, Harvinder; Koundal, Kirpa R; Gaikwad, Kishor; Mohapatra, Trilochan; Sharma, Tilak R

    2007-01-01

    The high-quality rice genome sequence is serving as a reference for comparative genome analysis in crop plants, especially cereals. However, early comparisons with bread wheat showed complex patterns of conserved synteny (gene content) and colinearity (gene order). Here, we show the presence of ancient duplicated segments in the progenitor of wheat, which were first identified in the rice genome. We also show that single-copy (SC) rice genes, those representing unique matches with wheat expressed sequence tag (EST) unigene contigs in the whole rice genome, show more than twice the proportion of genes mapping to syntenic wheat chromosome as compared to the multicopy (MC) or duplicated rice genes. While 58.7% of the 1,244 mapped SC rice genes were located in single syntenic wheat chromosome groups, the remaining 41.3% were distributed randomly to the other six non-syntenic wheat groups. This could only be explained by a background dispersal of genes in the genome through transposition or other unknown mechanism. The breakdown of rice-wheat synteny due to such transpositions was much greater near the wheat centromeres. Furthermore, the SC rice genes revealed a conserved primordial gene order that gives clues to the origin of rice and wheat chromosomes from a common ancestor through polyploidy, aneuploidy, centromeric fusions, and translocations. Apart from the bin-mapped wheat EST contigs, we also compared 56,298 predicted rice genes with 39,813 wheat EST contigs assembled from 409,765 EST sequences and identified 7,241 SC rice gene homologs of wheat. Based on the conserved colinearity of 1,063 mapped SC rice genes across the bins of individual wheat chromosomes, we predicted the wheat bin location of 6,178 unmapped SC rice gene homologs and validated the location of 213 of these in the telomeric bins of 21 wheat chromosomes with 35.4% initial success. This opens up the possibility of directed mapping of a large number of conserved SC rice gene homologs in wheat

  3. High incidence of interchromosomal transpositions in the evolutionary history of a subset of or genes in Drosophila.

    Science.gov (United States)

    Conceição, Inês C; Aguadé, Montserrat

    2008-04-01

    In insects, the odorant receptor (Or) multigene family is an intermediate-sized family with genes present in all chromosomes, indicating that duplication followed by interchromosomal transposition played an important role in the early stages of the family evolution. Here, we have explored the occurrence of interchromosomal transpositions in more recent stages through the comparative analysis of a subset of Or genes in Drosophila, where the gene content of chromosomal arms is highly conserved. The studied subset consisted of 11 Or genes located on the left arm of chromosome 3 (Muller's D element) in D. melanogaster. Our study focused on the number and chromosomal arm location of these members of the family across the 12 Drosophila species with complete genome sequences. In contrast to previous results from in situ hybridization comparative mapping that were mainly based on single-copy genes, our study, based on members of a multigene family of moderate size, revealed repeated interchromosomal transposition events and a complex history of some of the studied genes.

  4. Universal platform for quantitative analysis of DNA transposition

    Directory of Open Access Journals (Sweden)

    Pajunen Maria I

    2010-11-01

    Full Text Available Abstract Background Completed genome projects have revealed an astonishing diversity of transposable genetic elements, implying the existence of novel element families yet to be discovered from diverse life forms. Concurrently, several better understood transposon systems have been exploited as efficient tools in molecular biology and genomics applications. Characterization of new mobile elements and improvement of the existing transposition technology platforms warrant easy-to-use assays for the quantitative analysis of DNA transposition. Results Here we developed a universal in vivo platform for the analysis of transposition frequency with class II mobile elements, i.e., DNA transposons. For each particular transposon system, cloning of the transposon ends and the cognate transposase gene, in three consecutive steps, generates a multifunctional plasmid, which drives inducible expression of the transposase gene and includes a mobilisable lacZ-containing reporter transposon. The assay scores transposition events as blue microcolonies, papillae, growing within otherwise whitish Escherichia coli colonies on indicator plates. We developed the assay using phage Mu transposition as a test model and validated the platform using various MuA transposase mutants. For further validation and to illustrate universality, we introduced IS903 transposition system components into the assay. The developed assay is adjustable to a desired level of initial transposition via the control of a plasmid-borne E. coli arabinose promoter. In practice, the transposition frequency is modulated by varying the concentration of arabinose or glucose in the growth medium. We show that variable levels of transpositional activity can be analysed, thus enabling straightforward screens for hyper- or hypoactive transposase mutants, regardless of the original wild-type activity level. Conclusions The established universal papillation assay platform should be widely applicable to a

  5. DNA methylation inhibits expression and transposition of the Neurospora Tad retrotransposon.

    Science.gov (United States)

    Zhou, Y; Cambareri, E B; Kinsey, J A

    2001-06-01

    Tad is a LINE-like retrotransposon of the filamentous fungus Neurospora crassa. We have analyzed both expression and transposition of this element using strains with a single copy of Tad located in the 5' noncoding sequences of the am (glutamate dehydrogenase) gene. Tad in this position has been shown to carry a de novo cytosine methylation signal which causes reversible methylation of both Tad and am upstream sequences. Here we find that methylation of the Tad sequences inhibits both Tad expression and transposition. This inhibition can be relieved by the use of 5-azacytidine, a drug which reduces cytosine methylation, or by placing the Tad/am sequences in a dim-2 genetic background.

  6. Pig transgenesis by Sleeping Beauty DNA transposition

    DEFF Research Database (Denmark)

    Jakobsen, Jannik E.; Li, Juan; Kragh, Peter M.

    2011-01-01

    disease models. In this report, we present transgenic pigs created by Sleeping Beauty DNA transposition in primary porcine fibroblasts in combination with somatic cell nuclear transfer by handmade cloning. Göttingen minipigs expressing green fluorescent protein are produced by transgenesis with DNA...... plasmid DNA. Our findings illustrate critical issues related to DNA transposon-directed transgenesis, including coincidental plasmid insertion and relatively low Sleeping Beauty transposition activity in porcine fibroblasts, but also provide a platform for future development of porcine disease models......Modelling of human disease in genetically engineered pigs provides unique possibilities in biomedical research and in studies of disease intervention. Establishment of methodologies that allow efficient gene insertion by non-viral gene carriers is an important step towards development of new...

  7. Rapid and efficient introduction of a foreign gene into bacterial artificial chromosome-cloned varicella vaccine by Tn7-mediated site-specific transposition

    International Nuclear Information System (INIS)

    Somboonthum, Pranee; Koshizuka, Tetsuo; Okamoto, Shigefumi; Matsuura, Masaaki; Gomi, Yasuyuki; Takahashi, Michiaki; Yamanishi, Koichi; Mori, Yasuko

    2010-01-01

    Using a rapid and reliable system based on Tn7-mediated site-specific transposition, we have successfully constructed a recombinant Oka varicella vaccine (vOka) expressing the mumps virus (MuV) fusion protein (F). The backbone of the vector was our previously reported vOka-BAC (bacterial artificial chromosome) genome. We inserted the transposon Tn7 attachment sequence, LacZα-mini-attTn7, into the region between ORF12 and ORF13 to generate a vOka-BAC-Tn genome. The MuV-F expressing cassette was transposed into the vOka-BAC genome at the mini-attTn7 transposition site. MuV-F protein was expressed in recombinant virus, rvOka-F infected cells. In addition, the MuV-F protein was cleaved in the rvOka-F infected cells as in MuV-infected cells. The growth of rvOka-F was similar to that of the original recombinant vOka without the F gene. Thus, we show that Tn7-mediated transposition is an efficient method for introducing a foreign gene expression cassette into the vOka-BAC genome as a live virus vector.

  8. Insertion sequence transposition determines imipenem resistance in Acinetobacter baumannii.

    Science.gov (United States)

    Kuo, Han-Yueh; Chang, Kai-Chih; Liu, Chih-Chin; Tang, Chuan Yi; Peng, Jhih-Hua; Lu, Chia-Wei; Tu, Chi-Chao; Liou, Ming-Li

    2014-10-01

    This study employed genomewide analysis to investigate potential resistance mechanisms in Acinetobacter baumannii following imipenem exposure. Imipenem-selected mutants were generated from the imipenem-susceptible strain ATCC 17978 by multistep selection resistance. Antibiotic susceptibilities were examined, and the selected mutants originated from the ATCC 17978 strain were confirmed by pulsed-field gel electrophoresis. The genomic sequence of a resistant mutant was analyzed using a next-generation sequencing platform, and genetic recombination was further confirmed by PCR. The result showed that phenotypic resistance was observed with carbapenem upon exposure to various concentrations of imipenem. Genomewide analysis showed that ISAba1 transposition was initiated by imipenem exposure at concentrations up to 0.5 mg/L. Transposition of ISAba1 upstream of blaOXA-95 was detected in all the selected mutants. The expression of blaOXA-95 was further analyzed by quantitative PCR, and the results demonstrated that a 200-fold increase in gene expression was required for resistance to imipenem. This study concluded that imipenem exposure at a concentration of 0.5 mg/L mediated the transposition of ISAba1 upstream of the blaOXA-95 gene and resulted in the overexpression of blaOXA-95 gene, which may play a major role in the resistance to imipenem in A. baumannii.

  9. Mutational analysis of the PITX2 coding region revealed no common cause for transposition of the great arteries (dTGA

    Directory of Open Access Journals (Sweden)

    Goldmuntz Elizabeth

    2005-05-01

    Full Text Available Abstract Background PITX2 is a bicoid-related homeodomain transcription factor that plays an important role in asymmetric cardiogenesis. Loss of function experiments in mice cause severe heart malformations, including transposition of the great arteries (TGA. TGA accounts for 5–7% of all congenital heart diseases affecting 0.2 per 1000 live births, thereby representing the most frequent cyanotic heart defect diagnosed in the neonatal period. Methods To address whether altered PITX2 function could also contribute to the formation of dTGA in humans, we screened 96 patients with dTGA by means of dHPLC and direct sequencing for mutations within the PITX2 gene. Results Several SNPs could be detected, but no stop or frame shift mutation. In particular, we found seven intronic and UTR variants, two silent mutations and two polymorphisms within the coding region. Conclusion As most sequence variants were also found in controls we conclude that mutations in PITX2 are not a common cause of dTGA.

  10. Didactic Transposition in Mathematics Textbooks.

    Science.gov (United States)

    Kang, Wan; Kilpatrick, Jeremy

    1992-01-01

    Didactic transposition theory asserts that bodies of knowledge are designed not to be taught but to be used. Discusses didactic transposition, the transposition of knowledge regarded as a tool to be used to knowledge as something to be learned in mathematics textbooks. (14 references) (MDH)

  11. Bounded Rationality in Transposition Processes

    DEFF Research Database (Denmark)

    Vollaard, Hans; Martinsen, Dorte Sindbjerg

    2014-01-01

    Studies explaining the timeliness and correctness of the transposition of EU directives into national legislation have provided rather inconclusive findings. They do not offer a clear-cut prediction concerning the transposition of the patients’ rights directive, which is one of the first that con......Studies explaining the timeliness and correctness of the transposition of EU directives into national legislation have provided rather inconclusive findings. They do not offer a clear-cut prediction concerning the transposition of the patients’ rights directive, which is one of the first...... that concerns the organisation and financing of national healthcare systems. This article applies the perspective of bounded rationality to explain (irregularities in) the timely and correct transposition of EU directives. The cognitive and organisational constraints long posited by the bounded rationality...

  12. Transposition of the great arteries

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    Castela Eduardo

    2008-10-01

    Full Text Available Abstract Transposition of the great arteries (TGA, also referred to as complete transposition, is a congenital cardiac malformation characterised by atrioventricular concordance and ventriculoarterial (VA discordance. The incidence is estimated at 1 in 3,500–5,000 live births, with a male-to-female ratio 1.5 to 3.2:1. In 50% of cases, the VA discordance is an isolated finding. In 10% of cases, TGA is associated with noncardiac malformations. The association with other cardiac malformations such as ventricular septal defect (VSD and left ventricular outflow tract obstruction is frequent and dictates timing and clinical presentation, which consists of cyanosis with or without congestive heart failure. The onset and severity depend on anatomical and functional variants that influence the degree of mixing between the two circulations. If no obstructive lesions are present and there is a large VSD, cyanosis may go undetected and only be perceived during episodes of crying or agitation. In these cases, signs of congestive heart failure prevail. The exact aetiology remains unknown. Some associated risk factors (gestational diabetes mellitus, maternal exposure to rodenticides and herbicides, maternal use of antiepileptic drugs have been postulated. Mutations in growth differentiation factor-1 gene, the thyroid hormone receptor-associated protein-2 gene and the gene encoding the cryptic protein have been shown implicated in discordant VA connections, but they explain only a small minority of TGA cases. The diagnosis is confirmed by echocardiography, which also provides the morphological details required for future surgical management. Prenatal diagnosis by foetal echocardiography is possible and desirable, as it may improve the early neonatal management and reduce morbidity and mortality. Differential diagnosis includes other causes of central neonatal cyanosis. Palliative treatment with prostaglandin E1 and balloon atrial septostomy are usually

  13. Non-conformable, partial and conformable transposition

    DEFF Research Database (Denmark)

    König, Thomas; Mäder, Lars Kai

    2013-01-01

    and the Commission regarding a directive’s outcome, play a much more strategic role than has to date acknowledged in the transposition literature. Whereas disagreement of a member state delays conformable transposition, it speeds up non-conformable transposition. Disagreement of the Commission only prolongs...... the transposition process. We therefore conclude that a stronger focus on an effective sanctioning mechanism is warranted for safeguarding compliance with directives....

  14. Didactic Transposition

    DEFF Research Database (Denmark)

    Achiam, Marianne

    The term didactic transposition refers to the deconstruction and reconstruction of science knowledge, values or practices in order to make them teachable. In this paper, I present the theoretical framework that has grown around this notion. I use examples from different levels of science educatio...... framework to the more normative construct of today (the Anthropological Theory of Didactics or ATD), where it converges with other comparable frameworks, e.g. the Model of Educational Reconstruction.......The term didactic transposition refers to the deconstruction and reconstruction of science knowledge, values or practices in order to make them teachable. In this paper, I present the theoretical framework that has grown around this notion. I use examples from different levels of science education...... and different subjects to illustrate how science is transformed in any teaching undertaking, and how that transformation influences the way science is experienced and appropriated by learners. The chosen examples also illustrate the development of the notion of didactic transposition from a descriptive...

  15. Efficient Sleeping Beauty DNA Transposition From DNA Minicircles

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    Nynne Sharma

    2013-01-01

    Full Text Available DNA transposon-based vectors have emerged as new potential delivery tools in therapeutic gene transfer. Such vectors are now showing promise in hematopoietic stem cells and primary human T cells, and clinical trials with transposon-engineered cells are on the way. However, the use of plasmid DNA as a carrier of the vector raises safety concerns due to the undesirable administration of bacterial sequences. To optimize vectors based on the Sleeping Beauty (SB DNA transposon for clinical use, we examine here SB transposition from DNA minicircles (MCs devoid of the bacterial plasmid backbone. Potent DNA transposition, directed by the hyperactive SB100X transposase, is demonstrated from MC donors, and the stable transfection rate is significantly enhanced by expressing the SB100X transposase from MCs. The stable transfection rate is inversely related to the size of circular donor, suggesting that a MC-based SB transposition system benefits primarily from an increased cellular uptake and/or enhanced expression which can be observed with DNA MCs. DNA transposon and transposase MCs are easily produced, are favorable in size, do not carry irrelevant DNA, and are robust substrates for DNA transposition. In accordance, DNA MCs should become a standard source of DNA transposons not only in therapeutic settings but also in the daily use of the SB system.

  16. The politics of compliance : explaining the transposition of EC directives in the Netherlands

    NARCIS (Netherlands)

    Mastenbroek, Ellen

    2007-01-01

    The EU suffers from an implementation deficit. Member states often do not comply with EU policies, which in turn hampers the process of European integration. This book documents the problem with the timely transposition of EU directives. It explores the size and the causes of the transposition

  17. Random mutagenesis of the hyperthermophilic archaeon Pyrococcus furiosus using in vitro mariner transposition and natural transformation.

    Science.gov (United States)

    Guschinskaya, Natalia; Brunel, Romain; Tourte, Maxime; Lipscomb, Gina L; Adams, Michael W W; Oger, Philippe; Charpentier, Xavier

    2016-11-08

    Transposition mutagenesis is a powerful tool to identify the function of genes, reveal essential genes and generally to unravel the genetic basis of living organisms. However, transposon-mediated mutagenesis has only been successfully applied to a limited number of archaeal species and has never been reported in Thermococcales. Here, we report random insertion mutagenesis in the hyperthermophilic archaeon Pyrococcus furiosus. The strategy takes advantage of the natural transformability of derivatives of the P. furiosus COM1 strain and of in vitro Mariner-based transposition. A transposon bearing a genetic marker is randomly transposed in vitro in genomic DNA that is then used for natural transformation of P. furiosus. A small-scale transposition reaction routinely generates several hundred and up to two thousands transformants. Southern analysis and sequencing showed that the obtained mutants contain a single and random genomic insertion. Polyploidy has been reported in Thermococcales and P. furiosus is suspected of being polyploid. Yet, about half of the mutants obtained on the first selection are homozygous for the transposon insertion. Two rounds of isolation on selective medium were sufficient to obtain gene conversion in initially heterozygous mutants. This transposition mutagenesis strategy will greatly facilitate functional exploration of the Thermococcales genomes.

  18. A TALE of transposition: Tn3-like transposons play a major role in the spread of pathogenicity determinants of Xanthomonas citri and other xanthomonads.

    Science.gov (United States)

    Ferreira, Rafael Marini; de Oliveira, Amanda Carolina P; Moreira, Leandro M; Belasque, José; Gourbeyre, Edith; Siguier, Patricia; Ferro, Maria Inês T; Ferro, Jesus A; Chandler, Michael; Varani, Alessandro M

    2015-02-17

    Xanthomonas. We propose that several transposition events mediated by a Tn3-like element carrying different sets of passenger genes, such as different type III secretion system effectors (including transcription activation-like effectors [TALEs]), were determinant in the evolution and emergence of Xanthomonas pathogenicity. TALE genes are DNA-binding effectors that modulate plant transcription. We also present a model for generating TALE gene diversity based on fork slippage associated with the replicative transposition mechanism of Tn3-like transposons. This may provide a mechanism for niche adaptation, specialization, host-switching, and other lifestyle changes. These results will also certainly lead to novel insights into the evolution and emergence of the various diseases caused by different Xanthomonas species and pathovars. Copyright © 2015 Marini Ferreira et al.

  19. The RNAPII-CTD Maintains Genome Integrity through Inhibition of Retrotransposon Gene Expression and Transposition.

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    Maria J Aristizabal

    2015-10-01

    Full Text Available RNA polymerase II (RNAPII contains a unique C-terminal domain that is composed of heptapeptide repeats and which plays important regulatory roles during gene expression. RNAPII is responsible for the transcription of most protein-coding genes, a subset of non-coding genes, and retrotransposons. Retrotransposon transcription is the first step in their multiplication cycle, given that the RNA intermediate is required for the synthesis of cDNA, the material that is ultimately incorporated into a new genomic location. Retrotransposition can have grave consequences to genome integrity, as integration events can change the gene expression landscape or lead to alteration or loss of genetic information. Given that RNAPII transcribes retrotransposons, we sought to investigate if the RNAPII-CTD played a role in the regulation of retrotransposon gene expression. Importantly, we found that the RNAPII-CTD functioned to maintaining genome integrity through inhibition of retrotransposon gene expression, as reducing CTD length significantly increased expression and transposition rates of Ty1 elements. Mechanistically, the increased Ty1 mRNA levels in the rpb1-CTD11 mutant were partly due to Cdk8-dependent alterations to the RNAPII-CTD phosphorylation status. In addition, Cdk8 alone contributed to Ty1 gene expression regulation by altering the occupancy of the gene-specific transcription factor Ste12. Loss of STE12 and TEC1 suppressed growth phenotypes of the RNAPII-CTD truncation mutant. Collectively, our results implicate Ste12 and Tec1 as general and important contributors to the Cdk8, RNAPII-CTD regulatory circuitry as it relates to the maintenance of genome integrity.

  20. Mandibular Symmetrical Bilateral Canine-Lateral Incisors Transposition: Its Early Diagnosis and Treatment Considerations.

    Science.gov (United States)

    Shapira, Yehoshua; Finkelstein, Tamar; Kadry, Rana; Schonberger, Shirley; Shpack, Nir

    2016-01-01

    Bilateral mandibular tooth transposition is a relatively rare dental anomaly caused by distal migration of the mandibular lateral incisors and can be detected in the early mixed dentition by radiographic examination. Early diagnosis and interceptive intervention may reduce the risk of possible transposition between the mandibular canine and lateral incisor. This report illustrates the orthodontic management of bilateral mandibular canine-lateral incisor transposition. Correct positioning of the affected teeth was achieved on the left side while teeth on the right side were aligned in their transposed position. It demonstrates the outcome of good alignment of the teeth in the dental arch.

  1. Congenitally corrected transposition of great arteries with ischemic symptoms in middle age

    International Nuclear Information System (INIS)

    Zaidi, Syed M.; Al-Sharary, Mabrooke M.; Sajid, Najeb U.; Al-Khuwaitir, Tarig S.

    2007-01-01

    Congenitally corrected transposition of great arteries (CCTGA) is a rare congenital disease first described by Von Rokitansky in 1875. Transposition of the great arteries comprises 2.6-7.8% of all cases of congenital heart disease, and if uncorrected, is commonly fatal in first year of life. Patients with corrected transposition of the great arteries without associated defects may remain undiagnosed until adult life. Symptoms occur rarely before the fourth and fifth decades, when rhythm disturbance, left atrioventricular valve regurgitation and moderately impaired systemic ventricular function cause congestive cardiac failure. We report here a case of drug overdose with ischemic symptoms and CCTGA without associated anomalies in a 40-year-old male. (author)

  2. Mandibular Symmetrical Bilateral Canine-Lateral Incisors Transposition: Its Early Diagnosis and Treatment Considerations

    Directory of Open Access Journals (Sweden)

    Yehoshua Shapira

    2016-01-01

    Full Text Available Bilateral mandibular tooth transposition is a relatively rare dental anomaly caused by distal migration of the mandibular lateral incisors and can be detected in the early mixed dentition by radiographic examination. Early diagnosis and interceptive intervention may reduce the risk of possible transposition between the mandibular canine and lateral incisor. This report illustrates the orthodontic management of bilateral mandibular canine-lateral incisor transposition. Correct positioning of the affected teeth was achieved on the left side while teeth on the right side were aligned in their transposed position. It demonstrates the outcome of good alignment of the teeth in the dental arch.

  3. Permanent magnet machine with windings having strand transposition

    Science.gov (United States)

    Qu, Ronghai; Jansen, Patrick Lee

    2009-04-21

    This document discusses, among other things, a stator with transposition between the windings or coils. The coils are free from transposition to increase the fill factor of the stator slots. The transposition at the end connections between an inner coil and an outer coil provide transposition to reduce circulating current loss. The increased fill factor reduces further current losses. Such a stator is used in a dual rotor, permanent magnet machine, for example, in a compressor pump, wind turbine gearbox, wind turbine rotor.

  4. A 1.375-approximation algorithm for sorting by transpositions.

    Science.gov (United States)

    Elias, Isaac; Hartman, Tzvika

    2006-01-01

    Sorting permutations by transpositions is an important problem in genome rearrangements. A transposition is a rearrangement operation in which a segment is cut out of the permutation and pasted in a different location. The complexity of this problem is still open and it has been a 10-year-old open problem to improve the best known 1.5-approximation algorithm. In this paper, we provide a 1.375-approximation algorithm for sorting by transpositions. The algorithm is based on a new upper bound on the diameter of 3-permutations. In addition, we present some new results regarding the transposition diameter: we improve the lower bound for the transposition diameter of the symmetric group and determine the exact transposition diameter of simple permutations.

  5. Corrected transposition of the great arteries

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Young Hi; Park, Jae Hyung; Han, Man Chung [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1981-12-15

    The corrected transposition of the great arteries is an usual congenital cardiac malformation, which consists of transposition of great arteries and ventricular inversion, and which is caused by abnormal development of conotruncus and ventricular looping. High frequency of associated cardiac malformations makes it difficult to get accurate morphologic diagnosis. A total of 18 cases of corrected transposition of the great arteries is presented, in which cardiac catheterization and angiocardiography were done at the Department of Radiology, Seoul National University Hospital between September 1976 and June 1981. The clinical, radiographic, and operative findings with the emphasis on the angiocardiographic findings were analyzed. The results are as follows: 1. Among 18 cases, 13 cases have normal cardiac position, 2 cases have dextrocardia with situs solitus, 2 cases have dextrocardia with situs inversus and 1 case has levocardia with situs inversus. 2. Segmental sets are (S, L, L) in 15 cases, and (I, D,D) in 3 cases and there is no exception to loop rule. 3. Side by side interrelationships of both ventricles and both semilunar valves are noticed in 10 and 12 cases respectively. 4. Subaortic type conus is noted in all 18 cases. 5. Associated cardic malformations are VSD in 14 cases, PS in 11, PDA in 3, PFO in 3, ASD in 2, right aortic arch in 2, tricuspid insufficiency, mitral prolapse, persistent left SVC and persistent right SVC in 1 case respectively. 6. For accurate diagnosis of corrected TGA, selective biventriculography using biplane cineradiography is an essential procedure.

  6. Corrected transposition of the great arteries

    International Nuclear Information System (INIS)

    Choi, Young Hi; Park, Jae Hyung; Han, Man Chung

    1981-01-01

    The corrected transposition of the great arteries is an usual congenital cardiac malformation, which consists of transposition of great arteries and ventricular inversion, and which is caused by abnormal development of conotruncus and ventricular looping. High frequency of associated cardiac malformations makes it difficult to get accurate morphologic diagnosis. A total of 18 cases of corrected transposition of the great arteries is presented, in which cardiac catheterization and angiocardiography were done at the Department of Radiology, Seoul National University Hospital between September 1976 and June 1981. The clinical, radiographic, and operative findings with the emphasis on the angiocardiographic findings were analyzed. The results are as follows: 1. Among 18 cases, 13 cases have normal cardiac position, 2 cases have dextrocardia with situs solitus, 2 cases have dextrocardia with situs inversus and 1 case has levocardia with situs inversus. 2. Segmental sets are (S, L, L) in 15 cases, and (I, D,D) in 3 cases and there is no exception to loop rule. 3. Side by side interrelationships of both ventricles and both semilunar valves are noticed in 10 and 12 cases respectively. 4. Subaortic type conus is noted in all 18 cases. 5. Associated cardic malformations are VSD in 14 cases, PS in 11, PDA in 3, PFO in 3, ASD in 2, right aortic arch in 2, tricuspid insufficiency, mitral prolapse, persistent left SVC and persistent right SVC in 1 case respectively. 6. For accurate diagnosis of corrected TGA, selective biventriculography using biplane cineradiography is an essential procedure

  7. Theoretical Basics of the Transpositional Grammar of Russian Language

    Directory of Open Access Journals (Sweden)

    Victor Vasilievich Shigurov

    2016-09-01

    Full Text Available The article presents the theoretical basics of the transpositional grammar of the Russian language (as the special areas of the functional grammar, which serves as a mechanism for describing the subject of the transposition of the linguistic units from one class (or interclass semantic-syntactic category to another (or others. The relation to the transposition of the grammar and vocabulary (word-formation was displayed; a typology of the transpositional processes in grammatical structure of the Russian language was submitted, and above all, in the parts of the speech and inter part-of-speech classes, grammatical categories and lexical-grammatical classes; general and specific objectives of the study types of transposition of the linguistic units were defined; the fragments of the description of the transition and syncretism of the language units were offered using the technique of opposition analysis and indexation. The results can be used in the development of the theory of the transpositional grammar of the Russian language.

  8. Ovarian transposition in young women and fertility sparing.

    Science.gov (United States)

    Mossa, B; Schimberni, M; Di Benedetto, L; Mossa, S

    2015-09-01

    Ovarian transposition is a highly effective surgical procedure used to preserve ovarian function in premenopausal patients with cancers requiring postoperative or primary pelvic radiotherapy. Pelvic irradiation determines severe damage of ovarian DNA and iatrogenic ovarian failure with premature menopause, necessity of long-term hormone replacement therapy and infertility. We conducted an extensive research of the literature in Medline between January 2000 and April 2015 using the key-words "ovarian transposition radiotherapy", "radiotherapy gonadal function", radiotherapy fertility sparing". The population included young women with normal ovarian function affected by cancers that required pelvic radiotherapy. We have examined 32 articles reporting on 1189 women undergoing ovarian transposition. Median age was 32.5 years, follow up was median 48 months. The procedure has been performed in patients less than 40 years of age. Surgery has been achieved by laparotomy or laparoscoy. We have analyzed effects of radiotherapy on ovarian function. The proportion of women treated by ovarian transposition preserved ovarian function was 70%. About 86% of patients did not develop ovarian cysts and in 98-99% of cases did not occur any metastatic disease. Ovarian transposition is associated with significant preservation of ovarian function and a low frequency of complications as cysts and metastasis. In 31% of cases the procedure can fail. Further studies are needed to evaluate the efficacy of ovarian transposition and the follow up. Ovarian transposition should be discussed at the time of cancer diagnosis in every premenopausal woman requiring pelvic radiotherapy.

  9. A 5-methylcytosine DNA glycosylase/lyase demethylates the retrotransposon Tos17 and promotes its transposition in rice

    KAUST Repository

    La, Honggui; Ding, Bo; Mishra, Gyan Prakash; Zhou, Bo; Yang, Hongmei; Bellizzi, Maria Del Rosario; Chen, Songbiao; Meyers, Blake C.; Peng, Zhaohua; Zhu, Jian-Kang; Wang, Guoliang

    2011-01-01

    DNA 5-methylcytosine (5-meC) is an important epigenetic mark for transcriptional gene silencing in many eukaryotes. In Arabidopsis, 5-meC DNA glycosylase/lyases actively remove 5-meC to counter-act transcriptional gene silencing in a locus-specific manner, and have been suggested to maintain the expression of transposons. However, it is unclear whether plant DNA demethylases can promote the transposition of transposons. Here we report the functional characterization of the DNA glycosylase/lyase DNG701 in rice. DNG701 encodes a large (1,812 amino acid residues) DNA glycosylase domain protein. Recombinant DNG701 protein showed 5-meC DNA glycosylase and lyase activities in vitro. Knockout or knockdown of DNG701 in rice plants led to DNA hypermethylation and reduced expression of the retrotransposon Tos17. Tos17 showed less transposition in calli derived from dng701 knockout mutant seeds compared with that in wild-type calli. Overexpression of DNG701 in both rice calli and transgenic plants substantially reduced DNA methylation levels of Tos17 and enhanced its expression. The overexpression also led to more frequent transposition of Tos17 in calli. Our results demonstrate that rice DNG701 is a 5-meC DNA glycosylase/lyase responsible for the demethylation of Tos17 and this DNA demethylase plays a critical role in promoting Tos17 transposition in rice calli.

  10. A 5-methylcytosine DNA glycosylase/lyase demethylates the retrotransposon Tos17 and promotes its transposition in rice

    KAUST Repository

    La, Honggui

    2011-09-06

    DNA 5-methylcytosine (5-meC) is an important epigenetic mark for transcriptional gene silencing in many eukaryotes. In Arabidopsis, 5-meC DNA glycosylase/lyases actively remove 5-meC to counter-act transcriptional gene silencing in a locus-specific manner, and have been suggested to maintain the expression of transposons. However, it is unclear whether plant DNA demethylases can promote the transposition of transposons. Here we report the functional characterization of the DNA glycosylase/lyase DNG701 in rice. DNG701 encodes a large (1,812 amino acid residues) DNA glycosylase domain protein. Recombinant DNG701 protein showed 5-meC DNA glycosylase and lyase activities in vitro. Knockout or knockdown of DNG701 in rice plants led to DNA hypermethylation and reduced expression of the retrotransposon Tos17. Tos17 showed less transposition in calli derived from dng701 knockout mutant seeds compared with that in wild-type calli. Overexpression of DNG701 in both rice calli and transgenic plants substantially reduced DNA methylation levels of Tos17 and enhanced its expression. The overexpression also led to more frequent transposition of Tos17 in calli. Our results demonstrate that rice DNG701 is a 5-meC DNA glycosylase/lyase responsible for the demethylation of Tos17 and this DNA demethylase plays a critical role in promoting Tos17 transposition in rice calli.

  11. Transposition of Domain Knowledge into Educational Games

    DEFF Research Database (Denmark)

    Marchetti, Emanuela; Jensen, Kristoffer; Valente, Andrea

    2014-01-01

    Starting from Rogoff’s (1990) theory of apprenticeship in thinking and Apter’s (1987) reversal theory, this paper discusses the formulation of PlayDT (Playful Domain Transposition), a new approach to support the transposition of complex concepts, from different knowledge domains, into playful int...

  12. Syllable Transposition Effects in Korean Word Recognition

    Science.gov (United States)

    Lee, Chang H.; Kwon, Youan; Kim, Kyungil; Rastle, Kathleen

    2015-01-01

    Research on the impact of letter transpositions in visual word recognition has yielded important clues about the nature of orthographic representations. This study investigated the impact of syllable transpositions on the recognition of Korean multisyllabic words. Results showed that rejection latencies in visual lexical decision for…

  13. Allopatric integrations selectively change host transcriptomes, leading to varied expression efficiencies of exotic genes in Myxococcus xanthus.

    Science.gov (United States)

    Zhu, Li-Ping; Yue, Xin-Jing; Han, Kui; Li, Zhi-Feng; Zheng, Lian-Shuai; Yi, Xiu-Nan; Wang, Hai-Long; Zhang, You-Ming; Li, Yue-Zhong

    2015-07-22

    Exotic genes, especially clustered multiple-genes for a complex pathway, are normally integrated into chromosome for heterologous expression. The influences of insertion sites on heterologous expression and allotropic expressions of exotic genes on host remain mostly unclear. We compared the integration and expression efficiencies of single and multiple exotic genes that were inserted into Myxococcus xanthus genome by transposition and attB-site-directed recombination. While the site-directed integration had a rather stable chloramphenicol acetyl transferase (CAT) activity, the transposition produced varied CAT enzyme activities. We attempted to integrate the 56-kb gene cluster for the biosynthesis of antitumor polyketides epothilones into M. xanthus genome by site-direction but failed, which was determined to be due to the insertion size limitation at the attB site. The transposition technique produced many recombinants with varied production capabilities of epothilones, which, however, were not paralleled to the transcriptional characteristics of the local sites where the genes were integrated. Comparative transcriptomics analysis demonstrated that the allopatric integrations caused selective changes of host transcriptomes, leading to varied expressions of epothilone genes in different mutants. With the increase of insertion fragment size, transposition is a more practicable integration method for the expression of exotic genes. Allopatric integrations selectively change host transcriptomes, which lead to varied expression efficiencies of exotic genes.

  14. Inferior Oblique Overaction: Anterior Transposition Versus Myectomy.

    Science.gov (United States)

    Rajavi, Zhale; Feizi, Mohadeseh; Behradfar, Narges; Yaseri, Mehdi; Sayanjali, Shima; Motevaseli, Tahmine; Sabbaghi, Hamideh; Faghihi, Mohammad

    2017-07-01

    To compare the efficacy of inferior oblique myectomy and anterior transposition for correcting inferior oblique overaction (IOOA). This retrospective study was conducted on 56 patients with IOOA who had either myectomy or anterior transposition of the inferior oblique muscle from 2010 to 2015. The authors compared preoperative and postoperative inferior oblique muscle function grading (-4 to +4) as the main outcome measure and vertical and horizontal deviation, dissociated vertical deviation (DVD), and A- and V-pattern between the two surgical groups as secondary outcomes. A total of 99 eyes of 56 patients with a mean age of 5.9 ± 6.5 years were included (47 eyes in the myectomy group and 52 eyes in the anterior transposition group). There were no differences in preoperative best corrected visual acuity, amblyopia, spherical equivalent, and primary versus secondary IOOA between the two groups. Both surgical procedures were effective in reducing IOOA and satisfactory results were similar between the two groups: 61.7% and 67.3% in the myectomy and anterior transposition groups, respectively (P = .56). After adjustment for the preoperative DVD, there was no statistically significant difference between the two groups postoperatively. The preoperative hypertropia was 6 to 14 and 6 to 18 prism diopters (PD) in the myectomy and anterior transposition groups, respectively. After surgery, no patient had a vertical deviation greater than 5 PD. Both the inferior oblique myectomy and anterior transposition procedures are effective in reducing IOOA with similar satisfactory results. DVD and hypertropia were also corrected similarly by these two surgical procedures. [J Pediatr Ophthalmol Strabismus. 2017;54(4):232-237.]. Copyright 2017, SLACK Incorporated.

  15. The transposition distance for phylogenetic trees

    OpenAIRE

    Rossello, Francesc; Valiente, Gabriel

    2006-01-01

    The search for similarity and dissimilarity measures on phylogenetic trees has been motivated by the computation of consensus trees, the search by similarity in phylogenetic databases, and the assessment of clustering results in bioinformatics. The transposition distance for fully resolved phylogenetic trees is a recent addition to the extensive collection of available metrics for comparing phylogenetic trees. In this paper, we generalize the transposition distance from fully resolved to arbi...

  16. Macrovascular Decompression of the Brainstem and Cranial Nerves: Evolution of an Anteromedial Vertebrobasilar Artery Transposition Technique.

    Science.gov (United States)

    Choudhri, Omar; Connolly, Ian D; Lawton, Michael T

    2017-08-01

    Tortuous and dolichoectatic vertebrobasilar arteries can impinge on the brainstem and cranial nerves to cause compression syndromes. Transposition techniques are often required to decompress the brainstem with dolichoectatic pathology. We describe our evolution of an anteromedial transposition technique and its efficacy in decompressing the brainstem and relieving symptoms. To present the anteromedial vertebrobasilar artery transposition technique for macrovascular decompression of the brainstem and cranial nerves. All patients who underwent vertebrobasilar artery transposition were identified from the prospectively maintained database of the Vascular Neurosurgery service, and their medical records were reviewed retrospectively. The extent of arterial displacement was measured pre- and postoperatively on imaging. Vertebrobasilar arterial transposition and macrovascular decompression was performed in 12 patients. Evolution in technique was characterized by gradual preference for the far-lateral approach, use of a sling technique with muslin wrap, and an anteromedial direction of pull on the vertebrobasilar artery with clip-assisted tethering to the clival dura. With this technique, mean lateral displacement decreased from 6.6 mm in the first half of the series to 3.8 mm in the last half of the series, and mean anterior displacement increased from 0.8 to 2.5 mm, with corresponding increases in satisfaction and relief of symptoms. Compressive dolichoectatic pathology directed laterally into cranial nerves and posteriorly into the brainstem can be corrected with anteromedial transposition towards the clivus. Our technique accomplishes this anteromedial transposition from an inferolateral surgical approach through the vagoaccessory triangle, with sling fixation to clival dura using aneurysm clips. Copyright © 2017 by the Congress of Neurological Surgeons

  17. Involvement of a bifunctional, paired-like DNA-binding domain and a transpositional enhancer in Sleeping Beauty transposition.

    Science.gov (United States)

    Izsvák, Zsuzsanna; Khare, Dheeraj; Behlke, Joachim; Heinemann, Udo; Plasterk, Ronald H; Ivics, Zoltán

    2002-09-13

    Sleeping Beauty (SB) is the most active Tc1/mariner-like transposon in vertebrate species. Each of the terminal inverted repeats (IRs) of SB contains two transposase-binding sites (DRs). This feature, termed the IR/DR structure, is conserved in a group of Tc1-like transposons. The DNA-binding region of SB transposase, similar to the paired domain of Pax proteins, consists of two helix-turn-helix subdomains (PAI + RED = PAIRED). The N-terminal PAI subdomain was found to play a dominant role in contacting the DRs. Transposase was able to bind to mutant sites retaining the 3' part of the DRs; thus, primary DNA binding is not sufficient to determine the specificity of the transposition reaction. The PAI subdomain was also found to bind to a transpositional enhancer-like sequence within the left IR of SB, and to mediate protein-protein interactions between transposase subunits. A tetrameric form of the transposase was detected in solution, consistent with an interaction between the IR/DR structure and a transposase tetramer. We propose a model in which the transpositional enhancer and the PAI subdomain stabilize complexes formed by a transposase tetramer bound at the IR/DR. These interactions may result in enhanced stability of synaptic complexes, which might explain the efficient transposition of Sleeping Beauty in vertebrate cells.

  18. No-Go Zones for Mariner Transposition

    Directory of Open Access Journals (Sweden)

    Brian J. Akerley

    2016-10-01

    Full Text Available The property of transposons to randomly insert into target DNA has long been exploited for generalized mutagenesis and forward genetic screens. Newer applications that monitor the relative abundance of each transposon insertion in large libraries of mutants can be used to evaluate the roles in cellular fitness of all genes of an organism, provided that transposition is in fact random across all genes. In a recent article, Kimura and colleagues identified an important exception to the latter assumption [S. Kimura, T. P. Hubbard, B. M. Davis, M. K. Waldor, mBio 7(4:e01351-16, 2016, doi:10.1128/mBio.01351-16]. They provide evidence that the Mariner transposon exhibits locus-specific site preferences in the presence of the histone-like nucleoid structuring protein H-NS. This effect was shown to bias results for important virulence loci in Vibrio cholerae and to result in misidentification of genes involved in growth in vitro. Fortunately, the bulk of this bacterium’s genome was unaffected by this bias, and recognizing the H-NS effect allows filtering to improve the accuracy of the results.

  19. Regulation of mariner transposition: the peculiar case of Mos1.

    Directory of Open Access Journals (Sweden)

    Jérôme Jaillet

    Full Text Available BACKGROUND: Mariner elements represent the most successful family of autonomous DNA transposons, being present in various plant and animal genomes, including humans. The introduction and co-evolution of mariners within host genomes imply a strict regulation of the transposon activity. Biochemical data accumulated during the past decade have led to a convergent picture of the transposition cycle of mariner elements, suggesting that mariner transposition does not rely on host-specific factors. This model does not account for differences of transposition efficiency in human cells between mariners. We thus wondered whether apparent similarities in transposition cycle could hide differences in the intrinsic parameters that control mariner transposition. PRINCIPAL FINDINGS: We find that Mos1 transposase concentrations in excess to the Mos1 ends prevent the paired-end complex assembly. However, we observe that Mos1 transposition is not impaired by transposase high concentration, dismissing the idea that transposase over production plays an obligatory role in the down-regulation of mariner transposition. Our main finding is that the paired-end complex is formed in a cooperative way, regardless of the transposase concentration. We also show that an element framed by two identical ITRs (Inverted Terminal Repeats is more efficient in driving transposition than an element framed by two different ITRs (i.e. the natural Mos1 copy, the latter being more sensitive to transposase concentration variations. Finally, we show that the current Mos1 ITRs correspond to the ancestral ones. CONCLUSIONS: We provide new insights on intrinsic properties supporting the self-regulation of the Mos1 element. These properties (transposase specific activity, aggregation, ITR sequences, transposase concentration/transposon copy number ratio... could have played a role in the dynamics of host-genomes invasion by Mos1, accounting (at least in part for the current low copy number of

  20. FB elements can promote exon shuffling: a promoter-less white allele can be reactivated by FB mediated transposition in Drosophila melanogaster.

    Science.gov (United States)

    Moschetti, R; Marsano, R M; Barsanti, P; Caggese, C; Caizzi, R

    2004-05-01

    Foldback ( FB) elements are transposable elements found in many eukaryotic genomes; they are thought to contribute significantly to genome plasticity. In Drosophila melanogaster, FBs have been shown to be involved in the transposition of large chromosomal regions and in the genetic instability of some alleles of the white gene. In this report we show that FB mediated transposition of w(67C23), a mutation that deletes the promoter of the white gene and its first exon, containing the start codon, can restore expression of the white gene. We have characterized three independent events in which a 14-kb fragment from the w(67C23) locus was transposed into an intron region in three different genes. In each case a local promoter drives the expression of white, producing a chimeric mRNA. These findings suggest that, on an evolutionary timescale, FB elements may contribute to the creation of new genes via exon shuffling.

  1. Unilateral and bilateral dental transpositions in the maxilla

    DEFF Research Database (Denmark)

    Danielsen, Jakob Christian; Karimian, K; Ciarlantini, R

    2015-01-01

    and lateral incisor (Type 2). The dentitions were analysed regarding agenesis and dental morphological anomalies on panoramic radiographs, and craniofacial aspects were cephalometrically analysed on profile images The results were statistically evaluated. RESULTS: All groups demonstrated increased occurrences......AIM: This was to elucidate dental and skeletal findings in individuals with unilateral and bilateral maxillary dental transpositions. MATERIAL AND METHODS: The sample comprised of radiographic materials from 63 individuals with maxillary dental transpositions from the Departments of Odontology...... retrognathia (more pronounced in Type 1B). Type 2 showed a significant posterior inclination of the maxilla. CONCLUSION: Transpositions of maxillary canines involve dental and skeletal deviations. Dental deviations were predominantly taurodontic root morphology and agenesis. Regarding skeletal deviations...

  2. Target Capture during Mos1 Transposition*

    Science.gov (United States)

    Pflieger, Aude; Jaillet, Jerôme; Petit, Agnès; Augé-Gouillou, Corinne; Renault, Sylvaine

    2014-01-01

    DNA transposition contributes to genomic plasticity. Target capture is a key step in the transposition process, because it contributes to the selection of new insertion sites. Nothing or little is known about how eukaryotic mariner DNA transposons trigger this step. In the case of Mos1, biochemistry and crystallography have deciphered several inverted terminal repeat-transposase complexes that are intermediates during transposition. However, the target capture complex is still unknown. Here, we show that the preintegration complex (i.e., the excised transposon) is the only complex able to capture a target DNA. Mos1 transposase does not support target commitment, which has been proposed to explain Mos1 random genomic integrations within host genomes. We demonstrate that the TA dinucleotide used as the target is crucial both to target recognition and in the chemistry of the strand transfer reaction. Bent DNA molecules are better targets for the capture when the target DNA is nicked two nucleotides apart from the TA. They improve strand transfer when the target DNA contains a mismatch near the TA dinucleotide. PMID:24269942

  3. Nydiagnosticeret kongenit transposition hos en 76-årig kvinde

    DEFF Research Database (Denmark)

    Sloth, Astrid Drivsholm; Jensen, Jesper Khedri; Hald Steffensen, Flemming

    2009-01-01

    A case of congenitally corrected transposition presenting for the first time with second-degree AV block in a 76-year-old woman is presented. This case demonstrates that congenitally corrected transposition can remain asymptomatic and undiagnosed, especially when no other cardiac defects are pres...

  4. Airway ciliary dysfunction and respiratory symptoms in patients with transposition of the great arteries.

    Science.gov (United States)

    Zahid, Maliha; Bais, Abha; Tian, Xin; Devine, William; Lee, Dong Ming; Yau, Cyrus; Sonnenberg, Daniel; Beerman, Lee; Khalifa, Omar; Lo, Cecilia W

    2018-01-01

    Our prior work on congenital heart disease (CHD) with heterotaxy, a birth defect involving randomized left-right patterning, has shown an association of a high prevalence of airway ciliary dysfunction (CD; 18/43 or 42%) with increased respiratory symptoms. Furthermore, heterotaxy patients with ciliary dysfunction were shown to have more postsurgical pulmonary morbidities. These findings are likely a reflection of the common role of motile cilia in both airway clearance and left-right patterning. As CHD comprising transposition of the great arteries (TGA) is commonly thought to involve disturbance of left-right patterning, especially L-TGA with left-right ventricular inversion, we hypothesize CHD patients with transposition of great arteries (TGA) may have high prevalence of airway CD with increased respiratory symptoms. We recruited 75 CHD patients with isolated TGA, 28% L and 72% D-TGA. Patients were assessed using two tests typically used for evaluating airway ciliary dysfunction in patients with primary ciliary dyskinesia (PCD), a recessive sinopulmonary disease caused by respiratory ciliary dysfunction. This entailed the measurement of nasal nitric oxide (nNO), which is typically low with PCD. We also obtained nasal scrapes and conducted videomicroscopy to assess respiratory ciliary motion (CM). We observed low nNO in 29% of the patients, and abnormal CM in 57%, with 22% showing both low nNO and abnormal CM. No difference was observed for the prevalence of either low nNO or abnormal ciliary motion between patients with D vs. L-TGA. Respiratory symptoms were increased with abnormal CM, but not low nNO. Sequencing analysis showed no compound heterozygous or homozygous mutations in 39 genes known to cause PCD, nor in CFTR, gene causing cystic fibrosis. As both are recessive disorders, these results indicate TGA patients with ciliary dysfunction do not have PCD or cystic fibrosis (which can cause low nNO or abnormal ciliary motion). TGA patients have high

  5. Partial transposition on bi-partite system

    OpenAIRE

    Han, Y. -J.; Ren, X. J.; Wu, Y. C.; Guo, G. -C.

    2006-01-01

    Many of the properties of the partial transposition are not clear so far. Here the number of the negative eigenvalues of K(T)(the partial transposition of K) is considered carefully when K is a two-partite state. There are strong evidences to show that the number of negative eigenvalues of K(T) is N(N-1)/2 at most when K is a state in Hilbert space N*N. For the special case, 2*2 system(two qubits), we use this result to give a partial proof of the conjecture sqrt(K(T))(T)>=0. We find that thi...

  6. Partial Transposition on Bipartite System

    International Nuclear Information System (INIS)

    Xi-Jun, Ren; Yong-Jian, Han; Yu-Chun, Wu; Guang-Can, Guo

    2008-01-01

    Many properties of partial transposition are unclear as yet. Here we carefully consider the number of the negative eigenvalues of ρ T (ρ's partial transposition) when ρ is a two-partite state. There is strong evidence to show that the number of negative eigenvalues of ρ T is N(N − 1)/2 at most when ρ is a state in Hilbert space C N C N . For the special case, the 2 × 2 system, we use this result to give a partial proof of the conjecture |ρ T | T ≥ 0. We find that this conjecture is strongly connected with the entanglement of the state corresponding to the negative eigenvalue of ρ T or the negative entropy of ρ

  7. ALGORITMA PARALEL ODD EVEN TRANSPOSITION PADA MODEL JARINGAN NON-LINIER

    Directory of Open Access Journals (Sweden)

    Ernastuti .

    2012-05-01

    Full Text Available Odd-even-transposition adalah suatu algoritma paralel yang merupakan pengembangan dari algoritma sekuensial “bubble sort”. Algoritma odd-even-transposition ini didesain khusus untuk model jaringan array linier (homogen. Untuk n elemen data, kompleksitas waktu dari algoritma bubble sort adalah O(n2, sedangkan pada odd-even-transposition yang bekerja di atas n prosesor adalah (n. Ada peningkatan kecepatan waktu pada kinerja algoritma paralel ini sebesar n kali dibanding algoritma sekuensialnya. Hypercube dimensi k adalah model jaringan non-linier (non-homogen terdiri dari n = 2k prosesor, di mana setiap prosesor berderajat k. Model jaringan Fibonacci cube dan extended Lucas cube masing-masing merupakan model subjaringan hypercube dengan jumlah prosesor < 2k prosesor dan maksimum derajat prosesornya adalah k. Pada paper ini, diperlihatkan bagaimana algoritma odd-even-transposition dapat dijalankan juga pada model jaringan komputer cluster non-linier hypercube, Fibonacci cube, dan extended Lucas cube dengan kompleksitas waktu O(n. Odd-even-transposition is a parallel algorithm which is the development of sequential algorithm “bubble sort”. Odd-even transposition algorithm is specially designed for linear array network model (homogeneous. For n data elements, the time complexity of bubble sort algorithm is O(n2, while the odd-even-transposition that works with n processor is (n. There in an increase in the speed of time on the performance of this parallel algorithms for n times than its sequential algorithm. K-dimensional hypercube is a non-linear network model (non-homogeneous consists of n = 2k processors, where each processor has k degree . Network model of Fibonacci cube and extended Lucas cube are the hypercube sub-network model with the number of processors

  8. Anterior transposition of the radial nerve--a cadaveric study.

    Science.gov (United States)

    Yakkanti, Madhusudhan R; Roberts, Craig S; Murphy, Joshua; Acland, Robert D

    2008-01-01

    The radial nerve is at risk during the posterior plating of the humerus. The purpose of this anatomic study was to assess the extent of radial nerve dissection required for anterior transposition through the fracture site (transfracture anterior transposition). A cadaver study was conducted approaching the humerus by a posterior midline incision. The extent of dissection of the nerve necessary for plate fixation of the humerus fracture was measured. An osteotomy was created to model a humeral shaft fracture at the spiral groove (OTA classification 12-A2, 12-A3). The radial nerve was then transposed anterior to the humeral shaft through the fracture site. The additional dissection of the radial nerve and the extent of release of soft tissue from the humerus shaft to achieve the transposition were measured. Plating required a dissection of the radial nerve 1.78 cm proximal and 2.13 cm distal to the spiral groove. Transfracture anterior transposition of the radial nerve required an average dissection of 2.24 cm proximal and 2.68 cm distal to the spiral groove. The lateral intermuscular septum had to be released for 2.21 cm on the distal fragment to maintain laxity of the transposed nerve. Transfracture anterior transposition of the radial nerve before plating is feasible with dissection proximal and distal to the spiral groove and elevation of the lateral intermuscular septum. Potential clinical advantages of this technique include enhanced fracture site visualization, application of broader plates, and protection of the radial nerve during the internal fixation.

  9. Transposition of the great arteries in MRI; Transposition der grossen Arterien im MRT des Herzens

    Energy Technology Data Exchange (ETDEWEB)

    Zaehringer, C.; Leiner, T.; Maki, J.H.; Potthast, S.

    2014-02-15

    The contribution on transposition of the great arteries (TGA) in the heart NMR images covers the following issues: different forms of TGA (dextro-TGA and levo-TGA), therapeutic options, long-term complication of TGA and the importance of heart NMR imaging in case of TGA.

  10. Considerations and concerting on the european directive transposition to the internal gas market

    International Nuclear Information System (INIS)

    Bricq, N.

    1999-10-01

    In the framework of the directive 98/30/CE transposition on the the gas internal market, a report has been asked by the First Ministry to define the new form of the gas utilities. The directive deals with the competition opening. The first part presents the gas market organization in France, today and after the transposition. The second part analyses the big stakes of this transposition. (A.L.B)

  11. Inferior Alveolar Nerve Lateralization and Transposition for Dental Implant Placement. Part II: a Systematic Review of Neurosensory Complications

    Directory of Open Access Journals (Sweden)

    Boris Abayev

    2015-03-01

    Full Text Available Objectives: This article, the second in a two-part series, continues the discussion of inferior alveolar nerve lateralization/transposition for dental implant placement. The aim of this article is to review the scientific literature and clinical reports in order to analyse the neurosensory complications, risks and disadvantages of lateralization/transposition of the inferior alveolar nerve followed by implant placement in an edentulous atrophic posterior mandible. Material and Methods: A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed and PMC databases, as well as academic sites and books. The articles were searched from January 1997 to July 2014. Articles in English language, which included adult patients between 18 - 80 years of age who had minimal residual bone above the mandibular canal and had undergone inferior alveolar nerve (IAN repositioning, with minimum 6 months of follow-up, were included. Results: A total of 21 studies were included in this review. Ten were related to IAN transposition, 7 to IAN lateralization and 4 to both transposition and lateralization. The IAN neurosensory disturbance function was present in most patients (99.47% [376/378] for 1 to 6 months. In total, 0.53% (2/378 of procedures the disturbances were permanent. Conclusions: Inferior alveolar nerve repositioning is related to initial transient change in sensation in the majority of cases. The most popular causes of nerve damage are spatula-caused traction in the mucoperiosteal flap, pressure due to severe inflammation or retention of fluid around the nerve and subsequent development of transient ischemia, and mandibular body fracture.

  12. Considerations and concerting on the european directive transposition to the internal gas market; Mission de reflexion et de concertation sur la transposition de la directive europeenne sur ''le marche interieur du gaz''

    Energy Technology Data Exchange (ETDEWEB)

    Bricq, N

    1999-10-01

    In the framework of the directive 98/30/CE transposition on the the gas internal market, a report has been asked by the First Ministry to define the new form of the gas utilities. The directive deals with the competition opening. The first part presents the gas market organization in France, today and after the transposition. The second part analyses the big stakes of this transposition. (A.L.B)

  13. Desacralising Shakespeare’s “word” by means of cultural translation/transposition

    Directory of Open Access Journals (Sweden)

    José Roberto O’Shea

    2016-12-01

    Full Text Available This essay addresses ways in which cultural translation/transposition can ultimately bring about a positive “desacralisation” of Shakespeare’s Word. The discussion starts from the notion of Shakespeare’s Word as “sacred” and of sacred writings as highly sensitive language, and proceeds to overview the importance of the notions of denotation, connotation, and context in translation. Then, the essay offers working definitions of cultural translation or cultural transposition, and of non-literal translation. Finally, the essay highlights the author’s main aims in translating Shakespeare’s theatre and offers a few examples of cultural translation/transposition in his own rendering of Shakespeare’s drama into Brazilian Portuguese.

  14. Maxillary canine-first premolar bilateral transposition in a Class III patient: A case report.

    Science.gov (United States)

    Potrubacz, Maciej Iancu; Tepedino, Michele; Chimenti, Claudio

    2016-05-01

    Tooth transposition is a rare dental anomaly that often represents a challenge for the clinician. The case of a girl with skeletal Class III malocclusion and concomitant maxillary canine-first premolar bilateral transposition, followed from 7 to 17 years of age, is presented. After a first phase of treatment aimed at resolving the Class III malocclusion, the transposition was maintained and the case finalized with a multibracket appliance.

  15. Different Points of View Concerning the Didactic Transposition

    Directory of Open Access Journals (Sweden)

    Késia Caroline Ramires Neves

    2011-10-01

    Full Text Available The present article treats the concept of Didactic Transposition, taking as reference the work of Yves Chevallard, La transposición didáctica: del saber sabio al saber enseñado (2005. We compared the adduction of the concept in several works, such as thesis, dissertations and articles, and discussed the multiple impressions concerning the process of didactic transposition. These papers show that the conceptualizations are not well defined, entailing dubiousness and discussions. Some differences accrue from different areas of science, distinct of mathematics, others are inherent on the original ideas in Chevallard (2005, paper that served as bibliographical reference for the majority of the studied works.

  16. Desacralising Shakespeare’s “word” by means of cultural translation/transposition

    Directory of Open Access Journals (Sweden)

    José Roberto O’Shea

    2016-09-01

    Full Text Available http://dx.doi.org/10.5007/2175-7968.2016v36n3p124 This essay addresses ways in which cultural translation/transposition can ultimately bring about a positive “desacralisation” of Shakespeare’s Word. The discussion starts from the notion of Shakespeare’s Word as “sacred” and of sacred writings as highly sensitive language, and proceeds to overview the importance of the notions of denotation, connotation, and context in translation. Then, the essay offers working definitions of cultural translation or cultural transposition, and of non-literal translation. Finally, the essay highlights the author’s main aims in translating Shakespeare’s theatre and offers a few examples of cultural translation/transposition in his own rendering of Shakespeare’s drama into Brazilian Portuguese.

  17. Modified semitendinosus muscle transposition to repair ventral perineal hernia in 14 dogs.

    Science.gov (United States)

    Morello, E; Martano, M; Zabarino, S; Piras, L A; Nicoli, S; Bussadori, R; Buracco, P

    2015-06-01

    To describe a modified technique of semitendinosus muscle transposition for the repair of ventral perineal hernia. Retrospective review of case records of dogs with ventral perineal hernia that were treated by transposing the medial half of the longitudinally split semitendinosus muscle of one limb. The transposition of the internal obturator muscle was used when uni- or bilateral rectal sacculation was also present in addition to ventral perineal hernia; colopexy and vas deferens pexy were also performed. Fourteen dogs were included. In addition to ventral perineal hernia, unilateral and bilateral perineal hernia was also present in five and six of the dogs, respectively. The mean follow-up time was 890 days. Ventral perineal hernia was successfully managed by the modified semitendinosus muscle transposition with minor complications in all the dogs included in the study. Despite the small number of dogs included, the unilateral transposition of the medial half of the longitudinally split semitendinosus muscle consistently supported the ventral rectal enlargement in perineal hernia without obvious adverse effects. © 2015 British Small Animal Veterinary Association.

  18. Known knowns, known unknowns and unknown unknowns in prokaryotic transposition.

    Science.gov (United States)

    Siguier, Patricia; Gourbeyre, Edith; Chandler, Michael

    2017-08-01

    Although the phenomenon of transposition has been known for over 60 years, its overarching importance in modifying and streamlining genomes took some time to recognize. In spite of a robust understanding of transposition of some TE, there remain a number of important TE groups with potential high genome impact and unknown transposition mechanisms and yet others, only recently identified by bioinformatics, yet to be formally confirmed as mobile. Here, we point to some areas of limited understanding concerning well established important TE groups with DDE Tpases, to address central gaps in our knowledge of characterised Tn with other types of Tpases and finally, to highlight new potentially mobile DNA species. It is not exhaustive. Examples have been chosen to provide encouragement in the continued exploration of the considerable prokaryotic mobilome especially in light of the current threat to public health posed by the spread of multiple Ab R . Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Straight configuration saphenous vein transposition to popliteal artery for vascular access.

    Science.gov (United States)

    Caco, Gentian; Golemi, Dhurata; Likaj, Eriola

    2017-03-21

    The saphenous vein is commonly used as a vascular graft in peripheral artery surgery but rarely used for vascular access. The literature on straight configuration saphenous vein transposition to the popliteal artery is scarce. Here we present two cases of straight configuration saphenous vein transposition to the popliteal artery for vascular access, the surgical technique and respective follow-up. Two young men, aged 29 and 36 years, were chosen for lower-limb vascular access for hemodialysis. The first patient was paraplegic since birth. He used his arms to move so upper extremity vascular access was avoided. The second patient presented with an infected upper extremity arteriovenous graft (AVG) and after multiple closed AVFs he had no more available arm veins. Both patients received autologous lower extremity straight configuration saphenous vein transpositions to the popliteal artery under spinal anesthesia in May and October 2012, respectively. Cannulation of the fistula was allowed after one month. There were no early complications. Slight swelling on the leg appeared in one of the patients. Both fistulas were still functional after 36 and 32 months, respectively. The straight configuration saphenous vein transposition to popliteal artery is simple to perform, offers a long and straight segment for cannulation and may be a suitable autologous vascular access in selected patients.

  20. Internal limiting membrane flap transposition for surgical repair of macular holes in primary surgery and in persistent macular holes.

    Science.gov (United States)

    Leisser, Christoph; Hirnschall, Nino; Döller, Birgit; Varsits, Ralph; Ullrich, Marlies; Kefer, Katharina; Findl, Oliver

    2018-03-01

    Classical or temporal internal limiting membrane (ILM) flap transposition with air or gas tamponade are current trends with the potential to improve surgical results, especially in cases with large macular holes. A prospective case series included patients with idiopathic macular holes or persistent macular holes after 23-G pars plana vitrectomy (PPV) and ILM peeling with gas tamponade. In all patients, 23-G PPV and ILM peeling with ILM flap transposition with gas tamponade and postoperative face-down position was performed. In 7 of 9 eyes, temporal ILM flap transposition combined with pedicle ILM flap could be successfully performed and macular holes were closed in all eyes after surgery. The remaining 2 eyes were converted to pedicle ILM flap transposition with macular hole closure after surgery. Three eyes were scheduled as pedicle ILM flap transposition due to previous ILM peeling. In 2 of these eyes, the macular hole could be closed with pedicle ILM flap transposition. In 3 eyes, free ILM flap transposition was performed and in 2 of these eyes macular hole could be closed after surgery, whereas in 1 eye a second surgery, performed as pedicle ILM flap transposition, was performed and led to successful macular hole closure. Use of ILM flaps in surgical repair of macular hole surgery is a new option of treatment with excellent results independent of the diameter of macular holes. For patients with persistent macular holes, pedicle ILM flap transposition or free ILM flap transposition are surgical options.

  1. Orthodontic treatment of the transposition of a maxillary canine and a first premolar: a case report.

    Science.gov (United States)

    Teresa, Dinoi Maria; Stefano, Mummolo; Annalisa, Monaco; Enrico, Marchetti; Vincenzo, Campanella; Giuseppe, Marzo

    2015-03-01

    Transposition is an anomaly of tooth position, the most frequent of which involves the canine and the first maxillary premolar. We describe the orthodontic treatment of a unilateral transposition of an upper canine and an upper right first premolar in the permanent dentition. A 12-year-old Caucasian boy presented with transposition of his upper right canine and upper right first premolar. He had combined surgical-orthodontic treatment to correct the transposition and to obtain a Class I relationship between the molar and canine. This treatment resolved the dental crowding and achieved good functional and aesthetic results. In transposition, the choice of the most suitable treatment depends on the occlusion, level of dental crowding, aesthetics, position of the radicular apices, and the specific needs of the patient. In this case, orthodontic alignment of the transposed teeth into their physiological position achieved all of our objectives and our patient was satisfied with the aesthetic results obtained.

  2. Maxillary canine-first premolar transposition in the permanent dentition: treatment considerations and a case report.

    LENUS (Irish Health Repository)

    Synodinos, Philippos N

    2010-12-01

    Transposition is defined as the interchange of position between two adjacent teeth within the same quadrant of the dental arch. Permanent maxillary canine-premolar transposition is the most commonly observed transposition in the human dentition. Its prevalence is relatively low and its aetiology remains unclear, although it has been associated with genetic factors. It may also be related to a combination of localised factors such as malformation of adjacent teeth, tooth agenesis, retention of the deciduous canine and a history of local trauma. Treatment is selected on an individual case basis after thoroughly considering the overall facial and dental characteristics, duration of treatment, cost, patient preference and the orthodontist\\'s experience. This article provides a case report of maxillary canine transposition in the permanent dentition, successfully managed with orthodontic treatment.

  3. Early treatment of an ectopic premolar to prevent molar-premolar transposition.

    Science.gov (United States)

    Cannavale, Rosangela; Matarese, Giovanni; Isola, Gaetano; Grassia, Vincenzo; Perillo, Letizia

    2013-04-01

    Orthodontic treatment is planned on an individual, case-by-case basis after thoroughly considering the patient's overall facial and dental characteristics, the expected duration of treatment, costs, patient preferences, and the orthodontist's experience. This article reports the treatment of a patient with a maxillary premolar-molar transposition in the permanent dentition that was successfully managed with orthodontic treatment. A girl, aged 10 years 2 months, came for treatment with an ectopic maxillary left premolar. Radiographic analysis indicated a developing complete transposition of the maxillary left premolar. The patient was treated with extraction of the deciduous molar and surgical exposure and ligation of the premolar. Eruption was properly guided, and the correct order of the 2 teeth was restored in the arch. This challenging treatment approach is described in detail, including the mechanics used to align the ectopic premolar. Early treatment can, in many cases, prevent a molar-premolar transposition. Copyright © 2013 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

  4. A Modified Technique of Basilic Vein Transposition for Haemodialysis

    International Nuclear Information System (INIS)

    Chaudhary, F. A.; Parvez, Z.

    2014-01-01

    Objective: To modify the technique of basilic vein transposition for vascular accesss for haemodialysis aiming at better maturation rate, longer survival of fistula and lesser complications. Study Design: Case series. Place and Duration of Study: Shaikh Zayed Hospital and Omer Hospital, Lahore, from February 2008 to July 2011. Methodology: Patients referred for basilic vein transposition for haemodialysis vascular access were prospectively enrolled. The surgical technique included small tracking incisions, an extra 3 - 4 cm of vein length harvesting to avoid tension in the vein in its new course, an oval arteriotomy and a smooth curved pathway, away from vein harvesting incision to avoid entrapment of vein in the scar. Maturation rate, fistula survival and other complications were noted. Results: There was no immediate failure in 51 patients. The complications during follow-up period were infection and thrombosis, bleeding and non-development of basilic vein in 2 patients each; and false aneurysm formation in one. Four patients died during follow-up period. The maturation time was 4.9 A +- 1.1 weeks. The early patency rate was 92.2%, same at 6 months and 90.7% at 12 months. Conclusion: Arteriovenous fistula constructed with modified technique of basilic vein transposition is an acceptable and valid option of vascular access for haemodialysis. (author)

  5. [Foster Modification of Full Tendon Transposition of Vertical Rectus Muscles for Sixth Nerve Palsy].

    Science.gov (United States)

    Heede, Santa

    2018-04-11

    Since 1907 a variety of muscle transposition procedures for the treatment of abducens nerve palsy has been established internationally. Full tendon transposition of the vertical rectus muscle was initially described by O'Connor 1935 and then augmented by Foster 1997 with addition of posterior fixation sutures on the vertical rectus muscle. Full tendon transposition augmented by Foster belongs to the group of the most powerful surgical techniques to improve the abduction. Purpose of this study was to evaluate the results of full tendon vertical rectus transposition augmented with lateral fixation suture for patients with abducens nerve palsy. Full tendon transpositions of vertical rectus muscles augmented with posterior fixation suture was performed in 2014 on five patients with abducens nerve palsy. Two of the patients received Botox injections in the medial rectus muscle: one of them three months after the surgery and another during the surgery. One of the patients had a combined surgery of the horizontal muscles one year before. On three of the patients, who received a pure transposition surgery, the preoperative deviation at the distance (mean: + 56.6 pd; range: + 40 to + 80 pd) was reduced by a mean of 39.6 pd (range 34 to 50 pd), the abduction was improved by a mean of 3 mm (range 2 to 4 mm). The other two patients, who received besides the transposition procedure additional surgeries of the horizontal muscles, the preoperative deviation at the distance (+ 25 and + 126 pd respectively) was reduced by 20 and 81 pd respectively. The abduction was improved by 4 and 8 mm respectively. After surgery two patients developed a vertical deviation with a maximum of 4 pd. None of the patients had complications or signs of anterior segment ischemia. The elevation and/or depression was only marginally affected. There was no diplopia in up- or downgaze. Full tendon transposition of vertical rectus muscles, augmented with lateral posterior fixation suture is

  6. TRANSPOSITION OF GREAT ARTERIES: NEW INSIGHTS INTO THE PATHOGENESIS

    Directory of Open Access Journals (Sweden)

    Marta eUnolt

    2013-06-01

    Full Text Available Transposition of great arteries (TGA is one of the most common and severe congenital heart diseases (CHD. It is also one of the most mysterious CHD because it has no precedent in phylogenetic and ontogenetic development, it does not represent an alternative physiological model of blood circulation and its etiology and morphogenesis are still largely unknown. However, recent epidemiologic, experimental and genetic data suggest new insights into the pathogenesis. TGA is very rarely associated with the most frequent genetic syndromes, such as Turner, Noonan, Williams or Marfan syndromes, and in Down syndrome, it is virtually absent. The only genetic syndrome with a strong relation with TGA is Heterotaxy. Moreover, TGA is rather frequent in cases of isolated dextrocardia with situs solitus, showing link with defect of visceral situs. In lateralization defects TGA is frequently associated with asplenia syndrome. Nowadays, the most reliable method to induce TGA consists in treating pregnant mice with retinoic acid or with retinoic acid inhibitors. Following such treatment not only cases of TGA with d-ventricular loop have been registered, but also some cases of congenitally corrected transposition of great arteries (CCTGA. In another experiment, the embryos of mice treated with retinoic acid in day 6.5 presented Heterotaxy, suggesting a relationship among these morphologically different CHD. In some families, beside TGA cases, there were first-degree relatives with CCTGA. This data suggest that monogenic inheritance with a variable phenotypic expression could explain the familial aggregation of TGA and CCTGA. In some of these families we previously found multiple mutations in laterality genes including Nodal and ZIC3, confirming a pathogenetic relation between TGA and Heterotaxy. These overall data suggest to include TGA in the pathogenetic group of laterality defects instead of conotruncal abnormalities due to ectomesenchymal tissue migration.

  7. An extensive deletion causing overproduction of yeast iso-2-cytochrome c

    International Nuclear Information System (INIS)

    McKnight, G.L.; Cardillo, T.S.; Sherman, F.

    1981-01-01

    CYC7-H3 is a cis-dominant regulatory mutation that causes a 20-fold overproduction of yeast iso-2-cytochrome c. The CYC7-H3 mutation is an approximately 5 kb deletion with one breakpoint located in the 5' noncoding region of the CYC7 gene, approximately 200 base from the ATG initiation codon. The deletion apparently fuses a new regulatory region to the structural portion of the CYC7 locus. The CYC7-H3 deletion encompasses the RAD23 locus, which controls UV sensitivity and the ANP1 locus, which controls osmotic sensitivity. The gene cluster CYC7-RAD23-ANP1 displays striking similarity to the gene cluster CYC1-OSM1-RAD7, which controls, respectively, iso-1-cytochrome c, osmotic sensitivity and UV sensitivity. We suggest that these gene clusters are related by an ancient transpositional event

  8. Omental pedicle transposition and suture repair of peripheral nerve ...

    African Journals Online (AJOL)

    Abu wael

    This study aimed to compare the effectiveness of omental pedicle transposition and ... Assessment of the nerve regeneration was based on functional (motor and sensory), ..... peripheral nerve fibers regenerating after crush, multiple crush, and.

  9. Transposon display supports transpositional activity of P elements in ...

    Indian Academy of Sciences (India)

    . Abstract. Mobilization of two P element subfamilies (canonical and O-type) from Drosophila sturtevanti and D. saltans was evaluated for copy number and transposition activity using the transposon display (TD) technique. Pairwise distances ...

  10. Aging and experience in the recognition of musical transpositions.

    Science.gov (United States)

    Halpern, A R; Bartlett, J C; Dowling, W J

    1995-09-01

    The authors examined the effects of age, musical experience, and characteristics of musical stimuli on a melodic short-term memory task in which participants had to recognize whether a tune was an exact transposition of another tune recently presented. Participants were musicians and nonmusicians between ages 18 and 30 or 60 and 80. In 4 experiments, the authors found that age and experience affected different aspects of the task, with experience becoming more influential when interference was provided during the task. Age and experience interacted only weakly, and neither age nor experience influenced the superiority of tonal over atonal materials. Recognition memory for the sequences did not reflect the same pattern of results as the transposition task. The implications of these results for theories of aging, experience, and music cognition are discussed.

  11. Reactions of carbon radicals generated by 1,5-transposition of reactive centers

    Directory of Open Access Journals (Sweden)

    ZIVORAD CEKOVIC

    2005-03-01

    Full Text Available Radical intermediates can undergo specific reactions, such as intramolecular rearrangements, i.e., the transpositions of radical centers, which are not known in classical ionic organic reactions. 1,5-Transposition of a radical center to a non-activated carbon atom are of great synthetic importance. It can be successfully applied for the introduction of different functional groups (oxygen, nitrogen, sulfur, halogens onto a carbon atom remote from the present functional group. In addition to functionalization of a remote non-activated carbon atom, the formation of new C-C bonds on the d-carbon atom have also been achieved. 1,5-Transposition of the radical centers takes place from alkoxyl, aminyl and carbon radicals to a remote carbon atom. Relocation of the radical centers preferentially involves 1,5-transfer of a hydrogen atom, although migrations of some other groups are known. The reactions of the carbon radical generated by 1,5-relocation of the radical center are presented and their synthetic applications are reviewed.

  12. Successful surrogate pregnancy after ovarian transposition, pelvic irradiation and hysterectomy.

    Science.gov (United States)

    Zinger, Michael; Liu, James H; Husseinzadeh, Nader; Thomas, Michael A

    2004-07-01

    Treatment of cervical cancer is often effective but at the cost of the woman's fertility. Ovarian transposition with subsequent oocyte retrieval and surrogate pregnancy can enable these patients to become genetic parents. We present the third reported such case. A 22-year-old woman was diagnosed with bulky, stage IB cervical cancer. Following transposition of both ovaries to the upper abdomen, she underwent pelvic irradiation followed by total abdominal hysterectomy. Eleven years later she presented for assisted reproduction. Two oocytes were retrieved following ovarian stimulation and transcutaneous, abdominal oocyte retrieval. One embryo was transferred to the gestational surrogate, resulting in a single intrauterine pregnancy and successful delivery at term. These procedures can preservefertility while successfully treating cervical cancer.

  13. Didaktisk Transposition:Fra teori til forskningsprogram

    OpenAIRE

    Achiam, Marianne

    2014-01-01

    The term didactic transposition refers to the deconstruction and reconstruction of science knowledge, values or practices in order to make them teachable. In this paper, I present the theoretical framework that has grown around this notion. I use examples from different levels of science education and different subjects to illustrate how science is transformed in any teaching undertaking, and how that transformation influences the way science is experienced and appropriated by learners. The c...

  14. Coupled external fixator and skin flap transposition for treatment of exposed and nonunion bone.

    Science.gov (United States)

    Zhao, Yong-gang; Ding, Jing; Wang, Neng

    2011-02-01

    To discuss the effect of coupled external fixator and skin flap transposition on exposed and nonunion bones. The data of 12 cases of infected nonunion and exposed bone following open fracture treated in our hospital during the period of March 1998 to June 2008 were analysed. There were 10 male patients, 2 female patients, whose age were between 19-52 years and averaged 28 years. There were 10 tibial fractures and 2 femoral fractures. The course of diseases lasted for 12-39 months with the mean period of 19 months. All the cases were treated by the coupled external fixator and skin flap transposition. Primary healing were achieved in 10 cases and delayed healing in 2 cases in whom the tibia was exposed due to soft tissue defect and hence local flap transposition was performed. All the 12 cases had bony union within 6-12 months after operation with the average time of 8 months. They were followed up for 1-3 years and all fractures healed up with good function and no infection recurrence. The coupled external fixator and skin flap transposition therapy have shown optimal effects on treating infected, exposed and nonunion bones.

  15. New insights into the transposition mechanisms of IS6110 and its dynamic distribution between Mycobacterium tuberculosis Complex lineages.

    Science.gov (United States)

    Gonzalo-Asensio, Jesús; Pérez, Irene; Aguiló, Nacho; Uranga, Santiago; Picó, Ana; Lampreave, Carlos; Cebollada, Alberto; Otal, Isabel; Samper, Sofía; Martín, Carlos

    2018-04-01

    The insertion Sequence IS6110, only present in the pathogens of the Mycobacterium tuberculosis Complex (MTBC), has been the gold-standard epidemiological marker for TB for more than 25 years, but biological implications of IS6110 transposition during MTBC adaptation to humans remain elusive. By studying 2,236 clinical isolates typed by IS6110-RFLP and covering the MTBC, we remarked a lineage-specific content of IS6110 being higher in modern globally distributed strains. Once observed the IS6110 distribution in the MTBC, we selected representative isolates and found a correlation between the normalized expression of IS6110 and its abundance in MTBC chromosomes. We also studied the molecular regulation of IS6110 transposition and we found a synergistic action of two post-transcriptional mechanisms: a -1 ribosomal frameshift and a RNA pseudoknot which interferes translation. The construction of a transcriptionally active transposase resulted in 20-fold increase of the transposition frequency. Finally, we examined transposition in M. bovis and M. tuberculosis during laboratory starvation and in a mouse infection model of TB. Our results shown a higher transposition in M. tuberculosis, that preferably happens during TB infection in mice and after one year of laboratory culture, suggesting that IS6110 transposition is dynamically adapted to the host and to adverse growth conditions.

  16. Correction of incomplete penoscrotal transposition by a modified Glenn-Anderson technique

    Directory of Open Access Journals (Sweden)

    Saleh Amin

    2010-01-01

    Full Text Available Purpose: Penoscrotal transposition may be partial or complete, resulting in variable degrees of positional exchanges between the penis and the scrotum. Repairs of penoscrotal transposition rely on the creation of rotational flaps to mobilise the scrotum downwards or transpose the penis to a neo hole created in the skin of the mons-pubis. All known techniques result in complete circular incision around the root of the penis, resulting in severe and massive oedema of the penile skin, which delays correction of the associated hypospadias and increases the incidence of complications, as the skin vascularity and lymphatics are impaired by the designed incision. A new design to prevent this post-operative oedema, allowing early correction of the associated hypospadias and lowering the incidence of possible complications, had been used, whose results were compared with other methods of correction. Materials and Methods: Ten patients with incomplete penoscrotal transposition had been corrected by designing rotational flaps that push the scrotum back while the penile skin remains attached by small strip to the skin of the mons-pubis. Results : All patients showed an excellent cosmetic outcome. There was minimal post-operative oedema and no vascular compromise to the penile or scrotal skin. Correction of associated hypospadias can be performed in the same sitting or in another sitting, without or with minimal complications. Conclusion: This modification, which maintains the penile skin connected to the skin of the lower abdomen by a small strip of skin during correction of penoscrotal transposition, prevents post-operative oedema and improves healing with excellent cosmetic appearance, allows one-stage repair with minimal complications and reduce post-operative complications such as urinary fistula and flap necrosis.

  17. Vector for IS element entrapment and functional characterization based on turning on expression of distal promoterless genes.

    Science.gov (United States)

    Szeverényi, I; Hodel, A; Arber, W; Olasz, F

    1996-09-26

    We constructed and characterized a novel trap vector for rapid isolation of insertion sequences. The strategy used for the isolation of IS elements is based on the ability of many IS elements to turn on the expression of otherwise silent genes distal to some sites of insertion. The simple transposition of an IS element can sometimes cause the constitutive expression of promoterless antibiotic resistance genes resulting in selectable phenotypes. The trap vector pAW1326 is based on a pBR322 replicon, it carries ampicillin and streptomycin resistance genes, and also silenced genes that confer chloramphenicol and kanamycin resistance once activated. The trap vector pAW1326 proved to be efficient and 85 percent of all isolated mutations were insertions. The majority of IS elements resident in the studied Escherichia coli strains tested became trapped, namely IS2, IS3, IS5, IS150, IS186 and Tn1000. We also encountered an insertion sequence, called IS10L/R-2, which is a hybrid of the two IS variants IS10L and IS10R. IS10L/R-2 is absent from most E. coli strains, but it is detectable in some strains such as JM109 which had been submitted to Tn10 mutagenesis. The distribution of the insertion sequences within the trap region was not random. Rather, the integration of chromosomal mobile genetic elements into the offered target sequence occurred in element-specific clusters. This is explained both by the target specificity and by the specific requirements for the activation of gene transcription by the DNA rearrangement. The employed trap vector pAW1326 proved to be useful for the isolation of mobile genetic elements, for a demonstration of their transposition activity as well as for the further characterization of some of the functional parameters of transposition.

  18. Parallel transposition of sparse data structures

    DEFF Research Database (Denmark)

    Wang, Hao; Liu, Weifeng; Hou, Kaixi

    2016-01-01

    Many applications in computational sciences and social sciences exploit sparsity and connectivity of acquired data. Even though many parallel sparse primitives such as sparse matrix-vector (SpMV) multiplication have been extensively studied, some other important building blocks, e.g., parallel tr...... transposition in the latest vendor-supplied library on an Intel multicore CPU platform, and the MergeTrans approach achieves on average of 3.4-fold (up to 11.7-fold) speedup on an Intel Xeon Phi many-core processor....

  19. Repetitive transpositions of mitochondrial DNA sequences to the nucleus during the radiation of horseshoe bats (Rhinolophus, Chiroptera).

    Science.gov (United States)

    Shi, Huizhen; Dong, Ji; Irwin, David M; Zhang, Shuyi; Mao, Xiuguang

    2016-05-01

    Transposition of mitochondrial DNA into the nucleus, which gives rise to nuclear mitochondrial DNAs (NUMTs), has been well documented in eukaryotes. However, very few studies have assessed the frequency of these transpositions during the evolutionary history of a specific taxonomic group. Here we used the horseshoe bats (Rhinolophus) as a case study to determine the frequency and relative timing of nuclear transfers of mitochondrial control region sequences. For this, phylogenetic and coalescent analyzes were performed on NUMTs and authentic mtDNA sequences generated from eight horseshoe bat species. Our results suggest at least three independent transpositions, including two ancient and one more recent, during the evolutionary history of Rhinolophus. The two ancient transpositions are represented by the NUMT-1 and -2 clades, with each clade consisting of NUMTs from almost all studied species but originating from different portions of the mtDNA genome. Furthermore, estimates of the most recent common ancestor for each clade corresponded to the time of the initial diversification of this genus. The recent transposition is represented by NUMT-3, which was discovered only in a specific subgroup of Rhinolophus and exhibited a close relationship to its mitochondrial counterpart. Our similarity searches of mtDNA in the R. ferrumequinum genome confirmed the presence of NUMT-1 and NUMT-2 clade sequences and, for the first time, assessed the extent of NUMTs in a bat genome. To our knowledge, this is the first study to report on the frequency of transpositions of mtDNA occurring before the common ancestry of a genus. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Nonsurgical endodontic retreatment of fused teeth with transposition: a case report

    Directory of Open Access Journals (Sweden)

    Miguel Agostinho Beco Pinto Cardoso

    2016-05-01

    Full Text Available Tooth transposition is a disorder in which a permanent tooth develops and erupts in the normal position of another permanent tooth. Fusion and gemination are developmental disturbances presenting as the union of teeth. This article reports the nonsurgical retreatment of a very rare case of fused teeth with transposition. A patient was referred for endodontic treatment of her maxillary left first molar in the position of the first premolar, which was adjacent to it on the distobuccal side. Orthopantomography and periapical radiography showed two crowns sharing the same root, with a root canal treatment and an associated periapical lesion. Tooth fusion with transposition of a maxillary molar and a premolar was diagnosed. Nonsurgical endodontic retreatment was performed. At four yr follow-up, the tooth was asymptomatic and the radiolucency around the apical region had decreased, showing the success of our intervention. The diagnosis and treatment of fused teeth require special attention. The canal system should be carefully explored to obtain a full understanding of the anatomy, allowing it to be fully cleaned and obturated. Thermoplastic techniques were useful in obtaining hermetic obturation. A correct anatomical evaluation improves the set of treatment options under consideration, leading to a higher likelihood of esthetically and functionally successful treatment.

  1. Relationship between interatrial communication, ductus arteriosus, and pulmonary flow patterns in fetuses with transposition of the great arteries: prediction of neonatal desaturation.

    Science.gov (United States)

    Vaujois, Laurence; Boucoiran, Isabelle; Preuss, Christophe; Brassard, Myriam; Houde, Christine; Fouron, Jean C; Raboisson, Marie-Josée

    2017-09-01

    The relationship between interatrial communication, ductus arteriosus, and pulmonary flow in transposition of the great arteries and intact ventricular septum may help predict postnatal desaturation. Echocardiographic data of 45 fetuses with transposition of the great arteries and intact ventricular septum and 50 age-matched controls were retrospectively reviewed. Interatrial communication, left and right ventricular output, flow in the ductus arteriosus, as well as effective pulmonary flow were measured. Patients were divided into two groups on the basis of postnatal saturations: group 1 had saturations ⩽50% and group 2 >50%. Of 45 fetuses, 13 (26.7%) were classified into group 1. Compared with fetuses in group 2, they had a smaller interatrial communication (2.9 versus 4.0 mm, p=0.004) and more retrograde diastolic flow in the ductus arteriosus (92 versus 23%, p=0.002). Both groups showed a significant decrease in ductal flow compared with controls. Patients in group 2 had a higher effective pulmonary flow compared with controls. There was a mild correlation between left ventricular output and size of the interatrial communication (Spearman's rank correlation 0.44). A retrograde diastolic flow is present in most of the fetuses with postnatal desaturation. Fetuses with transposition of the great arteries have a lower flow through the ductus arteriosus compared with controls. Fetuses without restrictive foramen ovale have higher effective pulmonary flow. Peripheral pulmonary vasodilatation due to higher oxygen saturation in pulmonary arteries in the case of transposition of the great arteries could be one possible cause.

  2. Fat transposition with a single subdermal stitch for the treatment of deep tear trough.

    Science.gov (United States)

    Medel, Ramón; Hristodulopulos, Vanessa; Vásquez, LuzMaría

    2014-12-01

    To describe a fixation technique of the medial and central fat pads in the subperiosteal pocket for transconjunctival fat transposition, using a single subdermal, non-removable, non-absorbable stitch. Retrospective study of 19 patients with bilateral deep tear through treated by means of transconjunctival fat transposition. Charts and photographic records were reviewed. Photographical and clinical improvement of the deep tear through and fat prolapse was observed in all patients in variable degrees. There were no intraoperative complications. Significant periocular hematoma occurred in 1 patient and solved without complications. Two patients presented transitory fat pedicle hardening and one patient presented a conjunctival inferior fornix granuloma, surgically removed. All patients were satisfied. Transconjunctival subperiosteal fat transposition with single subdermal stitch to fix the medial and central fat pads, for the treatment of deep tear trough and fat prolapse demonstrated high patient satisfaction, good aesthetic results with no significant or permanent complications.

  3. [Transposition of the cephalic vein in free flap breast reconstruction: Technical note].

    Science.gov (United States)

    Silhol, T; Suffee, T; Hivelin, M; Lantieri, L

    2018-02-01

    Free flaps have become a reliable practice for breast reconstruction. However, the venous congestion is still the most frequent reason of flap failure. It is due to bad quality of the internal mammary veins, a preferential superficial venous outflow of the flap or due to venous thrombosis. The transposition of the cephalic vein could useful in some cases. We describe the surgical technique and suggest an intraoperative algorithm. Seventeen patients (15 DIEP and 2 PAP) were included. Twenty nine point four percent had an unusable internal mammary vein, 23.5% a preferential superficial venous outflow and 47.1% a venous thrombosis. The length of the cephalic vein dissected varied from 15 to 25cm. The mean time of dissection was 39min. There was no flap failure after cephalic vein transposition. The sequelae were one or two scars on the arm without any functional morbidity. The transposition of the cephalic vein is a reliable, less morbid alternative in case of bad quality internal mammary vein with a good quality internal mammary artery, in case of an additional venous outflow necessity or in case of venous thrombosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Method and structure for cache aware transposition via rectangular subsections

    Science.gov (United States)

    Gustavson, Fred Gehrung; Gunnels, John A

    2014-02-04

    A method and structure for transposing a rectangular matrix A in a computer includes subdividing the rectangular matrix A into one or more square submatrices and executing an in-place transposition for each of the square submatrices A.sub.ij.

  5. Transposition of the great arteries - a phenotype associated with 16p11.2 duplications?

    Science.gov (United States)

    Karunanithi, Zarmiga; Vestergaard, Else Marie; Lauridsen, Mette H

    2017-12-26

    Genetic analyses of patients with transposition of the great arteries have identified rare copy number variations, suggesting that they may be significant to the aetiology of the disease. This paper reports the identification of a 16p11.2 microduplication, a variation that has yet to be reported in association with transposition of the great arteries. The 16p11.2 microduplication is associated with autism spectrum disorder and developmental delay, but with highly variable phenotypic effects. Autism and attention deficit disorders are observed more frequently in children with congenital heart disease than in the general population. Neonatal surgery is proposed as a risk factor, but as yet unidentified genetic abnormalities should also be taken into account. Thus, congenital heart abnormalities may constitute a part of the phenotypic spectrum associated with duplications at 16p11.2. We suggest chromosomal microarray be considered part of the diagnostic work-up in patients with transposition of the great arteries.

  6. Barbara McClintock, Jumping Genes, and Transposition

    Science.gov (United States)

    McClintock Honored * Woman of Science * Educational Material * Resources with Additional Information Barbara McClintock's remarkable life spanned the history of genetics in the twentieth century. ... [T]he science of Dedicate Famous Scientist Stamps ... Woman of Science: McClintock, Barbara and the Jumping Genes, 4,000

  7. Symmetric Stream Cipher using Triple Transposition Key Method and Base64 Algorithm for Security Improvement

    Science.gov (United States)

    Nurdiyanto, Heri; Rahim, Robbi; Wulan, Nur

    2017-12-01

    Symmetric type cryptography algorithm is known many weaknesses in encryption process compared with asymmetric type algorithm, symmetric stream cipher are algorithm that works on XOR process between plaintext and key, to improve the security of symmetric stream cipher algorithm done improvisation by using Triple Transposition Key which developed from Transposition Cipher and also use Base64 algorithm for encryption ending process, and from experiment the ciphertext that produced good enough and very random.

  8. The Symbiodinium kawagutii genome illuminates dinoflagellate gene expression and coral symbiosis

    DEFF Research Database (Denmark)

    Lin, Senjie; Cheng, Shifeng; Song, Bo

    2015-01-01

    Symbiodinium-specific gene families. No whole-genome duplication was observed, but instead we found active (retro) transposition and gene family expansion, especially in processes important for successful symbiosis with corals. We also documented genes potentially governing sexual reproduction and cyst...... the molecular basis and evolution of coral symbiosis....

  9. Transpositions Within User-Posted YouTube Lyric Videos: A Corpus Study

    Directory of Open Access Journals (Sweden)

    Joseph Plazak

    2016-07-01

    Full Text Available There are many practical reasons why experiences of a given musical work tend to be heard repeatedly at the same pitch transposition level, especially recordings of musical works. Yet here, a corpus study is presented that challenges this very basic assumption of music perception. In 2011, an initial corpus of 100 user-posted YouTube videos was collected in order to investigate the prevalence of transposition and tempo alterations within these videos. Results found 42% of these videos contained nominal changes of pitch (36% and/or tempo (22%. Using the same methodology, a follow-up study was performed in 2015 and found only that 24% of user-posted videos contained these same alterations. Implications for these observations are discussed in light of musical communication models, YouTubeology, and absolute pitch memory.

  10. HERCA Action Plan in relation to the transposition and implementation of Directive 2013/59/Euratom (Euratom BSS)

    International Nuclear Information System (INIS)

    Fremout, An; Vanderlinck, Annie; Berlamont, Jolien; Van Bladel, Lodewijk; Petrova, Karla; Ulbak, Kaare; Mundigl, Stefan; ); Markkanen, Mika; Godet, Jean-Luc; Tran-Thien, Vivien; Koch, Isabell Christin; Hackstein, Matthias; Griebel, Juergen; Kamenopoulou, Vasiliki; Fennel, Stephan; Ryan, Tom; Schreiner, Alexandra; Majerus, Patrick; Vermeulen, Ton; Holo, Eldri; Wiklund, Asa; RYF, Salome; Thomas, Gareth; Wellens, Rob; Ebdon-Jackson, Steve

    2014-10-01

    On 5 December 2013, the Council of the European Union adopted Council Directive 2013/59/Euratom laying down basic safety standards for protection against the dangers arising from exposure to ionising radiation.1 Member States have to transpose the new Basic Safety Standards Directive (BSS Directive) into their national legal systems by 6 February 2018 at the latest. At the 13. meeting of the Board of HERCA (BoH) in Vilnius in June 2014, a proposal to establish a special Task Force (TF) to make proposals in relation to HERCA activities in support of the transposition and implementation of the new Euratom BSS Directive was agreed. The BSS-TF was established, commenced its work on the basis of a 'non-questionnaire' and a discussion document. It met on one occasion on 7 October 2014 and agreed an action plan for consideration by the BoH. The agreed action plan proposal was approved by the BoH on the occasion of its 14. meeting in Stockholm, on 21-22 October 2014. The approved Action Plan covers the following areas: - Identification of HERCA's role in the transposition of the new Euratom BSS; - Definition of actions for HERCA in relation to the transposition of the BSS; - Coordination between HERCA and the EC in relation to BSS transposition activities. The Actions identified relate to several subject areas: Emergency preparedness and response; Medical exposures; Radon; Non-medical imaging exposures; RPE/RPO; General exchange of information. HERCA is a voluntary association, in which the Heads of European Radiological Protection Competent Authorities work together in order to identify common issues and propose practical solutions for these issues. It has no statutory role in relation to the transposition of the Euratom BSS. However, additional work by HERCA can support the transposition process as indicated in the Action Plan. Uniform transposition or implementation in the Member States is not an objective of HERCA activities. Clearly it will remain a matter for

  11. Clinical outcome in MPFL reconstruction with and without tuberositas transposition.

    Science.gov (United States)

    Mulliez, A; Lambrecht, D; Verbruggen, D; Van Der Straeten, C; Verdonk, P; Victor, J

    2017-09-01

    There are several surgical options for recurrent patella dislocations. As the reconstruction of the medial patellofemoral ligament (MPFL) has been proven to restore stability, it has become more accepted. Aim of this study was to investigate the clinical outcome after MPFL reconstruction as an isolated procedure or in association with a transposition of the tibial tubercle (in case of patella alta or an excessive TT-TG) in a large prospective cohort study. Additionally, the effect on patellar height was analysed radiographically using the Caton-Deschamps index. In a large prospective cohort study of 129 knees in 124 patients (81 females, 48 males, mean age 22.8 ± 7.7 years), 91 knees received primary MPFL reconstruction (group 1) and 38 were a combination with a transposition of the tibial tubercle (group 2). The clinical follow-up was evaluated using KOOS and Kujala scores preoperatively and 1 year postoperatively. Patient satisfaction, complications and revision surgery were recorded. Overall, Kujala improved significantly from 53.5 (SD 22.7) preoperatively to 74.7 (SD 20.5) postoperatively (p < 0.01). All KOOS subdomains improved significantly (p < 0.01). No significant difference for Kujala score between groups was noticed. Revision rate was (5/129) 3.9 %. Reconstruction was supplemented with a transfer of the tibial tuberosity in (38/129) 29.4 % of the cases and shows a comparable outcome. MPFL reconstruction is a viable treatment option for episodic patellar dislocation. A concomitant tuberositas transposition is useful in selected patients. I.

  12. An extremely rare clinical entity: congenitally corrected transposition with situs ınversus and single coronary artery presented with complete atrioventricular block in a young man.

    Science.gov (United States)

    Cirakoglu, Omer Faruk; Bayraktar, Ali; Sayin, Muhammet Rasit

    2018-05-01

    Congenitally corrected transposition of the great arteries is a rare form of CHD. Situs inversus is a much less common variant of a congenitally corrected transposition of the great arteries. In rare cases, transposition events may be accompanied by various cardiac anomalies. However, situs inversus patients with congenitally corrected transposition, single coronary artery anomaly, and atrioventricular block together have not been reported previously. This combination of abnormalities is presented as a first in the literature.

  13. Non-existence of bipartite bound entanglement with negative partial transposition

    OpenAIRE

    Sperling, J.; Vogel, W.

    2009-01-01

    Bound entanglement with a nonpositive partial transposition (NPT) does not exist. For any NPT entangled state a distillation procedure can be based on a certain number of copies. This number is the minimal Schmidt rank of a pure state needed to witness the NPT entanglement under study.

  14. Effect of brushwood transposition on the leaf litter arthropod fauna in a cerrado area

    Directory of Open Access Journals (Sweden)

    Paula Cristina Benetton Vergílio

    2013-10-01

    Full Text Available The results of ecological restoration techniques can be monitored through biological indicators of soil quality such as the leaf litter arthropod fauna. This study aimed to determine the immediate effect of brushwood transposition transferred from an area of native vegetation to a disturbed area, on the leaf litter arthropod fauna in a degraded cerrado area. The arthropod fauna of four areas was compared: a degraded area with signal grass, two experimental brushwood transposition areas, with and without castor oil plants, and an area of native cerrado. In total, 7,660 individuals belonging to 23 taxa were sampled. Acari and Collembola were the most abundant taxa in all studied areas, followed by Coleoptera, Diptera, Hemiptera, Hymenoptera, and Symphyla. The brushwood transposition area without castor oil plants had the lowest abundance and dominance and the highest diversity of all areas, providing evidence of changes in the soil community. Conversely, the results showed that the presence of castor oil plants hampered early succession, negatively affecting ecological restoration in this area.

  15. Survival and health in liveborn infants with transposition of great arteries

    DEFF Research Database (Denmark)

    Garne, Ester; Loane, Maria A; Nelen, Vera

    2007-01-01

    OBJECTIVE: To describe treatment, survival, and morbidity for liveborn infants with isolated transposition of great arteries (TGA). DESIGN: Population-based data from 7 European registries of congenital malformations (EUROCAT). RESULTS: Ninety-seven infants were diagnosed with isolated TGA...

  16. Surrogate pregnancy in a patient who underwent radical hysterectomy and bilateral transposition of ovaries.

    Science.gov (United States)

    Azem, Foad; Yovel, Israel; Wagman, Israel; Kapostiansky, Rita; Lessing, Joseph B; Amit, Ami

    2003-05-01

    To evaluate IVF-surrogate pregnancy in a patient with ovarian transposition after radical hysterectomy for carcinoma of the cervix. Case report. A maternity hospital in Tel Aviv that is a major tertiary care and referral center. A 29-year-old woman who underwent Wertheim's hysterectomy for carcinoma of the uterine cervix and ovarian transposition before total pelvic irradiation. Standard IVF treatment, transabdominal oocyte retrieval, and transfer to surrogate mother. Outcome of IVF cycle. A twin pregnancy in the first cycle. This is the second reported case of controlled ovarian stimulation and oocyte retrieval performed on a transposed ovary.

  17. Esthetics with prosthetics in case of maxillary canine transposition: A ...

    African Journals Online (AJOL)

    Esthetics with prosthetics in case of maxillary canine transposition: A clinical report. ... provides a helpful Frequently Asked Questions about PDFs. Alternatively, you can download the PDF file directly to your computer, from where it can be opened using a PDF reader. To download the PDF, click the Download link above.

  18. Esthetics with prosthetics in case of maxillary canine transposition: A ...

    African Journals Online (AJOL)

    These are mainly genetically governed and are treated orthodontically if complete segment of tooth is present; in case of missing teeth, participation of cosmetic dentist is must. The present case report describes a situation where left canine to lateral incisor complete transposition was present along with a missing left central ...

  19. Interdisciplinary approach for bilateral maxillary canine: First premolar transposition with complex problems in an adult patient

    Directory of Open Access Journals (Sweden)

    Dhivakar Selvaraj

    2013-01-01

    Full Text Available Adult patients seeking orthodontic care were increased nowadays not only on esthetic need but also on functional demand. But problems with adult patients were not only malocclusions but also dental caries, pulpal pathology, missing teeth, muco-gingival problems and loss of supporting structures. We report here a case of 35-year-old female with complete transposition referred as a positional interchange of two permanent teeth within the same quadrant of the dental arch along with gingival recession of the lower anteriors and missing molars. Gingival health was improved by free gingival graft in lower anteriors followed by fixed orthodontic procedure to correct transposition. Based on transposition crown recontouring and restoration was done along with replacement of missing molars with fixed prosthesis. Thus, proper treatment planning with interdisciplinary management improves not only the esthetics and occlusal relationship but also with stable results.

  20. Pulmonary Arterial Hypertension and Neonatal Arterial Switch Surgery for Correction of Transposition of the Great Arteries.

    Science.gov (United States)

    Domínguez Manzano, Paula; Mendoza Soto, Alberto; Román Barba, Violeta; Moreno Galdó, Antonio; Galindo Izquierdo, Alberto

    2016-09-01

    There are few reports of the appearance of pulmonary arterial hypertension following arterial switch surgery in the neonatal period to correct transposition of the great arteries. We assessed the frequency and clinical pattern of this complication in our series of patients. Our database was reviewed to select patients with transposition of the great arteries corrected by neonatal arterial switch at our hospital and who developed pulmonary hypertension over time. We identified 2 (1.3%) patients with transposition of the great arteries successfully repaired in the first week of life who later experienced pulmonary arterial hypertension. The first patient was a 7-year-old girl diagnosed with severe pulmonary hypertension at age 8 months who did not respond to medical treatment and required lung transplantation. The anatomic pathology findings were consistent with severe pulmonary arterial hypertension. The second patient was a 24-month-old boy diagnosed with severe pulmonary hypertension at age 13 months who did not respond to medical therapy. Pulmonary hypertension is a rare but very severe complication that should be investigated in all patients with transposition of the great arteries who have undergone neonatal arterial switch, in order to start early aggressive therapy for affected patients, given the poor therapeutic response and poor prognosis involved. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  1. An O([Formula: see text]) algorithm for sorting signed genomes by reversals, transpositions, transreversals and block-interchanges.

    Science.gov (United States)

    Yu, Shuzhi; Hao, Fanchang; Leong, Hon Wai

    2016-02-01

    We consider the problem of sorting signed permutations by reversals, transpositions, transreversals, and block-interchanges. The problem arises in the study of species evolution via large-scale genome rearrangement operations. Recently, Hao et al. gave a 2-approximation scheme called genome sorting by bridges (GSB) for solving this problem. Their result extended and unified the results of (i) He and Chen - a 2-approximation algorithm allowing reversals, transpositions, and block-interchanges (by also allowing transversals) and (ii) Hartman and Sharan - a 1.5-approximation algorithm allowing reversals, transpositions, and transversals (by also allowing block-interchanges). The GSB result is based on introduction of three bridge structures in the breakpoint graph, the L-bridge, T-bridge, and X-bridge that models goodreversal, transposition/transreversal, and block-interchange, respectively. However, the paper by Hao et al. focused on proving the 2-approximation GSB scheme and only mention a straightforward [Formula: see text] algorithm. In this paper, we give an [Formula: see text] algorithm for implementing the GSB scheme. The key idea behind our faster GSB algorithm is to represent cycles in the breakpoint graph by their canonical sequences, which greatly simplifies the search for these bridge structures. We also give some comparison results (running time and computed distances) against the original GSB implementation.

  2. Heterogeneic dynamics of the structures of multiple gene clusters in two pathogenetically different lines originating from the same phytoplasma.

    Science.gov (United States)

    Arashida, Ryo; Kakizawa, Shigeyuki; Hoshi, Ayaka; Ishii, Yoshiko; Jung, Hee-Young; Kagiwada, Satoshi; Yamaji, Yasuyuki; Oshima, Kenro; Namba, Shigetou

    2008-04-01

    Phytoplasmas are phloem-limited plant pathogens that are transmitted by insect vectors and are associated with diseases in hundreds of plant species. Despite their small sizes, phytoplasma genomes have repeat-rich sequences, which are due to several genes that are encoded as multiple copies. These multiple genes exist in a gene cluster, the potential mobile unit (PMU). PMUs are present at several distinct regions in the phytoplasma genome. The multicopy genes encoded by PMUs (herein named mobile unit genes [MUGs]) and similar genes elsewhere in the genome (herein named fundamental genes [FUGs]) are likely to have the same function based on their annotations. In this manuscript we show evidence that MUGs and FUGs do not cluster together within the same clade. Each MUG is in a cluster with a short branch length, suggesting that MUGs are recently diverged paralogs, whereas the origin of FUGs is different from that of MUGs. We also compared the genome structures around the lplA gene in two derivative lines of the 'Candidatus Phytoplasma asteris' OY strain, the severe-symptom line W (OY-W) and the mild-symptom line M (OY-M). The gene organizations of the nucleotide sequences upstream of the lplA genes of OY-W and OY-M were dramatically different. The tra5 insertion sequence, an element of PMUs, was found only in this region in OY-W. These results suggest that transposition of entire PMUs and PMU sections has occurred frequently in the OY phytoplasma genome. The difference in the pathogenicities of OY-W and OY-M might be caused by the duplication and transposition of PMUs, followed by genome rearrangement.

  3. Classes of n-copy undistillable quantum states with negative partial transposition

    International Nuclear Information System (INIS)

    Bandyopadhyay, Somshubhro; Roychowdhury, Vwani

    2003-01-01

    The discovery of entangled quantum states from which one cannot distill pure entanglement constitutes a fundamental recent advance in the field of quantum information. Such bipartite bound-entangled (BE) quantum states could fall into two distinct categories: (1) Inseparable states with positive partial transposition (PPT), and (2) states with negative partial transposition (NPT). While the existence of PPT BE states has been confirmed, only one class of conjectured NPT BE states has been discovered so far. We provide explicit constructions of a variety of multicopy undistillable NPT states, and conjecture that they constitute families of NPT BE states. For example, we show that for every pure state of Schmidt rank greater than or equal to 3, one can construct n-copy undistillable NPT states, for any n≥1. The abundance of such conjectured NPT BE states, we believe, considerably strengthens the notion that being NPT is only a necessary condition for a state to be distillable

  4. Transposition and national level resources

    DEFF Research Database (Denmark)

    Vasev, Nikolay Rumenov; Vrangbæk, Karsten

    2014-01-01

    Several recent papers have summarised the status of EU implementation studies. In this paper we suggest that the issue of sector specific resources has received too little attention in previous studies. Sector specific resources include “health sector resources” and “state administrative resources......”. Our theoretical contribution is thus to add an explicit and more detailed concern for "sector specific resources" in national transposition. This can refine the understanding of resources, for example in the multi-variable models that are emerging as the state of the art in the field of EU...... implementation studies. To illustrate these points we have chosen an empirical design focusing on a directive with a potentially high impact on system resources and several ambiguous components (the Cross Border Health Care Directive). We have further chosen to focus on two Eastern European countries (Bulgaria...

  5. Loss of Sfpq Causes Long-Gene Transcriptopathy in the Brain

    Directory of Open Access Journals (Sweden)

    Akihide Takeuchi

    2018-05-01

    Full Text Available Summary: Genes specifically expressed in neurons contain members with extended long introns. Longer genes present a problem with respect to fulfilment of gene length transcription, and evidence suggests that dysregulation of long genes is a mechanism underlying neurodegenerative and psychiatric disorders. Here, we report the discovery that RNA-binding protein Sfpq is a critical factor for maintaining transcriptional elongation of long genes. We demonstrate that Sfpq co-transcriptionally binds to long introns and is required for sustaining long-gene transcription by RNA polymerase II through mediating the interaction of cyclin-dependent kinase 9 with the elongation complex. Phenotypically, Sfpq disruption caused neuronal apoptosis in developing mouse brains. Expression analysis of Sfpq-regulated genes revealed specific downregulation of developmentally essential neuronal genes longer than 100 kb in Sfpq-disrupted brains; those genes are enriched in associations with neurodegenerative and psychiatric diseases. The identified molecular machinery yields directions for targeted investigations of the association between long-gene transcriptopathy and neuronal diseases. : It has been a long-standing question how mammalian neuronal cells achieve full gene length transcription of extra-long genes. Takeuchi et al. show that RNA-binding protein Sfpq sustains long-gene transcription through Pol II-CTD activation. Loss of Sfpq caused long-gene transcriptopathy, which could be the cause of neurodegenerative and psychiatric disorders. Keywords: RNA-binding protein, transcriptional regulation, RNA polymerase II, cyclin-dependent kinase 9, RBP/transcript-dependent elongation, long-gene transcriptotherapy, neuronal development, neurological and psychiatric diseases, long-gene diseases, long genopathies

  6. Comparison of hemihypoglossal-facial nerve transposition with a cross-facial nerve graft and muscle transplant for the rehabilitation of facial paralysis using the facial clima method.

    Science.gov (United States)

    Hontanilla, Bernardo; Vila, Antonio

    2012-02-01

    To compare quantitatively the results obtained after hemihypoglossal nerve transposition and microvascular gracilis transfer associated with a cross facial nerve graft (CFNG) for reanimation of a paralysed face, 66 patients underwent hemihypoglossal transposition (n = 25) or microvascular gracilis transfer and CFNG (n = 41). The commissural displacement (CD) and commissural contraction velocity (CCV) in the two groups were compared using the system known as Facial clima. There was no inter-group variability between the groups (p > 0.10) in either variable. However, intra-group variability was detected between the affected and healthy side in the transposition group (p = 0.036 and p = 0.017, respectively). The transfer group had greater symmetry in displacement of the commissure (CD) and commissural contraction velocity (CCV) than the transposition group and patients were more satisfied. However, the transposition group had correct symmetry at rest but more asymmetry of CCV and CD when smiling.

  7. Situs Inversus with Levocardia and Congenitally Corrected Transposition of Great Vessels in a 35 year old Male: A Case report.

    Science.gov (United States)

    Ghorbnazadeh, Atefeh; Zirak, Nahid; Fazlinezhad, Afsoon; Moenipour, Aliasghar; Manshadi, Hamid Hoseinikhah; Teshnizi, Mohammad Abbasi

    2017-01-01

    Situs inversus with levocardia and congenitally corrected transposition of the great arteries represents a relatively very rare congenital condition and most patients are diagnosed in infancy or early age. This case report describes a 35-year old man with congenitally corrected transposition of the great arteries which presented with a five month history of exertional dyspnea. A diagnosis was confirmed by transesophageal echocardiogram, showing situs inversus, levocardia, atrioventricular and ventriculoarterial discordance. He underwent physiologic repair, and was discharged thirty five days after the operation, in a good general condition. Although management of the corrected transposition of the great arteries patients remains controversial, the recommendation is that physiologic repair may be the procedure of choice for some patients, particularly complicated cases.

  8. Inferior Alveolar Nerve Lateralization and Transposition for Dental Implant Placement. Part I: a Systematic Review of Surgical Techniques

    Directory of Open Access Journals (Sweden)

    Boris Abayev

    2015-03-01

    Full Text Available Objectives: The purpose of this first part of a two-part series was to review the literature concerning the indications, contraindications, advantages, disadvantages and surgical techniques of the lateralization and transposition of the inferior alveolar nerve, followed by the placement of an implant in an edentulous atrophic posterior mandible. Material and Methods: A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed and PMC database, academic sites and books. The articles were searched from January 1997 to July 2014 and comprised English-language articles that included adult patients between 18 and 80 years old with minimal residual bone above the mandibular canal who had undergone inferior alveolar nerve (IAN repositioning with a minimum 6 months of follow-up. Results: A total of 16 studies were included in this review. Nine were related to IAN transposition, 4 to IAN lateralization and 3 to both transposition and lateralization. Implant treatment results and complications were presented. Conclusions: Inferior alveolar nerve lateralization and transposition in combination with the installation of dental implants is sometimes the only possible procedure to help patients to obtain a fixed prosthesis, in edentulous atrophic posterior mandibles. With careful pre-operative surgical and prosthetic planning, imaging, and extremely precise surgical technique, this procedure can be successfully used for implant placement in edentulous posterior mandibular segments.

  9. Infraorbital nerve transposition to expand the endoscopic transnasal maxillectomy.

    Science.gov (United States)

    Salzano, Giovanni; Turri-Zanoni, Mario; Karligkiotis, Apostolos; Zocchi, Jacopo; Dell'Aversana Orabona, Giovanni; Califano, Luigi; Battaglia, Paolo; Castelnuovo, Paolo

    2017-02-01

    The infraorbital nerve (ION) is a terminal branch of the maxillary nerve (V2) providing sensory innervation to the malar skin. It is sometimes necessary to sacrifice the ION and its branches to obtain adequate maxillary sinus exposure for radical resection of sinonasal tumors. Consequently, patients suffer temporary or permanent paresthesia, hypoestesthia, and neuralgia of the face. We describe an innovative technique used for preservation of the ION while removing the anterior, superior, and lateral walls of the maxillary sinus through a medial endoscopic transnasal maxillectomy. All patients who underwent transnasal endoscopic maxillectomy with ION transposition in our institute were retrospectively reviewed. Two patients were identified who had been treated for sinonasal cancers using this approach. No major complications were observed. Transient loss of ION function was observed with complete recovery of skin sensory perception within 6 months of surgery. One patient referred to a mild permanent anesthesia of the upper incisors. No diplopia or enophthalmos were encountered in any of the patients. The ION transposition is useful for selected cases of benign and malignant sinonasal tumors that do not infiltrate the ION itself but involve the surrounding portion of the maxillary sinus. Anatomic preservation of the ION seems to be beneficial to the postoperative quality of life of such patients. © 2016 ARS-AAOA, LLC.

  10. The morphology of the coronary sinus in patients with congenitally corrected transposition: implications for cardiac catheterisation and re-synchronisation therapy.

    Science.gov (United States)

    Aiello, Vera D; Ferreira, Flávia C N; Scanavacca, Mauricio I; Anderson, Robert H; D'Avila, André

    2016-02-01

    Patients with congenitally corrected transposition frequently benefit from re-synchronisation therapy or ablation procedures. This is likely to require catheterisation of the coronary sinus. Its anatomy, however, is not always appreciated, despite being well-described. With this caveat in mind, we have evaluated its location and structure in hearts with congenitally corrected transposition in order to reinforce the guidance needed by the cardiac interventionist. We dissected and inspected the coronary sinus, the oblique vein of the left atrium, and the left-sided-circumflex venous channel in eight heart specimens with corrected transposition and eight controls, measuring the orifice and length of the sinus and the atrioventricular valves. In two-thirds of the malformed hearts, the sinus deviated from its anticipated course in the atrioventricular groove, ascending obliquely on the left atrial inferior wall to meet the left oblique vein. The maximal deviation coincided in all hearts with the point where the left oblique vein joined the left-sided-circumflex vein to form the coronary sinus. We describe a circumflex vein, rather than the great cardiac vein, as the latter venous channel is right-sided in the setting of corrected transposition. The length of the sinus correlated positively with the diameter of the tricuspid valve (p=0.02). Compared with controls, the left oblique vein in the malformed hearts joined the circumflex venous channel significantly closer to the mouth of the sinus. The unexpected course of the coronary sinus in corrected transposition and the naming of the cardiac veins have important implications for venous cannulation and interpretation of images.

  11. Improving the accuracy of flood forecasting with transpositions of ensemble NWP rainfall fields considering orographic effects

    Science.gov (United States)

    Yu, Wansik; Nakakita, Eiichi; Kim, Sunmin; Yamaguchi, Kosei

    2016-08-01

    The use of meteorological ensembles to produce sets of hydrological predictions increased the capability to issue flood warnings. However, space scale of the hydrological domain is still much finer than meteorological model, and NWP models have challenges with displacement. The main objective of this study to enhance the transposition method proposed in Yu et al. (2014) and to suggest the post-processing ensemble flood forecasting method for the real-time updating and the accuracy improvement of flood forecasts that considers the separation of the orographic rainfall and the correction of misplaced rain distributions using additional ensemble information through the transposition of rain distributions. In the first step of the proposed method, ensemble forecast rainfalls from a numerical weather prediction (NWP) model are separated into orographic and non-orographic rainfall fields using atmospheric variables and the extraction of topographic effect. Then the non-orographic rainfall fields are examined by the transposition scheme to produce additional ensemble information and new ensemble NWP rainfall fields are calculated by recombining the transposition results of non-orographic rain fields with separated orographic rainfall fields for a generation of place-corrected ensemble information. Then, the additional ensemble information is applied into a hydrologic model for post-flood forecasting with a 6-h interval. The newly proposed method has a clear advantage to improve the accuracy of mean value of ensemble flood forecasting. Our study is carried out and verified using the largest flood event by typhoon 'Talas' of 2011 over the two catchments, which are Futatsuno (356.1 km2) and Nanairo (182.1 km2) dam catchments of Shingu river basin (2360 km2), which is located in the Kii peninsula, Japan.

  12. Imprinted genes and transpositions: epigenomic targets for low dose radiation effects. Final report

    International Nuclear Information System (INIS)

    Jirtle, Randy L.

    2012-01-01

    The overall hypothesis of this grant application is that low dose ionizing radiation (LDIR) elicits adaptive responses in part by causing heritable DNA methylation changes in the epigenome. This novel postulate was tested by determining if the level of DNA methylation at the Agouti viable yellow (A vy ) metastable locus is altered, in a dose-dependent manner, by low dose radiation exposure ( vy locus in a sex-specific manner (p=0.004). Average DNA methylation was significantly increased in male offspring exposed to doses between 0.7 cGy and 7.6 cGy with maximum effects at 1.4 cGy and 3.0 cGy (p<0.01). Offspring coat color was concomitantly shifted towards pseudoagouti (p<0.01). Maternal dietary antioxidant supplementation mitigated both the DNA methylation changes and coat color shift in the irradiated offspring (p<0.05). Thus, LDIR exposure during gestation elicits epigenetic alterations that lead to positive adaptive phenotypic changes that are negated with antioxidants, indicating they are mediated in part by oxidative stress. These findings provide evidence that in the isogenic Avy mouse model epigenetic alterations resulting from LDIR play a role in radiation hormesis, bringing into question the assumption that every dose of radiation is harmful. Our findings not only have significant implications concerning the mechanism of hormesis, but they also emphasize the potential importance of this phenomenon in determining human risk at low radiation doses. Since the epigenetic regulation of genes varies markedly between species, the effect of LDIR on other epigenetically labile genes (e.g. imprinted genes) in animals and humans needs to be defined

  13. An original procedure for balanus repair with transposition of the testis

    Directory of Open Access Journals (Sweden)

    D. G. Kurbatov

    2016-01-01

    Full Text Available The paper presents the unique clinical experience of successful sexual rehabilitation of a patient who has undergone penile amputation for cancer. Complex reconstruction of all parts of the lost organ, by using known methods and those proposed for the first time in global practice (balanus repair with transposition of the testis, was performed in the patient.

  14. Transactivation of Ds by Ac-transposase gene fusions in tobacco

    NARCIS (Netherlands)

    Rommens, Caius M.T.; Haaren, Mark J.J. van; Buchel, Annemarie S.; Mol, Joseph N.M.; Tunen, Arjen J. van; Nijkamp, H. John J.; Hille, Jacques

    1992-01-01

    To study regulation of the (Ds) transposition process in heterologous plant species, the transposase gene of Ac was fused to several promoters that are active late during plant development. These promoters are the flower-specific chalcone synthase A promoter (CHS A), the anther-specific chalcone

  15. Superior Oblique Anterior Transposition with Horizontal Recti Recession-Resection for Total Third-Nerve Palsy

    Directory of Open Access Journals (Sweden)

    Muhsin Eraslan

    2015-01-01

    Full Text Available Aims. To report the results of lateral rectus muscle recession, medial rectus muscle resection, and superior oblique muscle transposition in the restoration and maintenance of ocular alignment in primary position for patients with total third-nerve palsy. Methods. The medical records of patients who underwent surgery between March 2007 and September 2011 for total third-nerve palsy were reviewed. All patients underwent a preoperative assessment, including a detailed ophthalmologic examination. Results. A total of 6 patients (age range, 14–45 years were included. The median preoperative horizontal deviation was 67.5 Prism Diopter (PD (interquartile range [IQR] 57.5–70 and vertical deviation was 13.5 PD (IQR 10–20. The median postoperative horizontal residual exodeviation was 8.0 PD (IQR 1–16, and the vertical deviation was 0 PD (IQR 0–4. The median correction of hypotropia following superior oblique transposition was 13.5 ± 2.9 PD (range, 10–16. All cases were vertically aligned within 5 PD. Four of the six cases were aligned within 10 PD of the horizontal deviation. Adduction and head posture were improved in all patients. All patients gained new area of binocular single vision in the primary position after the operation. Conclusion. Lateral rectus recession, medial rectus resection, and superior oblique transposition may be used to achieve satisfactory cosmetic and functional results in total third-nerve palsy.

  16. Character Decomposition and Transposition Processes in Chinese Compound Words Modulates Attentional Blink.

    Science.gov (United States)

    Cao, Hongwen; Gao, Min; Yan, Hongmei

    2016-01-01

    The attentional blink (AB) is the phenomenon in which the identification of the second of two targets (T2) is attenuated if it is presented less than 500 ms after the first target (T1). Although the AB is eliminated in canonical word conditions, it remains unclear whether the character order in compound words affects the magnitude of the AB. Morpheme decomposition and transposition of Chinese two-character compound words can provide an effective means to examine AB priming and to assess combinations of the component representations inherent to visual word identification. In the present study, we examined the processing of consecutive targets in a rapid serial visual presentation (RSVP) paradigm using Chinese two-character compound words in which the two characters were transposed to form meaningful words or meaningless combinations (reversible, transposed, or canonical words). We found that when two Chinese characters that form a compound word, regardless of their order, are presented in an RSVP sequence, the likelihood of an AB for the second character is greatly reduced or eliminated compared to when the two characters constitute separate words rather than a compound word. Moreover, the order of the report for the two characters is more likely to be reversed when the normal order of the two characters in a compound word is reversed, especially when the interval between the presentation of the two characters is extremely short. These findings are more consistent with the cognitive strategy hypothesis than the resource-limited hypothesis during character decomposition and transposition of Chinese two-character compound words. These results suggest that compound characters are perceived as a unit, rather than two separate words. The data further suggest that readers could easily understand the text with character transpositions in compound words during Chinese reading.

  17. Endovascular management of recurrent stenosis following left renal vein transposition for the treatment of Nutcracker syndrome.

    Science.gov (United States)

    Baril, Donald T; Polanco, Patricio; Makaroun, Michel S; Chaer, Rabih A

    2011-04-01

    Nutcracker syndrome is an entity resulting from left renal vein compression by the superior mesenteric artery and the aorta, leading to symptoms of left flank pain and hematuria. Conventional treatment has been surgical, commonly through transposition of the left renal vein to a more caudal location on the inferior vena cava. Additionally, endovascular approaches, primarily via renal vein stenting, have been described for treatment of this syndrome. We report the case of a patient with Nutcracker syndrome who underwent successful left renal vein transposition but then developed recurrent symptoms 10 months postoperatively and was successfully treated with angioplasty and stenting. Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

  18. A nucleolus-predominant piggyBac transposase, NP-mPB, mediates elevated transposition efficiency in mammalian cells.

    Science.gov (United States)

    Hong, Jin-Bon; Chou, Fu-Ju; Ku, Amy T; Fan, Hsiang-Hsuan; Lee, Tung-Lung; Huang, Yung-Hsin; Yang, Tsung-Lin; Su, I-Chang; Yu, I-Shing; Lin, Shu-Wha; Chien, Chung-Liang; Ho, Hong-Nerng; Chen, You-Tzung

    2014-01-01

    PiggyBac is a prevalent transposon system used to deliver transgenes and functionally explore the mammalian untouched genomic territory. The important features of piggyBac transposon are the relatively low insertion site preference and the ability of seamless removal from genome, which allow its potential uses in functional genomics and regenerative medicine. Efforts to increase its transposition efficiency in mammals were made through engineering the corresponding transposase (PBase) codon usage to enhance its expression level and through screening for mutant PBase variants with increased enzyme activity. To improve the safety for its potential use in regenerative medicine applications, site-specific transposition was achieved by using engineered zinc finger- and Gal4-fused PBases. An excision-prone PBase variant has also been successfully developed. Here we describe the construction of a nucleolus-predominant PBase, NP-mPB, by adding a nucleolus-predominant (NP) signal peptide from HIV-1 TAT protein to a mammalian codon-optimized PBase (mPB). Although there is a predominant fraction of the NP-mPB-tGFP fusion proteins concentrated in the nucleoli, an insertion site preference toward nucleolar organizer regions is not detected. Instead a 3-4 fold increase in piggyBac transposition efficiency is reproducibly observed in mouse and human cells.

  19. Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa

    Science.gov (United States)

    Daiger, Stephen P.; Bowne, Sara J.; Sullivan, Lori S.

    2015-01-01

    Retinitis pigmentosa (RP) has a prevalence of approximately one in 4000; 25%–30% of these cases are autosomal dominant retinitis pigmentosa (adRP). Like other forms of inherited retinal disease, adRP is exceptionally heterogeneous. Mutations in more than 25 genes are known to cause adRP, more than 1000 mutations have been reported in these genes, clinical findings are highly variable, and there is considerable overlap with other types of inherited disease. Currently, it is possible to detect disease-causing mutations in 50%–75% of adRP families in select populations. Genetic diagnosis of adRP has advantages over other forms of RP because segregation of disease in families is a useful tool for identifying and confirming potentially pathogenic variants, but there are disadvantages too. In addition to identifying the cause of disease in the remaining 25% of adRP families, a central challenge is reconciling clinical diagnosis, family history, and molecular findings in patients and families. PMID:25304133

  20. Is there an anatomic basis for subvalvular right ventricular outflow tract obstruction after an arterial switch repair for complete transposition? A morphometric study and review

    NARCIS (Netherlands)

    Akiba, T.; Neirotti, R.; Becker, A. E.

    1993-01-01

    The study was initiated by reports on right ventricular outflow tract obstruction in complete transposition of the great arteries after an arterial switch repair. We investigated 39 heart specimens with native, unoperated transposition of the great arteries. Of these, 14 hearts had a ventricular

  1. Transcription and somatic transposition of the maize En/Spm transposon system in rice

    NARCIS (Netherlands)

    Greco, R.; Ouwerkerk, P.B.F.; Taal, A.J.C.; Sallaud, C.; Guiderdoni, E.; Meijer, A.H.; Hoge, J.H.C.; Pereira, A.B.

    2004-01-01

    Transposition of the maize En/Spm system in rice was investigated using a two-component construct consisting of an immobilised transposase source driven by the CaMV 35S-promoter, and a modified I/dSpm transposon. Mobilization of I/dSpm in somatic sectors was demonstrated by sequencing of excision

  2. Letter-Transposition Effects Are Not Universal: The Impact of Transposing Letters in Hebrew

    Science.gov (United States)

    Velan, Hadas; Frost, Ram

    2009-01-01

    We examined the effects of letter-transposition in Hebrew in three masked-priming experiments. Hebrew, like English has an alphabetic orthography where sequential and contiguous letter strings represent phonemes. However, being a Semitic language it has a non-concatenated morphology that is based on root derivations. Experiment 1 showed that…

  3. Effect of lateral release and tibial tuberosity transposition on the patellar tilt analyzed by MRI

    International Nuclear Information System (INIS)

    Koskinen, S.; Kormano, M.; Kujala, U.M.; Research Institute for Sports and Exercise Medicine, Helsinki; City Hospital, Turku

    1990-01-01

    The preliminary results are presented from studies in which MRI techniques are used to analyze the effect of lateral release and tibial tuberosity transposition procedures on the patellofemoral relationships. (author). 4 refs.; 1 fig.; 1 tab

  4. Germline transgenic pigs by Sleeping Beauty transposition in porcine zygotes and targeted integration in the pig genome.

    Directory of Open Access Journals (Sweden)

    Wiebke Garrels

    Full Text Available Genetic engineering can expand the utility of pigs for modeling human diseases, and for developing advanced therapeutic approaches. However, the inefficient production of transgenic pigs represents a technological bottleneck. Here, we assessed the hyperactive Sleeping Beauty (SB100X transposon system for enzyme-catalyzed transgene integration into the embryonic porcine genome. The components of the transposon vector system were microinjected as circular plasmids into the cytoplasm of porcine zygotes, resulting in high frequencies of transgenic fetuses and piglets. The transgenic animals showed normal development and persistent reporter gene expression for >12 months. Molecular hallmarks of transposition were confirmed by analysis of 25 genomic insertion sites. We demonstrate germ-line transmission, segregation of individual transposons, and continued, copy number-dependent transgene expression in F1-offspring. In addition, we demonstrate target-selected gene insertion into transposon-tagged genomic loci by Cre-loxP-based cassette exchange in somatic cells followed by nuclear transfer. Transposase-catalyzed transgenesis in a large mammalian species expands the arsenal of transgenic technologies for use in domestic animals and will facilitate the development of large animal models for human diseases.

  5. Internal obturator muscle transposition for treatment of perineal hernia in dogs: 34 cases (1998-2012).

    Science.gov (United States)

    Shaughnessy, Magen; Monnet, Eric

    2015-02-01

    To evaluate the outcome of dogs with perineal hernia treated with transposition of the internal obturator muscle. Retrospective case series. 34 dogs. Medical records of dogs with perineal hernia surgically treated from 1998 to 2012 were reviewed. Diagnostic methods and surgical techniques were recorded. Dogs were assigned preoperative and postoperative clinical sign scores. Complication and recurrence rates were evaluated over time. Risk factors were determined. Median follow-up time was 345 days (range, 22 to 1,423 days). Complications were observed in 10 dogs. Tenesmus (n = 9), dyschezia (7), fecal impaction (3), stranguria (4), hematochezia (2), urinary incontinence (2), diarrhea (1), urinary tract infection (1), and megacolon (1) occurred following surgery. Bladder retroflexion at the time of initial evaluation or surgery was not a risk factor for complication (hazard ratio, 1.72). One year after surgery, 51.2% dogs were free of complications. Three dogs developed a perineal hernia on the contralateral side between 35 and 95 days after surgery. The 1-year recurrence rate was 27.4%. Median time for recurrence was 28 days after surgery (range, 2 to 364 days). Postoperative tenesmus was a risk factor for the development of recurrence (hazard ratio, 2.29). Internal obturator muscle transposition was used for primary repair of perineal hernia in dogs. Recurrence was recorded as long as 1 year after surgery. Tenesmus was a risk factor for the development of recurrence after treatment of perineal hernia with internal obturator muscle transposition.

  6. Imprinted genes and transpositions: epigenomic targets for low dose radiation effects. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Jirtle, Randy L.

    2012-10-11

    The overall hypothesis of this grant application is that low dose ionizing radiation (LDIR) elicits adaptive responses in part by causing heritable DNA methylation changes in the epigenome. This novel postulate was tested by determining if the level of DNA methylation at the Agouti viable yellow (A{sup vy}) metastable locus is altered, in a dose-dependent manner, by low dose radiation exposure (<10 cGy) during early gestation. This information is particularly important to ascertain given the increased use of CT scans in disease diagnosis, increased number of people predicted to live and work in space, and the present concern about radiological terrorism. We showed for the first time that LDIR significantly increased DNA methylation at the A{sup vy} locus in a sex-specific manner (p=0.004). Average DNA methylation was significantly increased in male offspring exposed to doses between 0.7 cGy and 7.6 cGy with maximum effects at 1.4 cGy and 3.0 cGy (p<0.01). Offspring coat color was concomitantly shifted towards pseudoagouti (p<0.01). Maternal dietary antioxidant supplementation mitigated both the DNA methylation changes and coat color shift in the irradiated offspring (p<0.05). Thus, LDIR exposure during gestation elicits epigenetic alterations that lead to positive adaptive phenotypic changes that are negated with antioxidants, indicating they are mediated in part by oxidative stress. These findings provide evidence that in the isogenic Avy mouse model epigenetic alterations resulting from LDIR play a role in radiation hormesis, bringing into question the assumption that every dose of radiation is harmful. Our findings not only have significant implications concerning the mechanism of hormesis, but they also emphasize the potential importance of this phenomenon in determining human risk at low radiation doses. Since the epigenetic regulation of genes varies markedly between species, the effect of LDIR on other epigenetically labile genes (e.g. imprinted genes) in

  7. Congenital Hypothyroidism Caused by a PAX8 Gene Mutation Manifested as Sodium/Iodide Symporter Gene Defect

    Directory of Open Access Journals (Sweden)

    Wakako Jo

    2010-01-01

    Full Text Available Loss-of-function mutations of the PAX8 gene are considered to mainly cause congenital hypothyroidism (CH due to thyroid hypoplasia. However, some patients with PAX8 mutation have demonstrated a normal-sized thyroid gland. Here we report a CH patient caused by a PAX8 mutation, which manifested as iodide transport defect (ITD. Hypothyroidism was detected by neonatal screening and L-thyroxine replacement was started immediately. Although 123I scintigraphy at 5 years of age showed that the thyroid gland was in the normal position and of small size, his iodide trapping was low. The ratio of the saliva/plasma radioactive iodide was low. He did not have goiter; however laboratory findings suggested that he had partial ITD. Gene analyses showed that the sodium/iodide symporter (NIS gene was normal; instead, a mutation in the PAX8 gene causing R31H substitution was identified. The present report demonstrates that individuals with defective PAX8 can have partial ITD, and thus genetic analysis is useful for differential diagnosis.

  8. Anterior subcutaneous transposition of the ulnar nerve improves neurological function in patients with cubital tunnel syndrome

    Directory of Open Access Journals (Sweden)

    Wei Huang

    2015-01-01

    Full Text Available Although several surgical procedures exist for treating cubital tunnel syndrome, the best surgical option remains controversial. To evaluate the efficacy of anterior subcutaneous transposition of the ulnar nerve in patients with moderate to severe cubital tunnel syndrome and to analyze prognostic factors, we retrospectively reviewed 62 patients (65 elbows diagnosed with cubital tunnel syndrome who underwent anterior subcutaneous transposition. Preoperatively, the initial severity of the disease was evaluated using the McGowan scale as modified by Goldberg: 18 patients (28% had grade IIA neuropathy, 20 (31% had grade IIB, and 27 (42% had grade III. Postoperatively, according to the Wilson & Krout criteria, treatment outcomes were excellent in 38 patients (58%, good in 16 (25%, fair in 7 (11%, and poor in 4 (6%, with an excellent and good rate of 83%. A negative correlation was found between the preoperative McGowan grade and the postoperative Wilson & Krout score. The patients having fair and poor treatment outcomes had more advanced age, lower nerve conduction velocity, and lower action potential amplitude compared with those having excellent and good treatment outcomes. These results suggest that anterior subcutaneous transposition of the ulnar nerve is effective and safe for the treatment of moderate to severe cubital tunnel syndrome, and initial severity, advancing age, and electrophysiological parameters can affect treatment outcome.

  9. Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion

    NARCIS (Netherlands)

    Jonkman, MF; Scheffer, H; Stulp, R; Pas, HH; Nijenhuis, Albertine; Heeres, K; Owaribe, K; Pulkkinen, L; Uitto, J

    1997-01-01

    Mitotic gene conversion acting as reverse mutation has not been previously demonstrated in human. We report here that the revertant mosaicism of a compound heterozygous proband with an autosomal recessive genodermatosis, generalized atrophic benign epidermolysis bullosa, is caused by mitotic gene

  10. Comparison of systemic right ventricular function in transposition of the great arteries after atrial switch and congenitally corrected transposition of the great arteries.

    Science.gov (United States)

    Morcos, Michael; Kilner, Philip J; Sahn, David J; Litt, Harold I; Valsangiacomo-Buechel, Emanuela R; Sheehan, Florence H

    2017-12-01

    In patients with transposition of the great arteries corrected by interatrial baffle (TGA) and those with congenitally corrected transposition of the great arteries (ccTGA) the right ventricle (RV) is subjected to systemic pressure and fails prematurely. Previous studies have demonstrated RV dysfunction may be more pronounced in patients with TGA. The present study sought to compare patients with TGA and ccTGA using three-dimensional (3D) techniques to comprehensively analyze the shape, volume, global and regional function in the systemic RV. We compared RV size, shape, and regional and global function in 25 patients with TGA, 17 patients with ccTGA, and 9 normal subjects. The RVs were reconstructed from cardiac Magnetic Resonance Images for 3D analyses. Compared to normal, the RV in TGA and ccTGA was dilated, rounded, and reduced in function. Compared to each other, TGA and ccTGA patients had similar RV size and shape. Global RV function was lower in TGA than ccTGA when assessed from ejection fraction (EF) (30 ± 7 vs. 35 ± 7, p = 0.02) and from normalized tricuspid annular systolic plane excursion (TAPSE) (0.10 ± 0.04 vs. 0.18 ± 0.04, p < 0.01). Basilar RV function was poorer in the TGA patients when compared to ccTGA. The systemic RVs in both TGA and ccTGA are dilated, spherical, and poorly functioning. Compared to ccTGA, TGA RVs have reduced TAPSE and worse basilar hypokinesis.

  11. Differential gene expression patterns between smokers and non-smokers : cause or consequence?

    NARCIS (Netherlands)

    Vink, Jacqueline M; Jansen, Rick; Brooks, Andy; Willemsen, Gonneke; van Grootheest, Gerard; de Geus, Eco; Smit, Jan H; Penninx, Brenda W; Boomsma, Dorret I

    The molecular mechanisms causing smoking-induced health decline are largely unknown. To elucidate the molecular pathways involved in cause and consequences of smoking behavior, we conducted a genome-wide gene expression study in peripheral blood samples targeting 18 238 genes. Data of 743 smokers,

  12. Differential gene expression patterns between smokers and non-smokers: Cause or consequence?

    NARCIS (Netherlands)

    Vink, J.M.; Jansen, R.; Brooks, A.I.; Willemsen, G.; Grootheest, G. van; Geus, E.J.C. de; Smit, J.H.; Penninx, B.W.J.H.; Boomsma, D.I.

    2017-01-01

    The molecular mechanisms causing smoking-induced health decline are largely unknown. To elucidate the molecular pathways involved in cause and consequences of smoking behavior, we conducted a genome-wide gene expression study in peripheral blood samples targeting 18 238 genes. Data of 743 smokers,

  13. Echocardiographic diagnosis of transposition of the great arteries associated with anomalous pulmonary venous connection

    Directory of Open Access Journals (Sweden)

    Lilian Maria Lopes

    2001-07-01

    Full Text Available We report 2 cases of transposition of the great arteries associated with anomalous pulmonary venous connection emphasizing the clinical findings, the diagnosis, and the evolution of the association. One of the patients had the anomalous pulmonary venous connection in its total infradiaphragmatic form, in the portal system, and the other patient had a partial form, in which an anomalous connection of the left superior lobar vein with the innominate vein existed. At the time of hospital admission, the patients had cyanosis and respiratory distress with clinical findings suggesting transposition of the great arteries. The diagnosis in 1 of the cases, in which the anomalous connection was partial, was established only with echocardiography, without invasive procedures that would represent risk for the patient; in the other case, in which the anomalous connection was total, the malformation was only evidenced with catheterization. The patients underwent surgery for anatomical correction of the heart disease. Only 1 patient had a good outcome.

  14. Implementation of Super-Encryption with Trithemius Algorithm and Double Transposition Cipher in Securing PDF Files on Android Platform

    Science.gov (United States)

    Budiman, M. A.; Rachmawati, D.; Jessica

    2018-03-01

    This study aims to combine the trithemus algorithm and double transposition cipher in file security that will be implemented to be an Android-based application. The parameters being examined are the real running time, and the complexity value. The type of file to be used is a file in PDF format. The overall result shows that the complexity of the two algorithms with duper encryption method is reported as Θ (n 2). However, the processing time required in the encryption process uses the Trithemius algorithm much faster than using the Double Transposition Cipher. With the length of plaintext and password linearly proportional to the processing time.

  15. Misfits and compliance patterns in the transposition and implementation of the Habitats Directive—four cases

    NARCIS (Netherlands)

    Frederiksen, Pia; Sluis, van der Theo; Vadineanu, Angheluta; Terkenli, Theano S.; Gaube, Veronika; Gravsholt Busck, Anne; Vesterager, Jens Peter; Geamana, Nicoleta; Schistou, Despoina E.; Pedroli, Bas

    2017-01-01

    This paper investigates the transposition and implementation of the Habitats Directive in four European member states, namely Denmark, the Netherlands, Greece, and Romania, and the role that institutional misfits have played in more or less successful implementation processes. Departing in the

  16. Feasibility of transposition of the ovaries in the surgical and radiotherapeutical treatment of cervical cancer

    NARCIS (Netherlands)

    van Beurden, M.; Schuster-Uitterhoeve, A. L.; Lammes, F. B.

    1990-01-01

    Ovaries are seldom subject to metastases and therefore their preservation is possible in radical cervical cancer surgery. However, with postoperative radiotherapy they cannot be preserved unless they are placed outside the radiation field. The practicality of this transposition was analysed in a

  17. Axillary Reconstruction for Hidradenitis Suppurativa with an Inner-Arm Transposition Flap Creating a Brachioplasty Effect

    Directory of Open Access Journals (Sweden)

    Daniel L. Ching

    2017-05-01

    Full Text Available BackgroundHidradenitis suppurativa (HS is a chronic skin condition that can affect any area with apocrine sweat glands and has the potential to involve multiple sites concurrently. Commonly affected sites include the axilla, groin, perineum and perianal areas. In this study we performed a literature review on the surgical methods for HS and describe an innovative technique for reconstructing axilla HS using an inner-arm transposition flap.MethodsWe reviewed all cases (5 cases from 4 patients of transposition flap reconstruction performed by the senior author at a single London tertiary hospital from 2008–2013. Patient related outcome measures were collected using the Derriford appearance scale (DAS 24 and a study specific questionnaire.ResultsAll patients were satisfied with their final result. One out of five cases had a complication but did not result in flap failure. There is no disease recurrence to date. DAS 24 scores collected demonstrated acceptable postoperative distress that did not deviate far from the norm tables while study specific questionnaire reveal desirable outcomes.ConclusionsWe have managed to achieve our aim through the use of the innovative inner-arm transposition flap. Our study hopes to provide an additional technique for axillary reconstruction. This technique offers the effective concealment of scars with the benefit of tightening of the arm tissue producing ‘brachioplasty like’ effects. All things considered it would be reasonable to conclude the innovative flap technique is a reliable, effective, and simple method that results in multiple benefits.

  18. Deletion of the pluripotency-associated Tex19.1 gene causes activation of endogenous retroviruses and defective spermatogenesis in mice

    DEFF Research Database (Denmark)

    Ollinger, Rupert; Childs, Andrew J; Burgess, Hannah M

    2008-01-01

    . During male spermatogenesis, Tex19.1 expression is highest in mitotic spermatogonia and diminishes as these cells differentiate and progress through meiosis. In pluripotent stem cells, Tex19.1 expression is also downregulated upon differentiation. However, it is not clear whether Tex19.1 has an essential...... spermatogenesis. Immunostaining and histological analysis revealed defects in meiotic chromosome synapsis, the persistence of DNA double-strand breaks during meiosis, and a loss of post-meiotic germ cells in the testis. Furthermore, expression of a class of endogenous retroviruses is upregulated during meiosis...... in the Tex19.1(-/-) testes. Increased transposition of endogenous retroviruses in the germline of Tex19.1(-/-) mutant mice, and the concomitant increase in DNA damage, may be sufficient to disrupt the normal processes of recombination and chromosome synapsis during meiosis and cause defects...

  19. An unreported type of coronary artery naomaly in congenitally corrected transposition of great arteries

    Energy Technology Data Exchange (ETDEWEB)

    Kwak, Min Kyu; Jeong, Yeon Joo; Lee, Gee Won; Lee, Nam Kyung; Choi, Jung Hyun; Lee, Ji Won [Medical Research Institute, Pusan National University Hospital, Busan (Korea, Republic of)

    2016-07-15

    Coronary artery variations are associated anomalies in 45% of congenitally corrected transposition of the great arteries (ccTGA) cases, and it is important to detect any coronary artery anomalies before cardiac surgery. We report a case of a 51-year-old woman with ccTGA and an unreported type of coronary artery anomaly.

  20. KMeyeDB: a graphical database of mutations in genes that cause eye diseases.

    Science.gov (United States)

    Kawamura, Takashi; Ohtsubo, Masafumi; Mitsuyama, Susumu; Ohno-Nakamura, Saho; Shimizu, Nobuyoshi; Minoshima, Shinsei

    2010-06-01

    KMeyeDB (http://mutview.dmb.med.keio.ac.jp/) is a database of human gene mutations that cause eye diseases. We have substantially enriched the amount of data in the database, which now contains information about the mutations of 167 human genes causing eye-related diseases including retinitis pigmentosa, cone-rod dystrophy, night blindness, Oguchi disease, Stargardt disease, macular degeneration, Leber congenital amaurosis, corneal dystrophy, cataract, glaucoma, retinoblastoma, Bardet-Biedl syndrome, and Usher syndrome. KMeyeDB is operated using the database software MutationView, which deals with various characters of mutations, gene structure, protein functional domains, and polymerase chain reaction (PCR) primers, as well as clinical data for each case. Users can access the database using an ordinary Internet browser with smooth user-interface, without user registration. The results are displayed on the graphical windows together with statistical calculations. All mutations and associated data have been collected from published articles. Careful data analysis with KMeyeDB revealed many interesting features regarding the mutations in 167 genes that cause 326 different types of eye diseases. Some genes are involved in multiple types of eye diseases, whereas several eye diseases are caused by different mutations in one gene.

  1. Bilateral Superior Labial Mucosal Transposition Flaps to Correct Stenosis of the Nares Following Bilateral Rostral Maxillectomy Combined with Nasal Planum Resection in a Dog.

    Science.gov (United States)

    Séguin, Bernard; Steinke, Julia R

    2016-04-01

    To describe a technique using labial mucosal flaps to correct stenosis of the nares subsequent to bilateral rostral maxillectomy and nasal planum resection. Case report Client-owned dog. A 10-year-old, neutered male Golden Retriever developed repeated stenosis of the nares, at first after bilateral rostral maxillectomy and nasal planum resection, and again after revision surgery. Bilateral, superior labial mucosal transposition flaps were created and interpolated between the nasal mucosa and skin after debridement of scar tissue. The stenosis did not recur after mucosal flap transposition and the dog returned to normal quality of life (last follow-up 25 months postoperative). Single-stage, superior labial mucosal transposition flaps can be used to correct nares stenosis subsequent to previous surgery. © Copyright 2016 by The American College of Veterinary Surgeons.

  2. The challenge of staphylococcal pacemaker endocarditis in a patient with transposition of the great arteries endocarditis in congenital heart disease

    International Nuclear Information System (INIS)

    Ch'ng, Julie; Chan, William; Lee, Paul; Joshi, Subodh; Grigg, Leanne E.; Ajani, Andrew E.

    2003-01-01

    Staphylococcus aureus is a leading cause of septicaemia and infective endocarditis. The overall incidence of staphylococcal bacteraemia is increasing, contributing to 16% of all hospital-acquired bacteraemias. The use of cardiac pacemakers has revolutionized the management of rhythm disturbances, yet this has also resulted in a group of patients at risk of pacemaker lead endocarditis and seeding in the range of 1% to 7%. We describe a 26-year-old man with transposition of the great arteries who had a pacemaker implanted and presented with S. aureus septicaemia 2 years postpacemaker implantation and went on to develop pacemaker lead endocarditis. This report illustrates the risk of endocarditis in the population with congenital heart disease and an intracardiac device

  3. Transposition of the gas directive in French law

    International Nuclear Information System (INIS)

    Anon.

    2002-01-01

    On September 25, 2002, the French government adopted the project of law relative to the energy markets. This project of law takes up the essential part of the measures proposed by the directive no 98/30/CE of the European Union from June 22, 1998, about the 'common rules of the internal natural gas market'. This paper makes a brief comment of the version of this project adopted by the senate. It presents also the position of the French gas association (AFG) about this transposition, its action during the first phase of the parliamentary debate, and what will be AFG's role after the enforcement of this law. Finally, a testimony of the Swiss society of gas and waters industry (SSIGE) about the opening of the natural gas market is given in conclusion. (J.S.)

  4. The natural history of congenitally corrected transposition of the great arteries.

    Science.gov (United States)

    Huhta, James

    2011-01-01

    The natural history of congenitally corrected transposition of the great arteries is of clinical/surgical importance once the fetus is born without heart block or signs of heart failure. Without significant tricuspid valve malformation, associated defects such as ventricular septal defect and left ventricular outflow obstruction can be repaired surgically. The mortality and long-term outcome appear to be linked strongly with the severity of tricuspid valve regurgitation. Some patients with an intact ventricular septum and no right ventricular dysfunction will live long lives without detection, and some women will successfully complete pregnancy.

  5. Mutations in the pericentrin (PCNT) gene cause primordial dwarfism

    NARCIS (Netherlands)

    Rauch, Anita; Thiel, Christian T.; Schindler, Detlev; Wick, Ursula; Crow, Yanick J.; Ekici, Arif B.; van Essen, Anthonie J.; Goecke, Timm O.; Al-Gazali, Lihadh; Chrzanowska, Krystyna H.; Zweier, Christiane; Brunner, Han G.; Becker, Kristin; Curry, Cynthia J.; Dallapiccola, Bruno; Devriendt, Koenraad; Doerfler, Arnd; Kinning, Esther; Megarbane, Andre; Meinecke, Peter; Semple, Robert K.; Spranger, Stephanie; Toutain, Annick; Trembath, Richard C.; Voss, Egbert; Wilson, Louise; Hennekam, Raoul; de Zegher, Francis; Doerr, Helmuth-Guenther; Reis, Andre

    2008-01-01

    Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss- of- function mutations in the centrosomal pericentrin ( PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial

  6. A New Generalizable Test for Detection of Mutations Affecting Tn10 Transposition

    OpenAIRE

    Huisman, Olivier; Kleckner, Nancy

    1987-01-01

    We describe here a new rapid screen that allows easy detection of transposon or host mutations that affect Tn10 transposition in Escherichia coli. This test involves a new Tn10 derivative called the "mini-lacZ-kanR fusion hopper" or mini-Tn10-LK for short. This element does not direct expression of β-galactosidase when present at its original starting location on a suitably engineered plasmid or phage genome because it lacks appropriate transcription and translation start signals. However, t...

  7. Differential gene expression patterns between smokers and non‐smokers: cause or consequence?

    Science.gov (United States)

    Jansen, Rick; Brooks, Andy; Willemsen, Gonneke; van Grootheest, Gerard; de Geus, Eco; Smit, Jan H.; Penninx, Brenda W.; Boomsma, Dorret I.

    2015-01-01

    Abstract The molecular mechanisms causing smoking‐induced health decline are largely unknown. To elucidate the molecular pathways involved in cause and consequences of smoking behavior, we conducted a genome‐wide gene expression study in peripheral blood samples targeting 18 238 genes. Data of 743 smokers, 1686 never smokers and 890 ex‐smokers were available from two population‐based cohorts from the Netherlands. In addition, data of 56 monozygotic twin pairs discordant for ever smoking were used. One hundred thirty‐two genes were differentially expressed between current smokers and never smokers (P smokers into account, expression of these 132 genes was classified into reversible (94 genes), slowly reversible (31 genes), irreversible (6 genes) or inconclusive (1 gene). Expression of 6 of the 132 genes (three reversible and three slowly reversible) was confirmed to be reactive to smoking as they were differentially expressed in monozygotic pairs discordant for smoking. Cis‐expression quantitative trait loci for GPR56 and RARRES3 (downregulated in smokers) were associated with increased number of cigarettes smoked per day in a large genome‐wide association meta‐analysis, suggesting a causative effect of GPR56 and RARRES3 expression on smoking behavior. In conclusion, differential gene expression patterns in smokers are extensive and cluster in several underlying disease pathways. Gene expression differences seem mainly direct consequences of smoking, and largely reversible after smoking cessation. However, we also identified DNA variants that may influence smoking behavior via the mediating gene expression. PMID:26594007

  8. Mutations in the pericentrin (PCNT) gene cause primordial dwarfism

    NARCIS (Netherlands)

    Rauch, Anita; Thiel, Christian T.; Schindler, Detlev; Wick, Ursula; Crow, Yanick J.; Ekici, Arif B.; van Essen, Anthonie J.; Goecke, Timm O.; Al-Gazali, Lihadh; Chrzanowska, Krystyna H.; Zweier, Christiane; Brunner, Han G.; Becker, Kristin; Curry, Cynthia J.; Dallapiccola, Bruno; Devriendt, Koenraad; Dörfler, Arnd; Kinning, Esther; Megarbane, André; Meinecke, Peter; Semple, Robert K.; Spranger, Stephanie; Toutain, Annick; Trembath, Richard C.; Voss, Egbert; Wilson, Louise; Hennekam, Raoul; de Zegher, Francis; Dörr, Helmuth-Günther; Reis, André

    2008-01-01

    Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism

  9. Mining tissue specificity, gene connectivity and disease association to reveal a set of genes that modify the action of disease causing genes

    Directory of Open Access Journals (Sweden)

    Reverter Antonio

    2008-09-01

    Full Text Available Abstract Background The tissue specificity of gene expression has been linked to a number of significant outcomes including level of expression, and differential rates of polymorphism, evolution and disease association. Recent studies have also shown the importance of exploring differential gene connectivity and sequence conservation in the identification of disease-associated genes. However, no study relates gene interactions with tissue specificity and disease association. Methods We adopted an a priori approach making as few assumptions as possible to analyse the interplay among gene-gene interactions with tissue specificity and its subsequent likelihood of association with disease. We mined three large datasets comprising expression data drawn from massively parallel signature sequencing across 32 tissues, describing a set of 55,606 true positive interactions for 7,197 genes, and microarray expression results generated during the profiling of systemic inflammation, from which 126,543 interactions among 7,090 genes were reported. Results Amongst the myriad of complex relationships identified between expression, disease, connectivity and tissue specificity, some interesting patterns emerged. These include elevated rates of expression and network connectivity in housekeeping and disease-associated tissue-specific genes. We found that disease-associated genes are more likely to show tissue specific expression and most frequently interact with other disease genes. Using the thresholds defined in these observations, we develop a guilt-by-association algorithm and discover a group of 112 non-disease annotated genes that predominantly interact with disease-associated genes, impacting on disease outcomes. Conclusion We conclude that parameters such as tissue specificity and network connectivity can be used in combination to identify a group of genes, not previously confirmed as disease causing, that are involved in interactions with disease causing

  10. Increased Ac excision (iae): Arabidopsis thaliana mutations affecting Ac transposition

    International Nuclear Information System (INIS)

    Jarvis, P.; Belzile, F.; Page, T.; Dean, C.

    1997-01-01

    The maize transposable element Ac is highly active in the heterologous hosts tobacco and tomato, but shows very much reduced levels of activity in Arabidopsis. A mutagenesis experiment was undertaken with the aim of identifying Arabidopsis host factors responsible for the observed low levels of Ac activity. Seed from a line carrying a single copy of the Ac element inserted into the streptomycin phosphotransferase (SPT) reporter fusion, and which displayed typically low levels of Ac activity, were mutagenized using gamma rays. Nineteen mutants displaying high levels of somatic Ac activity, as judged by their highly variegated phenotypes, were isolated after screening the M2 generation on streptomycin-containing medium. The mutations fall into two complementation groups, iae1 and iae2, are unlinked to the SPT::Ac locus and segregate in a Mendelian fashion. The iae1 mutation is recessive and the iae2 mutation is semi-dominant. The iae1 and iae2 mutants show 550- and 70-fold increases, respectively, in the average number of Ac excision sectors per cotyledon. The IAE1 locus maps to chromosome 2, whereas the SPT::Ac reporter maps to chromosome 3. A molecular study of Ac activity in the iae1 mutant confirmed the very high levels of Ac excision predicted using the phenotypic assay, but revealed only low levels of Ac re-insertion. Analyses of germinal transposition in the iae1 mutant demonstrated an average germinal excision frequency of 3% and a frequency of independent Ac re-insertions following germinal excision of 22%. The iae mutants represents a possible means of improving the efficiency of Ac/Ds transposon tagging systems in Arabidopsis, and will enable the dissection of host involvement in Ac transposition and the mechanisms employed for controlling transposable element activity

  11. Prevalence of coagulase gene polymorphism in Staphylococcus aureus isolates causing bovine mastitis

    DEFF Research Database (Denmark)

    Aarestrup, Frank Møller; Dangler, C. A.; Sordillo, L. M.

    1995-01-01

    This study was conducted to investigate polymorphism of the coagulase gene of Staphylococcus aureus causing bovine mastitis. One hundred eighty-seven strains of S. aureus were isolated from bovine mastitic milk samples obtained from 187 different Danish dairy farms. The isolates were characterised......% of the isolates. The ease of analysing coagulase gene polymorphisms among a large number of strains, and the multiple distinct polymorphic patterns generated, supports the use of this technique in epidemiological investigations of bovine mastitis. The predominating variants may have predelection for causing...

  12. Clinical study of DMD gene point mutation causing Becker muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Ji-qing CAO

    2015-07-01

    Full Text Available Background  DMD gene point mutation, mainly nonsense mutation, always cause the most severe Duchenne muscular dystrophy (DMD. However, we also observed some cases of Becker muscular dystrophy (BMD carrying DMD point mutation. This paper aims to explore the mechanism of DMD point mutation causing BMD, in order to enhance the understanding of mutation types of BMD.  Methods  Sequence analysis was performed in 11 cases of BMD confirmed by typical clinical manifestations and muscle biopsy. The exon of DMD gene was detected non-deletion or duplication by multiplex ligation-dependent probe amplification (MLPA.  Results  Eleven patients carried 10 mutation types without mutational hotspot. Six patients carried nonsense mutations [c.5002G>T, p.(Glu1668X; c.1615C > T, p.(Arg539X; c.7105G > T, p.(Glu2369X; c.5287C > T, p.(Arg1763X; c.9284T > G, p.(Leu3095X]. One patient carried missense mutation [c.5234G > A, p.(Arg1745His]. Two patients carried frameshift mutations (c.10231dupT, c.10491delC. Two patients carried splicing site mutations (c.4518 + 3A > T, c.649 + 2T > C.  Conclusions  DMD gene point mutation may result in BMD with mild clinical symptoms. When clinical manifestations suggest the possibility of BMD and MLPA reveals non?deletion or duplication mutation of DMD gene, BMD should be considered. Study on the mechanism of DMD point mutation causing BMD is very important for gene therapy of DMD. DOI: 10.3969/j.issn.1672-6731.2015.06.005

  13. Comparison of hemihypoglossal nerve versus masseteric nerve transpositions in the rehabilitation of short-term facial paralysis using the Facial Clima evaluating system.

    Science.gov (United States)

    Hontanilla, Bernardo; Marré, Diego

    2012-11-01

    Masseteric and hypoglossal nerve transfers are reliable alternatives for reanimating short-term facial paralysis. To date, few studies exist in the literature comparing these techniques. This work presents a quantitative comparison of masseter-facial transposition versus hemihypoglossal facial transposition with a nerve graft using the Facial Clima system. Forty-six patients with complete unilateral facial paralysis underwent reanimation with either hemihypoglossal transposition with a nerve graft (group I, n = 25) or direct masseteric-facial coaptation (group II, n = 21). Commissural displacement and commissural contraction velocity were measured using the Facial Clima system. Postoperative intragroup commissural displacement and commissural contraction velocity means of the reanimated versus the normal side were first compared using a paired sample t test. Then, mean percentages of recovery of both parameters were compared between the groups using an independent sample t test. Onset of movement was also compared between the groups. Significant differences of mean commissural displacement and commissural contraction velocity between the reanimated side and the normal side were observed in group I but not in group II. Mean percentage of recovery of both parameters did not differ between the groups. Patients in group II showed a significantly faster onset of movement compared with those in group I (62 ± 4.6 days versus 136 ± 7.4 days, p = 0.013). Reanimation of short-term facial paralysis can be satisfactorily addressed by means of either hemihypoglossal transposition with a nerve graft or direct masseteric-facial coaptation. However, with the latter, better symmetry and a faster onset of movement are observed. In addition, masseteric nerve transfer avoids morbidity from nerve graft harvesting. Therapeutic, III.

  14. Genome-wide target profiling of piggyBac and Tol2 in HEK 293: pros and cons for gene discovery and gene therapy

    Science.gov (United States)

    2011-01-01

    Background DNA transposons have emerged as indispensible tools for manipulating vertebrate genomes with applications ranging from insertional mutagenesis and transgenesis to gene therapy. To fully explore the potential of two highly active DNA transposons, piggyBac and Tol2, as mammalian genetic tools, we have conducted a side-by-side comparison of the two transposon systems in the same setting to evaluate their advantages and disadvantages for use in gene therapy and gene discovery. Results We have observed that (1) the Tol2 transposase (but not piggyBac) is highly sensitive to molecular engineering; (2) the piggyBac donor with only the 40 bp 3'-and 67 bp 5'-terminal repeat domain is sufficient for effective transposition; and (3) a small amount of piggyBac transposases results in robust transposition suggesting the piggyBac transpospase is highly active. Performing genome-wide target profiling on data sets obtained by retrieving chromosomal targeting sequences from individual clones, we have identified several piggyBac and Tol2 hotspots and observed that (4) piggyBac and Tol2 display a clear difference in targeting preferences in the human genome. Finally, we have observed that (5) only sites with a particular sequence context can be targeted by either piggyBac or Tol2. Conclusions The non-overlapping targeting preference of piggyBac and Tol2 makes them complementary research tools for manipulating mammalian genomes. PiggyBac is the most promising transposon-based vector system for achieving site-specific targeting of therapeutic genes due to the flexibility of its transposase for being molecularly engineered. Insights from this study will provide a basis for engineering piggyBac transposases to achieve site-specific therapeutic gene targeting. PMID:21447194

  15. Transposition of the acetabulum after iliac ischial osteotomy in the treatment of hip dysplasia in infants

    Directory of Open Access Journals (Sweden)

    Vladimir E Baskov

    2016-06-01

    Conclusion. Transposition of the acetabulum after iliac and ischial pelvic osteotomy is an effective treatment for dysplastic instability of the acetabulum in children aged 9–16 years. The procedure is indicated when it is necessary to rotate the acetabular fragment by more than 25°, and there is no need for hip medialization.

  16. LEGAL ASPECTS OF THE TRANSPOSITION OF DIRECTIVE 2001/23/EC REGARDING THE SAFEGUARDING OF EMPLOYEES’ RIGHTS IN THE EVENT OF TRANSFERS IN THE ROMANIAN LAW

    Directory of Open Access Journals (Sweden)

    FELICIA BEJAN

    2013-05-01

    Full Text Available The transfer of undertakings, businesses or parts of undertakings or businesses by legal transfer or merger determine important changes in the structure of the participant entities. The change of their juridical organisation has significant consequences on the employees’ rights, reason why, both nationally and internationally, normative acts that would regulate appropriate safeguarding mechanisms have been adopted. The paper aims to analyse the transposition into national law of the communitarian norms in the field. As a result, the legal aspects with regards to which the legislator chose a restrictive transposition, as well as the additional rights established by them in favour of the employees, in comparison to the directive are identified. At the same time, the study emphasizes the aspects with regards to which the Romanian law requires to be changed and therefore makes some proposals de lege ferenda, so that the transposition of the communitarian normative act into national law would be a precise one and consistent to the other dispositions regarding national law.

  17. Induction of transposon TN1 translocation under the action of different mutagens

    International Nuclear Information System (INIS)

    Kubanejshvili, M.G.; Smirnov, S.P.; Tarasov, V.A.

    1983-01-01

    Migration of ampicillin transposon Tn1 under normal conditions in Escherichia coli cells proceeds with low frequency (10 -4 transpositions for cell). The low transposition frequency is conditioned by the transposition repression, realized by the gene-repressor in transposon structure and, probably, by other regulating genes of the bacterium-host. E. coli cell treatment by physical and chemical mutagens resulted in induction of translocation of ampicillin transposon Tn1 from plasmid RP4 into other replicons. Mitomycin C and ultraviolet radiation produced stronger inducing effect as compared to nitroso-guanidine (NG). The effect of the given mutagens on transposition Tn1 correlated with their activating capacity with respect to inducible SOS-functions of E coli. The mutation of rec A didn't influence on spontaneous Tn1 transposition, but blocked completely the induction of transposition process under mutagen effect. The relationship of inducible transposition with SOS-functions in E. coli cells, controlled by recA and lexA genes, as well as the possible role of the process in genetic microorganism variability are discussed in the paper

  18. Functional reorganization of human motor cortex after unaffected side C7 nerve root transposition

    International Nuclear Information System (INIS)

    Gao Gejun; Feng Xiaoyuan; Xu Wendong; Gu Yudong; Tang Weijun; Sun Guixin; Li Ke; Li Yuan; Geng Daoying

    2006-01-01

    Objective: To assess the characteristics of neuronal activity in human motor cortex after the seventh cervical nerve root transposition of the unaffected side by using functional MRI (fMRI). Methods: Thirteen patients who accepted the seventh cervical nerve root transposition of the unaffected side, due to total brachial plexus traction injury diagnosed by manifestation and operation, were examined retrospectively by using fMRI. 10 patients were injured on the left side and 3 on the right side. According to functional recovery of the affected hand, all subjects can be divided into 2 groups. The patients of the first group could not move the affected hand voluntarily. The patients of the second group could move the affected hand self-determined. 12 healthy volunteer's were also involved in this study as control. The fMRI examinations were performed by using echo-planer BOLD sequence. Then the SPM 99 software was used for post-processing. Results: The neuronal activation induced by the movement of both unaffected and affected upper' limb was seen in the contralateral PMC in all patients; Neuronal activation in the ipsilateral PMC evoked by movement of the unaffected extremity was seen in 10 cases, and induced by movement of the affected limb was seen in 7 cases. In the first group, the sharp of clusters in the contralateral PMC resulted by movement of the unaffected extremity showed normal in 9 eases, the average size of clusters resulted by the unaffected hand was 3159 (voxel), and resulted by the unaffected shoulder was 1746(voxel). The sharp of clusters in the contralateral PMC resulted by the affected shoulder or hand were revealed enlargement in 6 cases of each. In the second group, 1 case showed neuronal activation induced by movement of the affected limb in the PMC in both sides of motor cortex, and 2 cases showed neuronal activation in the contralateral PMC. Conclusions: Peripheral nerve injury was able to cause changes of motor cortex in human brain

  19. A Theoretical and Experimental Comparison of One Time Pad Cryptography using Key and Plaintext Insertion and Transposition (KPIT and Key Coloumnar Transposition (KCT Method

    Directory of Open Access Journals (Sweden)

    Pryo Utomo

    2017-06-01

    Full Text Available One Time Pad (OTP is a cryptographic algorithm that is quite easy to be implemented. This algorithm works by converting plaintext and key into decimal then converting into binary number and calculating Exclusive-OR logic. In this paper, the authors try to make the comparison of OTP cryptography using KPI and KCT so that the ciphertext will be generated more difficult to be known. In the Key and Plaintext Insertion (KPI Method, we modify the OTP algorithm by adding the key insertion in the plaintext that has been splitted. Meanwhile in the Key Coloumnar Transposition (KCT Method, we modify the OTP algorithm by dividing the key into some parts in matrix of rows and coloumns. Implementation of the algorithms using PHP programming language.

  20. Gene repair of an Usher syndrome causing mutation by zinc-finger nuclease mediated homologous recombination.

    Science.gov (United States)

    Overlack, Nora; Goldmann, Tobias; Wolfrum, Uwe; Nagel-Wolfrum, Kerstin

    2012-06-26

    Human Usher syndrome (USH) is the most frequent cause of inherited deaf-blindness. It is clinically and genetically heterogeneous, assigned to three clinical types of which the most severe type is USH1. No effective treatment for the ophthalmic component of USH exists. Gene augmentation is an attractive strategy for hereditary retinal diseases. However, several USH genes, like USH1C, are expressed in various isoforms, hampering gene augmentation. As an alternative treatment strategy, we applied the zinc-finger nuclease (ZFN) technology for targeted gene repair of an USH1C, causing mutation by homologous recombination. We designed ZFNs customized for the p.R31X nonsense mutation in Ush1c. We evaluated ZFNs for DNA cleavage capability and analyzed ZFNs biocompatibilities by XTT assays. We demonstrated ZFNs mediated gene repair on genomic level by digestion assays and DNA sequencing, and on protein level by indirect immunofluorescence and Western blot analyses. The specifically designed ZFNs did not show cytotoxic effects in a p.R31X cell line. We demonstrated that ZFN induced cleavage of their target sequence. We showed that simultaneous application of ZFN and rescue DNA induced gene repair of the disease-causing mutation on the genomic level, resulting in recovery of protein expression. In our present study, we analyzed for the first time ZFN-activated gene repair of an USH gene. The data highlight the ability of ZFNs to induce targeted homologous recombination and mediate gene repair in USH. We provide further evidence that the ZFN technology holds great potential to recover disease-causing mutations in inherited retinal disorders.

  1. The transposition of musical knowledge in intellectual education

    Directory of Open Access Journals (Sweden)

    Carla Cuomo

    2014-05-01

    Full Text Available The construction of European citizenship in the era of complexity requires that the transmission of knowledge be directed towards an intellectual formation, that is, the ‘shaping’ of a critical mind, one that is able to problematize, and hence to discern. This can be achieved by educating towards comprehension. In facing this issue, musicologists ask themselves ‘what to teach’ and ‘how to teach’ it, in order to prepare students to the comprehension of music – these questions form the basis of music didactics as the science of ‘transposing’ savoir savant (learned knowledge into savoir enseigné (didactic knowledge. The paper proposes a model appraoch to music comprehension, through the didactic transposition of a piece by Claude Debussy, La cathédrale engloutie. The example is based on a strategy developed by musicological and methodological-didactic research, and focuses on the continuity among listening, music performance, and music history.

  2. Tibiofibula Transposition in High-Energy Fractures

    Directory of Open Access Journals (Sweden)

    Peter R. Loughenbury

    2016-01-01

    Full Text Available We report two cases of failed attempts at closed reduction of high-energy tibial fractures with an associated fibula fracture. The first case was a 39-year-old male involved in high-speed motorbike collision, while the second was a 14-year-old male who injured his leg following a fall of three metres. Emergency medical services at the scenes of the accidents reported a 90-degree valgus deformity of the injured limb and both limbs were realigned on scene and stabilized. Adequate alignment of the tibia could not be achieved by manipulation under sedation or anaesthesia. Open reduction and exposure of the fracture sites revealed that the distal fibula fragment was “transposed” and entrapped in the medulla of the proximal tibial fragment. Reduction required simulation of the mechanism of injury in order to disengage the fragments and allow reduction. Tibiofibula transposition is a rare complication of high-energy lower limb fractures which has not previously been reported and may prevent adequate closed reduction. Impaction of the distal fibula within the tibial medulla occurs as the limb is realigned by paramedic staff before transfer to hospital. We recommend that when this complication is identified the patient is transferred to the operating room for open reduction and stabilization of the fracture.

  3. Noonan syndrome-causing genes: Molecular update and an assessment of the mutation rate

    Directory of Open Access Journals (Sweden)

    Ihssane El Bouchikhi

    2016-12-01

    Full Text Available Noonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease and facial dysmorphia with an incidence of 1/1000 to 2500 live births. Up to now, several genes have been proven to be involved in the disturbance of the transduction signal through the RAS-MAP Kinase pathway and the manifestation of Noonan syndrome. The first gene described was PTPN11, followed by SOS1, RAF1, KRAS, BRAF, NRAS, MAP2K1, and RIT1, and recently SOS2, LZTR1, and A2ML1, among others. Progressively, the physiopathology and molecular etiology of most signs of Noonan syndrome have been demonstrated, and inheritance patterns as well as genetic counseling have been established. In this review, we summarize the data concerning clinical features frequently observed in Noonan syndrome, and then, we describe the molecular etiology as well as the physiopathology of most Noonan syndrome-causing genes. In the second part of this review, we assess the mutational rate of Noonan syndrome-causing genes reported up to now in most screening studies. This review should give clinicians as well as geneticists a full view of the molecular aspects of Noonan syndrome and the authentic prevalence of the mutational events of its causing-genes. It will also facilitate laying the groundwork for future molecular diagnosis research, and the development of novel treatment strategies.

  4. Primary structure and mapping of the hupA gene of Salmonella typhimurium.

    Science.gov (United States)

    Higgins, N P; Hillyard, D

    1988-01-01

    In bacteria, the complex nucleoid structure is folded and maintained by negative superhelical tension and a set of type II DNA-binding proteins, also called histonelike proteins. The most abundant type II DNA-binding protein is HU. Southern blot analysis showed that Salmonella typhimurium contained two HU genes that corresponded to Escherichia coli genes hupA (encoding HU-2 protein) and hupB (encoding HU-1). Salmonella hupA was cloned, and the nucleotide sequence of the gene was determined. Comparison of hupA of E. coli and S. typhimurium revealed that the HU-2 proteins were identical and that there was high conservation of nucleotide sequences outside the coding frames of the genes. A 300-member genomic library of S. typhimurium was constructed by using random transposition of MudP, a specialized chimeric P22-Mu phage that packages chromosomal DNA unidirectionally from its insertion point. Oligonucleotide hybridization against the library identified one MudP insertion that lies within 28 kilobases of hupA; the MudP was 12% linked to purH at 90.5 min on the standard map. Plasmids expressing HU-2 had a surprising phenotype; they caused growth arrest when they were introduced into E. coli strains bearing a himA or hip mutation. These results suggest that IHF and HU have interactive roles in bacteria. Images PMID:3056912

  5. Hif1α down-regulation is associated with transposition of great arteries in mice treated with a retinoic acid antagonist

    Directory of Open Access Journals (Sweden)

    Amati Francesca

    2010-09-01

    Full Text Available Abstract Background Congenital heart defect (CHD account for 25% of all human congenital abnormalities. However, very few CHD-causing genes have been identified so far. A promising approach for the identification of essential cardiac regulators whose mutations may be linked to human CHD, is the molecular and genetic analysis of heart development. With the use of a triple retinoic acid competitive antagonist (BMS189453 we previously developed a mouse model of congenital heart defects (81%, thymic abnormalities (98% and neural tube defects (20%. D-TGA (D-transposition of great arteries was the most prevalent cardiac defect observed (61%. Recently we were able to partially rescue this abnormal phenotype (CHD were reduced to 64.8%, p = 0.05, by oral administration of folic acid (FA. Now we have performed a microarray analysis in our mouse models to discover genes/transcripts potentially implicated in the pathogenesis of this CHD. Results We analysed mouse embryos (8.5 dpc treated with BMS189453 alone and with BMS189453 plus folic acid (FA by microarray and qRT-PCR. By selecting a fold change (FC ≥ ± 1.5, we detected 447 genes that were differentially expressed in BMS-treated embryos vs. untreated control embryos, while 239 genes were differentially expressed in BMS-treated embryos whose mothers had also received FA supplementation vs. BMS-treated embryos. On the basis of microarray and qRT-PCR results, we further analysed the Hif1α gene. In fact Hif1α is down-regulated in BMS-treated embryos vs. untreated controls (FCmicro = -1.79; FCqRT-PCR = -1.76; p = 0.005 and its expression level is increased in BMS+FA-treated embryos compared to BMS-treated embryos (FCmicro = +1.17; FCqRT-PCR = +1.28: p = 0.005. Immunofluorescence experiments confirmed the under-expression of Hif1α protein in BMS-treated embryos compared to untreated and BMS+FA-treated embryos and, moreover, we demonstrated that at 8.5 dpc, Hif1α is mainly expressed in the embryo heart

  6. Minimally invasive basilic vein transposition in the arm or forearm for autogenous haemodialysis access: A less morbid alternative to the conventional technique

    Directory of Open Access Journals (Sweden)

    Ankush Jairath

    2017-06-01

    Conclusion: Minimally invasive dissection of the basilic vein for vascular access transposition is a safe, reliable procedure with patency and functional outcomes comparable with those of conventional BVT.

  7. A Novel Mutation in ERCC8 Gene Causing Cockayne Syndrome

    Directory of Open Access Journals (Sweden)

    Maryam Taghdiri

    2017-08-01

    Full Text Available Cockayne syndrome (CS is a rare autosomal recessive multisystem disorder characterized by impaired neurological and sensory functions, cachectic dwarfism, microcephaly, and photosensitivity. This syndrome shows a variable age of onset and rate of progression, and its phenotypic spectrum include a wide range of severity. Due to the progressive nature of this disorder, diagnosis can be more important when additional signs and symptoms appear gradually and become steadily worse over time. Therefore, mutation analysis of genes involved in CS pathogenesis can be helpful to confirm the suspected clinical diagnosis. Here, we report a novel mutation in ERCC8 gene in a 16-year-old boy who suffers from poor weight gain, short stature, microcephaly, intellectual disability, and photosensitivity. The patient was born to consanguineous family with no previous documented disease in his parents. To identify disease-causing mutation in the patient, whole exome sequencing utilizing next-generation sequencing on an Illumina HiSeq 2000 platform was performed. Results revealed a novel homozygote mutation in ERCC8 gene (NM_000082: exon 11, c.1122G>C in our patient. Another gene (ERCC6, which is also involved in CS did not have any disease-causing mutations in the proband. The new identified mutation was then confirmed by Sanger sequencing in the proband, his parents, and extended family members, confirming co-segregation with the disease. In addition, different bioinformatics programs which included MutationTaster, I-Mutant v2.0, NNSplice, Combined Annotation Dependent Depletion, The PhastCons, Genomic Evolutationary Rate Profiling conservation score, and T-Coffee Multiple Sequence Alignment predicted the pathogenicity of the mutation. Our study identified a rare novel mutation in ERCC8 gene and help to provide accurate genetic counseling and prenatal diagnosis to minimize new affected individuals in this family.

  8. A Novel Mutation in ERCC8 Gene Causing Cockayne Syndrome.

    Science.gov (United States)

    Taghdiri, Maryam; Dastsooz, Hassan; Fardaei, Majid; Mohammadi, Sanaz; Farazi Fard, Mohammad Ali; Faghihi, Mohammad Ali

    2017-01-01

    Cockayne syndrome (CS) is a rare autosomal recessive multisystem disorder characterized by impaired neurological and sensory functions, cachectic dwarfism, microcephaly, and photosensitivity. This syndrome shows a variable age of onset and rate of progression, and its phenotypic spectrum include a wide range of severity. Due to the progressive nature of this disorder, diagnosis can be more important when additional signs and symptoms appear gradually and become steadily worse over time. Therefore, mutation analysis of genes involved in CS pathogenesis can be helpful to confirm the suspected clinical diagnosis. Here, we report a novel mutation in ERCC8 gene in a 16-year-old boy who suffers from poor weight gain, short stature, microcephaly, intellectual disability, and photosensitivity. The patient was born to consanguineous family with no previous documented disease in his parents. To identify disease-causing mutation in the patient, whole exome sequencing utilizing next-generation sequencing on an Illumina HiSeq 2000 platform was performed. Results revealed a novel homozygote mutation in ERCC8 gene (NM_000082: exon 11, c.1122G>C) in our patient. Another gene ( ERCC6 ), which is also involved in CS did not have any disease-causing mutations in the proband. The new identified mutation was then confirmed by Sanger sequencing in the proband, his parents, and extended family members, confirming co-segregation with the disease. In addition, different bioinformatics programs which included MutationTaster, I-Mutant v2.0, NNSplice, Combined Annotation Dependent Depletion, The PhastCons, Genomic Evolutationary Rate Profiling conservation score, and T-Coffee Multiple Sequence Alignment predicted the pathogenicity of the mutation. Our study identified a rare novel mutation in ERCC8 gene and help to provide accurate genetic counseling and prenatal diagnosis to minimize new affected individuals in this family.

  9. Isolation of the right subclavian artery in a patient with d-transposition of the great arteries.

    Science.gov (United States)

    Arunamata, Alisa; Perry, Stanton B; Kipps, Alaina K; Vasanawala, Shreyas S; Axelrod, David M

    2015-01-01

    Isolation of the right subclavian artery (RSCA) is rare, and this finding in association with d-transposition of the great arteries (d-TGA) is extremely unusual. We present a case of an isolated RSCA in a newborn with d-TGA in whom the clinical presentation was diagnostic. We discuss the imaging modalities used to confirm the diagnosis, the embryological basis of the finding, and the surgical repair.

  10. Comparison of Total Arch and Partial Arch Transposition During Hybrid Endovascular Repair for Aortic Arch Disease.

    Science.gov (United States)

    Kang, W C; Ko, Y-G; Oh, P C; Shin, E K; Park, C-H; Choi, D; Youn, Y N; Lee, D Y

    2016-08-01

    Total arch transposition (TAT) during hybrid endovascular repair for aortic arch disease is believed to allow a better landing zone, but also to be associated with higher peri-operative mortality than partial arch transposition (PAT). Information on this issue is limited. This study was a retrospective analysis. All 53 consecutive patients with aortic arch disease (41 males, mean age 65.0 years) who underwent hybrid endovascular repair with TAT (zone 0, n=20) or PAT (zone 1 or 2, n=33) from 2008 to 2014 were analyzed retrospectively. The peri-operative and late outcomes of these two groups were compared. Baseline characteristics, including EuroSCORE II results, were similar in the two groups. After procedures, peri-operative mortalities and stroke rates were similar in the two groups (5.0% vs. 9.1%, p=1.000, and 10.0% vs. 6.1%, p=.627). Interestingly, all four strokes occurred in patients with a type III aortic arch irrespective of transposition type. Primary success rates (80.0% vs. 69.7%, p=.527) and type I endoleak incidences (20.0% vs. 27.3%, p=.744) were not significantly different. During follow up (mean duration 36.9 months), overall survival (89.7% vs. 87.4% at 1 year and 89.7% vs. 79.3% at 3 years; p=.375) and re-intervention free survival rates (78.6% vs. 92.0% at 1 year; 72.0% vs. 62.2% at 3 years, p=.872) were similar in the two groups. Morbidity and mortality were high within the first year of hybrid endovascular therapy for aortic arch disease, implying that candidates for hybrid procedures need to be selected carefully. Hybrid endovascular repair with TAT was found to have peri-operative mortality, stroke, and long-term survival rates comparable with PAT, so hybrid endovascular repair may be considered, irrespective of type of arch reconstruction, when clinically indicated. Copyright © 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

  11. Germ line transformation of the yellow fever mosquito, Aedes aegypti, mediated by transpositional insertion of a piggyBac vector.

    Science.gov (United States)

    Lobo, N F; Hua-Van, A; Li, X; Nolen, B M; Fraser, M J

    2002-04-01

    Mosquito-vectored diseases such as yellow fever and dengue fever continue to have a substantial impact on human populations world-wide. Novel strategies for control of these mosquito vectored diseases can arise through the development of reliable systems for genetic manipulation of the insect vector. A piggyBac vector marked with the Drosophila melanogaster cinnabar (cn) gene was used to transform the white-eyed khw strain of Aedes aegypti. Microinjection of preblastoderm embryos resulted in four families of cinnabar transformed insects. An overall transformation frequency of 4%, with a range of 0% to as high as 13% for individual experiments, was achieved when using a heat-shock induced transposase providing helper plasmid. Southern hybridizations indicated multiple insertion events in three of four transgenic lines, while the presence of duplicated target TTAA sites at either ends of individual insertions confirmed characteristic piggyBac transposition events in these three transgenic lines. The transgenic phenotype has remained stable for more than twenty generations. The transformations effected using the piggyBac element establish the potential of this element as a germ-line transformation vector for Aedine mosquitoes.

  12. Retinoschisislike alterations in the mouse eye caused by gene targeting of the Norrie disease gene.

    Science.gov (United States)

    Ruether, K; van de Pol, D; Jaissle, G; Berger, W; Tornow, R P; Zrenner, E

    1997-03-01

    To investigate the retinal function and morphology of mice carrying a replacement mutation in exon 2 of the Norrie disease gene. Recently, Norrie disease mutant mice have been generated using gene targeting technology. The mutation removes the 56 N-terminal amino acids of the Norrie gene product. Ganzfeld electroretinograms (ERGs) were obtained in five animals hemizygous or homozygous for the mutant gene and in three female animals heterozygous for the mutant gene. As controls, three males carrying the wild-type gene were examined. Electroretinogram testing included rod a- and b-wave V-log I functions, oscillatory potentials, and cone responses. The fundus morphology has been visualized by scanning laser ophthalmoscopy. Rod and cone ERG responses and fundus morphology were not significantly different among female heterozygotes and wild-type mice. In contrast, the hemizygous mice displayed a severe loss of ERG b-wave, leading to a negatively shaped scotopic ERG and a marked reduction of oscillatory potentials. The a-wave was normal at low intensities, and only with brighter flashes was there a moderate amplitude loss. Cone amplitudes were barely recordable in the gene-targeted males. Ophthalmoscopy revealed snowflakelike vitreal changes, retinoschisis, and pigment epithelium irregularities in hemizygotes and homozygotes, but no changes in female heterozygotes. The negatively shaped scotopic ERG in male mice with a Norrie disease gene mutation probably was caused by retinoschisis. Pigment epithelial changes and degenerations of the outer retina are relatively mild. These findings may be a clue to the embryonal retinoschisislike pathogenesis of Norrie disease in humans or it may indicate a different expression of the Norrie disease gene defect in mice compared to that in humans.

  13. Isolation of the right subclavian artery in a patient with d-transposition of the great arteries

    Directory of Open Access Journals (Sweden)

    Alisa Arunamata

    2015-01-01

    Full Text Available Isolation of the right subclavian artery (RSCA is rare, and this finding in association with d-transposition of the great arteries (d-TGA is extremely unusual. We present a case of an isolated RSCA in a newborn with d-TGA in whom the clinical presentation was diagnostic. We discuss the imaging modalities used to confirm the diagnosis, the embryological basis of the finding, and the surgical repair.

  14. [Diagnosis and treatment of strabismus caused by nasal endoscopic surgery].

    Science.gov (United States)

    Ai, L K; Wu, X; Wang, J N; Li, J; Wu, Y; Zhou, J; Song, W X; Guo, R L

    2017-12-11

    Objective: Strabismus with diplopia is the main orbital complication of functional endoscopic sinus surgery (FESS). This study was to analyze clinical findings, treatment and outcomes of such cases. Methods: Retrospective case series. Twenty-three cases were divided into 3 groups based on the disease severity: group A, partial transection of the medial rectus muscle, group B, complete transection of the medical rectus, group C, transection of the medial rectus combined with the other orbital injuries. Complete ophthalmology examinations, including eye alignment, eye motility, force duction test, force generation test, general eye exam, and medical imaging (orbital CT or MRI), were performed for each case. The treatment included botulinum toxin (Botox) injection to the lateral rectus muscle, transposition of the vertical rectus muscle, and orbital surgery if needed. Results: In group A with Botox injection, all the cases achieved single vision in primary position, but still remained some adduction weakness. In group B treated by vertical transposition surgery combined with Botox, 22% of the cases got single vision in primary gaze. In group C, even with more efforts of treatment, the cases with orbital injury can only get cosmetic improvement, and diplopia and adduction dysfunction were found in most cases. Conclusions: Due to the variety of the complications of FESS, force duction test is a crucial exam to detect the direction and severity of synechia in the orbit, which will give solid information to surgery approach as well as prognosis. Botox injection at early stage will minimize the contraction of antagonist lateral rectus, helping to postpone the transposition surgery which may cause anterior segment ischemia when performed right after the medial rectus transection injury. Botox may even reduce the synechia by minimizing the scarring process. Partial vertical rectus transposition combined with muscle resection may effectively correct the eye misalignment in

  15. The Applied Aspects of Transposition and Integration of Development Resources in the System of Strategic Management of the Pharmaceutical Industry Enterprises

    Directory of Open Access Journals (Sweden)

    Mykhailiuk Myroslava О.

    2018-02-01

    Full Text Available The article is aimed at researching the transposition and integration of development resources in the system of strategic management of pharmaceutical enterprises. It has been determined that in the current of market functioning, resources are transformed into development resources. The proposed scheme of transposition and integration of development resources in the system of strategic management of enterprises provides a combination of resource opportunities of company with market conditions and reflects synergistic interaction between two classical theories of strategic management: the M. Porter’s sectoral competition theory and the resource theory. The basic priorities of development of the pharmaceutical industry in the contemporary market environment are defined and trends of activity of pharmaceutical companies are indicated. Enterprises are distributed according to the criterion of introduction of development resources strategy, measures on increase of efficiency of their activity are suggested.

  16. As the transposition goes on in France: new rules

    International Nuclear Information System (INIS)

    Kiffel, T.

    2002-01-01

    European directive transposition in radioprotection (96-29 EURATOM for workers and 97-43 for patients) in association with the reformation of radioprotection structures in France will change drastically the situation of radioprotection. New laws (L.1333-1 and L.1333-11) enforce justification, optimisation for the medical exposures and formation of all professionals using radiation. A new ministerial administration (Direction Generale de la Surete Nucleaire et de la Radioprotection) and a new technical operator (Institut de Radioprotection et de Surete Nucleaire) will also change radioprotection. In the new system, radioprotection of the patient becomes as important as for the workers... It's new and will change comportment of professionals. The new rules will probably change the mentality at long term in term of guidelines. Even if radioprotection becomes a very important matter, it is still the time to say that radiation is necessary for medical use in 21. century as well as in the 20. century. (author)

  17. Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant

    DEFF Research Database (Denmark)

    Al-Mashhadi, Rozh Husain; Sørensen, Charlotte Brandt; Kragh, Peter M.

    2013-01-01

    dominant hypercholesterolemia and accelerates atherosclerosis in humans. Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9. D374Y-PCSK9 transgenic pigs displayed reduced hepatic low...

  18. [Transposition errors during learning to reproduce a sequence by the right- and the left-hand movements: simulation of positional and movement coding].

    Science.gov (United States)

    Liakhovetskiĭ, V A; Bobrova, E V; Skopin, G N

    2012-01-01

    Transposition errors during the reproduction of a hand movement sequence make it possible to receive important information on the internal representation of this sequence in the motor working memory. Analysis of such errors showed that learning to reproduce sequences of the left-hand movements improves the system of positional coding (coding ofpositions), while learning of the right-hand movements improves the system of vector coding (coding of movements). Learning of the right-hand movements after the left-hand performance involved the system of positional coding "imposed" by the left hand. Learning of the left-hand movements after the right-hand performance activated the system of vector coding. Transposition errors during learning to reproduce movement sequences can be explained by neural network using either vector coding or both vector and positional coding.

  19. Deletion of P2 promoter of GJB1 gene a cause of Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Kulshrestha, R; Burton-Jones, S; Antoniadi, T; Rogers, M; Jaunmuktane, Z; Brandner, S; Kiely, N; Manuel, R; Willis, T

    2017-08-01

    X-linked Charcot-Marie-Tooth disease (CMT) is the second most common cause of CMT, and is usually caused by mutations in the gap junction protein beta 1 (GJB1) gene. This gene has nerve specific P2 promoter that work synergistically with SOX10 and EGR2 genes to initiate transcription. Mutation in this region is known to cause Schwann cell dysfunction. A single large family of X linked peripheral neuropathy was identified in our practice. Next generation sequencing for targeted panel assay identified an upstream exon-splicing deletion identified extending from nucleotide c.-5413 to approximately - c.-49. This matches the sequence of 32 nucleotides at positions c.*218-*249 in the 3'UTR downstream of the GJB1 gene. The deleted fragment included the entire P2 promoter region. The deletion segregated with the disease. To our knowledge a deletion of the P2 promoter alone as a cause of CMT has not been reported previously. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Hydrocephalus caused by conditional ablation of the Pten or beta-catenin gene

    Directory of Open Access Journals (Sweden)

    Ohtoshi Akihira

    2008-10-01

    Full Text Available Abstract To investigate the roles of Pten and β-Catenin in the midbrain, either the Pten gene or the β-catenin gene was conditionally ablated, using Dmbx1 (diencephalon/mesencephalon-expressed brain homeobox gene 1-Cre mice. Homozygous disruption of the Pten or β-catenin gene in Dmbx1-expressing cells caused severe hydrocephalus and mortality during the postnatal period. Conditional deletion of Pten resulted in enlargement of midbrain structures. β-catenin conditional mutant mice showed malformation of the superior and inferior colliculi and stenosis of the midbrain aqueduct. These results demonstrate that both Pten and β-Catenin are essential for proper midbrain development, and provide the direct evidence that mutations of both Pten and β-catenin lead to hydrocephalus.

  1. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.

    Science.gov (United States)

    Braun, Daniela A; Rao, Jia; Mollet, Geraldine; Schapiro, David; Daugeron, Marie-Claire; Tan, Weizhen; Gribouval, Olivier; Boyer, Olivia; Revy, Patrick; Jobst-Schwan, Tilman; Schmidt, Johanna Magdalena; Lawson, Jennifer A; Schanze, Denny; Ashraf, Shazia; Ullmann, Jeremy F P; Hoogstraten, Charlotte A; Boddaert, Nathalie; Collinet, Bruno; Martin, Gaëlle; Liger, Dominique; Lovric, Svjetlana; Furlano, Monica; Guerrera, I Chiara; Sanchez-Ferras, Oraly; Hu, Jennifer F; Boschat, Anne-Claire; Sanquer, Sylvia; Menten, Björn; Vergult, Sarah; De Rocker, Nina; Airik, Merlin; Hermle, Tobias; Shril, Shirlee; Widmeier, Eugen; Gee, Heon Yung; Choi, Won-Il; Sadowski, Carolin E; Pabst, Werner L; Warejko, Jillian K; Daga, Ankana; Basta, Tamara; Matejas, Verena; Scharmann, Karin; Kienast, Sandra D; Behnam, Babak; Beeson, Brendan; Begtrup, Amber; Bruce, Malcolm; Ch'ng, Gaik-Siew; Lin, Shuan-Pei; Chang, Jui-Hsing; Chen, Chao-Huei; Cho, Megan T; Gaffney, Patrick M; Gipson, Patrick E; Hsu, Chyong-Hsin; Kari, Jameela A; Ke, Yu-Yuan; Kiraly-Borri, Cathy; Lai, Wai-Ming; Lemyre, Emmanuelle; Littlejohn, Rebecca Okashah; Masri, Amira; Moghtaderi, Mastaneh; Nakamura, Kazuyuki; Ozaltin, Fatih; Praet, Marleen; Prasad, Chitra; Prytula, Agnieszka; Roeder, Elizabeth R; Rump, Patrick; Schnur, Rhonda E; Shiihara, Takashi; Sinha, Manish D; Soliman, Neveen A; Soulami, Kenza; Sweetser, David A; Tsai, Wen-Hui; Tsai, Jeng-Daw; Topaloglu, Rezan; Vester, Udo; Viskochil, David H; Vatanavicharn, Nithiwat; Waxler, Jessica L; Wierenga, Klaas J; Wolf, Matthias T F; Wong, Sik-Nin; Leidel, Sebastian A; Truglio, Gessica; Dedon, Peter C; Poduri, Annapurna; Mane, Shrikant; Lifton, Richard P; Bouchard, Maxime; Kannu, Peter; Chitayat, David; Magen, Daniella; Callewaert, Bert; van Tilbeurgh, Herman; Zenker, Martin; Antignac, Corinne; Hildebrandt, Friedhelm

    2017-10-01

    Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

  2. A duplicated PLP gene causing Pelizaeus-Merzbacher disease detected by comparative multiplex PCR

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, K.; Sugiyama, N.; Kawanishi, C. [Yokohama City Univ., Yokohama (Japan)] [and others

    1996-07-01

    Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder caused by abnormalities in the proteolipid protein (PLP) gene, which is essential for oligodendrocyte differentiation and CNS myelin formation. Although linkage analysis has shown the homogeneity at the PLP locus in patients with PMD, exonic mutations in the PLP gene have been identified in only 10% - 25% of all cases, which suggests the presence of other genetic aberrations, including gene duplication. In this study, we examined five families with PMD not carrying exonic mutations in PLP gene, using comparative multiplex PCR (CM-PCR) as a semiquantitative assay of gene dosage. PLP gene duplications were identified in four families by CM-PCR and confirmed in three families by densitometric RFLP analysis. Because a homologous myelin protein gene, PMP22, is duplicated in the majority of patients with Charcot-Marie-Tooth 1A, PLP gene overdosage may be an important genetic abnormality in PMD and affect myelin formation. 38 ref., 5 figs., 2 tabs.

  3. A novel nonsense mutation in the WFS1 gene causes the Wolfram syndrome.

    Science.gov (United States)

    Noorian, Shahab; Savad, Shahram; Mohammadi, Davood Shah

    2016-05-01

    Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder, which is mostly caused by mutations in the WFS1 gene. The WFS1 gene product, which is called wolframin, is thought to regulate the function of endoplasmic reticulum. The endoplasmic reticulum has a critical role in protein folding and material transportation within the cell or to the surface of the cell. Identification of new mutations in WFS1 gene will unravel the molecular pathology of WS. The aim of this case report study is to describe a novel mutation in exon 4 of the WFS1 gene (c.330C>A) in a 9-year-old boy with WS.

  4. A novel mutation of the fibrillin gene causing Ectopia lentis

    Energy Technology Data Exchange (ETDEWEB)

    Loennqvist, L.; Kainulainen, K.; Puhakka, L.; Peltonen, L. (National Public Health Institute, Helsinki (Finland)); Child, A. (St. George' s Hospital Medical School, London (United Kingdom)); Peltonen, L. (Duncan Guthrie Institute, Glasgow, Scotland (United Kingdom))

    1994-02-01

    Ectopia lentis (EL), a dominantly inherited connective tissue disorder, has been genetically linked to the fibrillin gene on chromosome 15 (FBN1) in earlier studies. Here, the authors report the first EL mutation in the FBN1 gene confirming that EL is caused by mutations of this gene. So far, several mutations in the FBN1 gene have been reported in patients with Marfan syndrome (MFS). EL and MFS are clinically related but distinct conditions with typical manifestations in the ocular and skeletal systems, the fundamental difference between them being the absence of cardiovascular involvement in EL. They report a point mutation, cosegregating with the disease in the described family, that displays EL over four generations. The mutation changes a conserved glutamic acid residue in an EGF-like motif, which is the major structural component of the fibrillin and is repeated throughout the polypeptide. In vitro mutagenetic studies have demonstrated the necessity of an analogous glutamic acid residue for calcium binding in an EGF-like repeat of human factor IX. This provides a possible explanation for the role of this mutation in the disease pathogenesis. 32 refs., 2 figs., 1 tab.

  5. Comparison of the dental anomalies found in maxillary canine-first premolar transposition cases with those in palatally displaced canine cases.

    Science.gov (United States)

    Scerri, Erica Sultana; McDonald, Fraser; Camilleri, Simon

    2016-02-01

    To compare the developmental dental anomalies associated with maxillary canine-first premolar (MxCP1) transposition and those of palatally displaced canine (PDC) with each other and with the background prevalence in the Maltese population in order to elucidate whether the two conditions have similar or differing genetic backgrounds. Dental records of 477 subjects with PDC, 57 subjects with MxCP1, and a control group of 500 subjects with no history of a PDC or tooth transposition were compared for canine eruption anomalies and hypodontia. A high frequency of bilateral occurrence was present for both canine malpositions and when unilateral, a trend to right-sided occurrence was evident. The occurrence of transpositions in the PDC group and of PDC in the MxCP1 group was higher than expected. The prevalence of incisor hypodontia was significantly higher in subjects with PDC and MxCP1, as compared to the control group. The size of the MxCP1 group is relatively small. The study population is a small isolated Caucasian population and the results may not be applicable to other populations. There is no significant difference between the MxCP1 and PDC groups in the prevalence or distribution of hypodontia and each of these groups exhibits a higher prevalence of the other canine anomaly. These findings support the theory that PDC and MxCP1 form part of a group of interrelated dental anomalies that share a common genetic basis. © The Author 2015. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  6. Evolution of the DAZ gene and the AZFc region on primate Y chromosomes

    Directory of Open Access Journals (Sweden)

    Yu Jane-Fang

    2008-03-01

    Full Text Available Abstract Background The Azoospermia Factor c (AZFc region of the human Y chromosome is a unique product of segmental duplication. It consists almost entirely of very long amplicons, represented by different colors, and is frequently deleted in subfertile men. Most of the AZFc amplicons have high sequence similarity with autosomal segments, indicating recent duplication and transposition to the Y chromosome. The Deleted in Azoospermia (DAZ gene within the red-amplicon arose from an ancestral autosomal DAZ-like (DAZL gene. It varies significantly between different men regarding to its copy number and the numbers of RNA recognition motif and DAZ repeat it encodes. We used Southern analyses to study the evolution of DAZ and AZFc amplicons on the Y chromosomes of primates. Results The Old World monkey rhesus macaque has only one DAZ gene. In contrast, the great apes have multiple copies of DAZ, ranging from 2 copies in bonobos and gorillas to at least 6 copies in orangutans, and these DAZ genes have polymorphic structures similar to those of their human counterparts. Sequences homologous to the various AZFc amplicons are present on the Y chromosomes of some but not all primates, indicating that they arrived on the Y chromosome at different times during primate evolution. Conclusion The duplication and transposition of AZFc amplicons to the human Y chromosome occurred in three waves, i.e., after the branching of the New World monkey, the gorilla, and the chimpanzee/bonobo lineages, respectively. The red-amplicon, one of the first to arrive on the Y chromosome, amplified by inverted duplication followed by direct duplication after the separation of the Old World monkey and the great ape lineages. Subsequent duplication/deletion in the various lineages gave rise to a spectrum of DAZ gene structure and copy number found in today's great apes.

  7. A faster 1.375-approximation algorithm for sorting by transpositions.

    Science.gov (United States)

    Cunha, Luís Felipe I; Kowada, Luis Antonio B; Hausen, Rodrigo de A; de Figueiredo, Celina M H

    2015-11-01

    Sorting by Transpositions is an NP-hard problem for which several polynomial-time approximation algorithms have been developed. Hartman and Shamir (2006) developed a 1.5-approximation [Formula: see text] algorithm, whose running time was improved to O(nlogn) by Feng and Zhu (2007) with a data structure they defined, the permutation tree. Elias and Hartman (2006) developed a 1.375-approximation O(n(2)) algorithm, and Firoz et al. (2011) claimed an improvement to the running time, from O(n(2)) to O(nlogn), by using the permutation tree. We provide counter-examples to the correctness of Firoz et al.'s strategy, showing that it is not possible to reach a component by sufficient extensions using the method proposed by them. In addition, we propose a 1.375-approximation algorithm, modifying Elias and Hartman's approach with the use of permutation trees and achieving O(nlogn) time.

  8. [Exstrophy of rectal duplication associated with anorectal malformation and penoscrotal transposition with perineal hypospadias. A case report].

    Science.gov (United States)

    Fernández Fernández, Jesús Angel; Parodi Hueck, Luis; Carrasco Fermín, Joanna

    2014-06-01

    We present the case of a male patient who required treaatment due to anorectal agenesis with recto urethral fistula and penoscrotal transposition with perineal hypospadias, associated with a perineal tumor. The perineal tumor was found strongly adhered and contiguous to the rectum which makes it compatible with an exstrophy of rectal duplication. Surgical reconstruction of the birth defect was performed in stages until acceptable biological function and esthetic results were obtained.

  9. Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation.

    Science.gov (United States)

    Auclair, Jessie; Leroux, Dominique; Desseigne, Françoise; Lasset, Christine; Saurin, Jean Christophe; Joly, Marie Odile; Pinson, Stéphane; Xu, Xiao Li; Montmain, Gilles; Ruano, Eric; Navarro, Claudine; Puisieux, Alain; Wang, Qing

    2007-11-01

    Since the first report by our group in 1999, more than 20 unrelated biallelic mutations in DNA mismatch repair genes (MMR) have been identified. In the present report, we describe two novel cases: one carrying compound heterozygous mutations in the MSH6 gene; and the other, compound heterozygous mutations in the PMS2 gene. Interestingly, the inactivation of one PMS2 allele was likely caused by gene conversion. Although gene conversion has been suggested to be a mutation mechanism underlying PMS2 inactivation, this is the first report of its involvement in a pathogenic mutation. The clinical features of biallelic mutation carriers were similar to other previously described patients, with the presence of café-au-lait spots (CALS), early onset of brain tumors, and colorectal neoplasia. Our data provide further evidence of the existence, although rare, of a distinct recessively inherited syndrome on the basis of MMR constitutional inactivation. The identification of this syndrome should be useful for genetic counseling, especially in families with atypical hereditary nonpolyposis colon cancer (HNPCC) associated with childhood cancers, and for the clinical surveillance of these mutation carriers. 2007 Wiley-Liss, Inc.

  10. A comparison of surgical outcome of fasciocutaneous V–Y advancement flap and Limberg transposition flap for recurrent sacrococcygeal pilonidal sinus disease

    Directory of Open Access Journals (Sweden)

    Bahadır Öz

    2017-05-01

    Conclusion: Limberg transposition flap may be use in recurrent cases of PSD, because of the lower recurrence rate and less hospital stay time, early return to work. Most important advantage of fasciocutaneous V–Y advancement flap is the ability to close larger defects in recurrent cases.

  11. Minos as a novel Tc1/mariner-type transposable element for functional genomic analysis in Aspergillus nidulans.

    Science.gov (United States)

    Evangelinos, Minoas; Anagnostopoulos, Gerasimos; Karvela-Kalogeraki, Iliana; Stathopoulou, Panagiota M; Scazzocchio, Claudio; Diallinas, George

    2015-08-01

    Transposons constitute powerful genetic tools for gene inactivation, exon or promoter trapping and genome analyses. The Minos element from Drosophila hydei, a Tc1/mariner-like transposon, has proved as a very efficient tool for heterologous transposition in several metazoa. In filamentous fungi, only a handful of fungal-specific transposable elements have been exploited as genetic tools, with the impala Tc1/mariner element from Fusarium oxysporum being the most successful. Here, we developed a two-component transposition system to manipulate Minos transposition in Aspergillus nidulans (AnMinos). Our system allows direct selection of transposition events based on re-activation of niaD, a gene necessary for growth on nitrate as a nitrogen source. On average, among 10(8) conidiospores, we obtain up to ∼0.8×10(2) transposition events leading to the expected revertant phenotype (niaD(+)), while ∼16% of excision events lead to AnMinos loss. Characterized excision footprints consisted of the four terminal bases of the transposon flanked by the TA target duplication and led to no major DNA rearrangements. AnMinos transposition depends on the presence of its homologous transposase. Its frequency was not significantly affected by temperature, UV irradiation or the transcription status of the original integration locus (niaD). Importantly, transposition is dependent on nkuA, encoding an enzyme essential for non-homologous end joining of DNA in double-strand break repair. AnMinos proved to be an efficient tool for functional analysis as it seems to transpose in different genomic loci positions in all chromosomes, including a high proportion of integration events within or close to genes. We have used Minos to obtain morphological and toxic analogue resistant mutants. Interestingly, among morphological mutants some seem to be due to Minos-elicited over-expression of specific genes, rather than gene inactivation. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Flail Tricuspid Valve in an Adult Patient with Congenitally Corrected Transposition of the Great Arteries.

    Science.gov (United States)

    Meloni, Luigi; Abbruzzese, Piero A.; Pirisi, Raimondo; Cherchi, Angelo

    1997-01-01

    We describe a case of a 50-year-old woman with congenitally corrected transposition of the great vessels, in whom severe left-sided tricuspid (systemic atrioventricular) valve insufficiency was the only associated anomaly. The tricuspid valve was dysplastic and abnormally oriented toward the interventricular septum, without the downward displacement of Ebstein's anomaly. The mechanism of atrioventricular regurgitation was unusual in that it consisted of the rupture of chordae tendineae of both the anterior and septal leaflets. The left-sided tricuspid valve was replaced with a St. Jude prosthesis and the postoperative course was uneventful.

  13. Environmental and chemotherapeutic agents induce breakage at genes involved in leukemia-causing gene rearrangements in human hematopoietic stem/progenitor cells

    Energy Technology Data Exchange (ETDEWEB)

    Thys, Ryan G., E-mail: rthys@wakehealth.edu [Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1016 (United States); Lehman, Christine E., E-mail: clehman@wakehealth.edu [Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1016 (United States); Pierce, Levi C.T., E-mail: Levipierce@gmail.com [Human Longevity, Inc., San Diego, California 92121 (United States); Wang, Yuh-Hwa, E-mail: yw4b@virginia.edu [Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Avenue, Charlottesville, VA 22908-0733 (United States)

    2015-09-15

    Highlights: • Environmental/chemotherapeutic agents cause DNA breakage in MLL and CBFB in HSPCs. • Diethylnitrosamine-induced DNA breakage at MLL and CBFB shown for the first time. • Chemical-induced DNA breakage occurs at topoisomerase II cleavage sites. • Chemical-induced DNA breaks display a pattern similar to those in leukemia patients. • Long-term exposures suggested to generate DNA breakage at leukemia-related genes. - Abstract: Hematopoietic stem and progenitor cells (HSPCs) give rise to all of the cells that make up the hematopoietic system in the human body, making their stability and resilience especially important. Damage to these cells can severely impact cell development and has the potential to cause diseases, such as leukemia. Leukemia-causing chromosomal rearrangements have largely been studied in the context of radiation exposure and are formed by a multi-step process, including an initial DNA breakage and fusion of the free DNA ends. However, the mechanism for DNA breakage in patients without previous radiation exposure is unclear. Here, we investigate the role of non-cytotoxic levels of environmental factors, benzene, and diethylnitrosamine (DEN), and chemotherapeutic agents, etoposide, and doxorubicin, in generating DNA breakage at the patient breakpoint hotspots of the MLL and CBFB genes in human HSPCs. These conditions represent exposure to chemicals encountered daily or residual doses from chemotherapeutic drugs. Exposure of HSPCs to non-cytotoxic levels of environmental chemicals or chemotherapeutic agents causes DNA breakage at preferential sites in the human genome, including the leukemia-related genes MLL and CBFB. Though benzene, etoposide, and doxorubicin have previously been linked to leukemia formation, this is the first study to demonstrate a role for DEN in the generation of DNA breakage at leukemia-specific sites. These chemical-induced DNA breakpoints coincide with sites of predicted topoisomerase II cleavage. The

  14. Environmental and chemotherapeutic agents induce breakage at genes involved in leukemia-causing gene rearrangements in human hematopoietic stem/progenitor cells

    International Nuclear Information System (INIS)

    Thys, Ryan G.; Lehman, Christine E.; Pierce, Levi C.T.; Wang, Yuh-Hwa

    2015-01-01

    Highlights: • Environmental/chemotherapeutic agents cause DNA breakage in MLL and CBFB in HSPCs. • Diethylnitrosamine-induced DNA breakage at MLL and CBFB shown for the first time. • Chemical-induced DNA breakage occurs at topoisomerase II cleavage sites. • Chemical-induced DNA breaks display a pattern similar to those in leukemia patients. • Long-term exposures suggested to generate DNA breakage at leukemia-related genes. - Abstract: Hematopoietic stem and progenitor cells (HSPCs) give rise to all of the cells that make up the hematopoietic system in the human body, making their stability and resilience especially important. Damage to these cells can severely impact cell development and has the potential to cause diseases, such as leukemia. Leukemia-causing chromosomal rearrangements have largely been studied in the context of radiation exposure and are formed by a multi-step process, including an initial DNA breakage and fusion of the free DNA ends. However, the mechanism for DNA breakage in patients without previous radiation exposure is unclear. Here, we investigate the role of non-cytotoxic levels of environmental factors, benzene, and diethylnitrosamine (DEN), and chemotherapeutic agents, etoposide, and doxorubicin, in generating DNA breakage at the patient breakpoint hotspots of the MLL and CBFB genes in human HSPCs. These conditions represent exposure to chemicals encountered daily or residual doses from chemotherapeutic drugs. Exposure of HSPCs to non-cytotoxic levels of environmental chemicals or chemotherapeutic agents causes DNA breakage at preferential sites in the human genome, including the leukemia-related genes MLL and CBFB. Though benzene, etoposide, and doxorubicin have previously been linked to leukemia formation, this is the first study to demonstrate a role for DEN in the generation of DNA breakage at leukemia-specific sites. These chemical-induced DNA breakpoints coincide with sites of predicted topoisomerase II cleavage. The

  15. Analysis of phage Mu DNA transposition by whole-genome Escherichia coli tiling arrays reveals a complex relationship to distribution of target selection protein B, transcription and chromosome architectural elements.

    Science.gov (United States)

    Ge, Jun; Lou, Zheng; Cui, Hong; Shang, Lei; Harshey, Rasika M

    2011-09-01

    Of all known transposable elements, phage Mu exhibits the highest transposition efficiency and the lowest target specificity. In vitro, MuB protein is responsible for target choice. In this work, we provide a comprehensive assessment of the genome-wide distribution of MuB and its relationship to Mu target selection using high-resolution Escherichia coli tiling DNA arrays. We have also assessed how MuB binding and Mu transposition are influenced by chromosome-organizing elements such as AT-rich DNA signatures, or the binding of the nucleoid-associated protein Fis, or processes such as transcription. The results confirm and extend previous biochemical and lower resolution in vivo data. Despite the generally random nature of Mu transposition and MuB binding, there were hot and cold insertion sites and MuB binding sites in the genome, and differences between the hottest and coldest sites were large. The new data also suggest that MuB distribution and subsequent Mu integration is responsive to DNA sequences that contribute to the structural organization of the chromosome.

  16. X-Linked Dyskeratosis Congenita Is Predominantly Caused by Missense Mutations in the DKC1 Gene

    OpenAIRE

    Knight, S.W.; Heiss, N.S.; Vulliamy, T.J.; Greschner, S.; Stavrides, G.; Pai, G.S.; Lestringant, G.; Varma, N.; Mason, P.J.; Dokal, I.; Poustka, A.

    1999-01-01

    Dyskeratosis congenita is a rare inherited bone marrow-failure syndrome characterized by abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia. More than 80% of patients develop bone-marrow failure, and this is the major cause of premature death. The X-linked form of the disease (MIM 305000) has been shown to be caused by mutations in the DKC1 gene. The gene encodes a 514-amino-acid protein, dyskerin, that is homologous to Saccharomyces cerevisiae Cbf5p and rat Nap57 proteins. B...

  17. Long term follow up after surgery in congenitally corrected transposition of the great arteries with a right ventricle in the systemic circulation

    NARCIS (Netherlands)

    A.J.J.C. Bogers (Ad); S.J. Head (Stuart); P.L. de Jong (Peter); M. Witsenburg (Maarten); A.P. Kappetein (Arie Pieter)

    2010-01-01

    textabstractAim of the study: To investigate the long-term outcome of surgical treatment for congenitally corrected transposition of the great arteries (CCTGA), in patients with biventricular repair with the right ventricle as systemic ventricle.Methods: A total of 32 patients with CCTGA were

  18. Network analysis of differential expression for the identification of disease-causing genes.

    Directory of Open Access Journals (Sweden)

    Daniela Nitsch

    Full Text Available Genetic studies (in particular linkage and association studies identify chromosomal regions involved in a disease or phenotype of interest, but those regions often contain many candidate genes, only a few of which can be followed-up for biological validation. Recently, computational methods to identify (prioritize the most promising candidates within a region have been proposed, but they are usually not applicable to cases where little is known about the phenotype (no or few confirmed disease genes, fragmentary understanding of the biological cascades involved. We seek to overcome this limitation by replacing knowledge about the biological process by experimental data on differential gene expression between affected and healthy individuals. Considering the problem from the perspective of a gene/protein network, we assess a candidate gene by considering the level of differential expression in its neighborhood under the assumption that strong candidates will tend to be surrounded by differentially expressed neighbors. We define a notion of soft neighborhood where each gene is given a contributing weight, which decreases with the distance from the candidate gene on the protein network. To account for multiple paths between genes, we define the distance using the Laplacian exponential diffusion kernel. We score candidates by aggregating the differential expression of neighbors weighted as a function of distance. Through a randomization procedure, we rank candidates by p-values. We illustrate our approach on four monogenic diseases and successfully prioritize the known disease causing genes.

  19. Assessing Tn5 and Sleeping Beauty for transpositional transgenesis by cytoplasmic injection into bovine and ovine zygotes

    Science.gov (United States)

    Bevacqua, R. J.; Fernandez-Martin, R.; Canel, N. G.; Gibbons, A.; Texeira, D.; Lange, F.; Vans Landschoot, G.; Savy, V.; Briski, O.; Hiriart, M. I.; Grueso, E.; Ivics, Z.; Taboga, O.; Kues, W. A.; Ferraris, S.

    2017-01-01

    Transgenic domestic animals represent an alternative to bioreactors for large-scale production of biopharmaceuticals and could also provide more accurate biomedical models than rodents. However, their generation remains inefficient. Recently, DNA transposons allowed improved transgenesis efficiencies in mice and pigs. In this work, Tn5 and Sleeping Beauty (SB) transposon systems were evaluated for transgenesis by simple cytoplasmic injection in livestock zygotes. In the case of Tn5, the transposome complex of transposon nucleic acid and Tn5 protein was injected. In the case of SB, the supercoiled plasmids encoding a transposon and the SB transposase were co-injected. In vitro produced bovine zygotes were used to establish the cytoplasmic injection conditions. The in vitro cultured blastocysts were evaluated for reporter gene expression and genotyped. Subsequently, both transposon systems were injected in seasonally available ovine zygotes, employing transposons carrying the recombinant human factor IX driven by the beta-lactoglobulin promoter. The Tn5 approach did not result in transgenic lambs. In contrast, the Sleeping Beauty injection resulted in 2 lambs (29%) carrying the transgene. Both animals exhibited cellular mosaicism of the transgene. The extraembryonic tissues (placenta or umbilical cord) of three additional animals were also transgenic. These results show that transpositional transgenesis by cytoplasmic injection of SB transposon components can be applied for the production of transgenic lambs of pharmaceutical interest. PMID:28301581

  20. Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy.

    Science.gov (United States)

    Maugeri, A; Klevering, B J; Rohrschneider, K; Blankenagel, A; Brunner, H G; Deutman, A F; Hoyng, C B; Cremers, F P

    2000-10-01

    The photoreceptor cell-specific ATP-binding cassette transporter gene (ABCA4; previously denoted "ABCR") is mutated, in most patients, with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients from Germany and The Netherlands with isolated CRD. Single-strand conformation-polymorphism analysis and sequencing revealed 19 ABCA4 mutations in 13 (65%) of 20 patients. In six patients, mutations were identified in both ABCA4 alleles; in seven patients, mutations were detected in one allele. One complex ABCA4 allele (L541P;A1038V) was found exclusively in German patients with CRD; one patient carried this complex allele homozygously, and five others were compound heterozygous. These findings suggest that mutations in the ABCA4 gene are the major cause of AR CRD. A primary role of the ABCA4 gene in STGD1/FFM and AR CRD, together with the gene's involvement in an as-yet-unknown proportion of cases with AR RP, strengthens the idea that mutations in the ABCA4 gene could be the most frequent cause of inherited retinal dystrophy in humans.

  1. Insights into the transposable mobilome of Paracoccus spp. (Alphaproteobacteria).

    Science.gov (United States)

    Dziewit, Lukasz; Baj, Jadwiga; Szuplewska, Magdalena; Maj, Anna; Tabin, Mateusz; Czyzkowska, Anna; Skrzypczyk, Grazyna; Adamczuk, Marcin; Sitarek, Tomasz; Stawinski, Piotr; Tudek, Agnieszka; Wanasz, Katarzyna; Wardal, Ewa; Piechucka, Ewa; Bartosik, Dariusz

    2012-01-01

    Several trap plasmids (enabling positive selection of transposition events) were used to identify a pool of functional transposable elements (TEs) residing in bacteria of the genus Paracoccus (Alphaproteobacteria). Complex analysis of 25 strains representing 20 species of this genus led to the capture and characterization of (i) 37 insertion sequences (ISs) representing 9 IS families (IS3, IS5, IS6, IS21, IS66, IS256, IS1182, IS1380 and IS1634), (ii) a composite transposon Tn6097 generated by two copies of the ISPfe2 (IS1634 family) containing two predicted genetic modules, involved in the arginine deiminase pathway and daunorubicin/doxorubicin resistance, (iii) 3 non-composite transposons of the Tn3 family, including Tn5393 carrying streptomycin resistance and (iv) a transposable genomic island TnPpa1 (45 kb). Some of the elements (e.g. Tn5393, Tn6097 and ISs of the IS903 group of the IS5 family) were shown to contain strong promoters able to drive transcription of genes placed downstream of the target site of transposition. Through the application of trap plasmid pCM132TC, containing a promoterless tetracycline resistance reporter gene, we identified five ways in which transposition can supply promoters to transcriptionally silent genes. Besides highlighting the diversity and specific features of several TEs, the analyses performed in this study have provided novel and interesting information on (i) the dynamics of the process of transposition (e.g. the unusually high frequency of transposition of TnPpa1) and (ii) structural changes in DNA mediated by transposition (e.g. the generation of large deletions in the recipient molecule upon transposition of ISPve1 of the IS21 family). We also demonstrated the great potential of TEs and transposition in the generation of diverse phenotypes as well as in the natural amplification and dissemination of genetic information (of adaptative value) by horizontal gene transfer, which is considered the driving force of bacterial

  2. Insights into the transposable mobilome of Paracoccus spp. (Alphaproteobacteria.

    Directory of Open Access Journals (Sweden)

    Lukasz Dziewit

    Full Text Available Several trap plasmids (enabling positive selection of transposition events were used to identify a pool of functional transposable elements (TEs residing in bacteria of the genus Paracoccus (Alphaproteobacteria. Complex analysis of 25 strains representing 20 species of this genus led to the capture and characterization of (i 37 insertion sequences (ISs representing 9 IS families (IS3, IS5, IS6, IS21, IS66, IS256, IS1182, IS1380 and IS1634, (ii a composite transposon Tn6097 generated by two copies of the ISPfe2 (IS1634 family containing two predicted genetic modules, involved in the arginine deiminase pathway and daunorubicin/doxorubicin resistance, (iii 3 non-composite transposons of the Tn3 family, including Tn5393 carrying streptomycin resistance and (iv a transposable genomic island TnPpa1 (45 kb. Some of the elements (e.g. Tn5393, Tn6097 and ISs of the IS903 group of the IS5 family were shown to contain strong promoters able to drive transcription of genes placed downstream of the target site of transposition. Through the application of trap plasmid pCM132TC, containing a promoterless tetracycline resistance reporter gene, we identified five ways in which transposition can supply promoters to transcriptionally silent genes. Besides highlighting the diversity and specific features of several TEs, the analyses performed in this study have provided novel and interesting information on (i the dynamics of the process of transposition (e.g. the unusually high frequency of transposition of TnPpa1 and (ii structural changes in DNA mediated by transposition (e.g. the generation of large deletions in the recipient molecule upon transposition of ISPve1 of the IS21 family. We also demonstrated the great potential of TEs and transposition in the generation of diverse phenotypes as well as in the natural amplification and dissemination of genetic information (of adaptative value by horizontal gene transfer, which is considered the driving force of

  3. SCREEN FOR DOMINANT BEHAVIORAL MUTATIONS CAUSED BY GENOMIC INSERTION OF P-ELEMENT TRANSPOSONS IN DROSOPHILA: AN EXAMINATION OF THE INTEGRATION OF VIRAL VECTOR SEQUENCES

    OpenAIRE

    FOX, LYLE E.; GREEN, DAVID; YAN, ZIYING; ENGELHARDT, JOHN F.; WU, CHUN-FANG

    2007-01-01

    Here we report the development of a high-throughput screen to assess dominant mutation rates caused by P-element transposition within the Drosophila genome that is suitable for assessing the undesirable effects of integrating foreign regulatory sequences (viral cargo) into a host genome. Three different behavioral paradigms were used: sensitivity to mechanical stress, response to heat stress, and ability to fly. The results, from our screen of 35,000 flies, indicate that mutations caused by t...

  4. Germline heterozygous variants in genes associated with familial hemophagocytic lymphohistiocytosis as a cause of increased bleeding

    DEFF Research Database (Denmark)

    Fager Ferrari, Marcus; Leinoe, Eva; Rossing, Maria

    2018-01-01

    Familial hemophagocytic lymphohistiocytosis (FHL) is caused by biallelic variants in genes regulating granule secretion in cytotoxic lymphocytes. In FHL3-5, the affected genes UNC13D, STX11 and STXBP2 have further been shown to regulate the secretion of platelet granules, giving rise to compromised...

  5. Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects

    DEFF Research Database (Denmark)

    Koene, S; Rodenburg, R J; van der Knaap, M S

    2012-01-01

    cases and 126 from literature) with mutations in nuclear genes encoding structural complex I proteins or those involved in its assembly. Complex I deficiency caused by a nuclear gene defect is usually a non-dysmorphic syndrome, characterized by severe multi-system organ involvement and a poor prognosis...

  6. Continuous inhaled iloprost in a neonate with d-transposition of the great arteries and severe pulmonary arterial hypertension.

    Science.gov (United States)

    Dykes, John C; Torres, Marilyn; Alexander, Plato J

    2016-03-01

    This report describes the case of a neonate with d-transposition of the great arteries and severe pulmonary arterial hypertension stabilised in the post-operative period with continuous iloprost nebulisation. To our knowledge, this is the first documented method of treating post-operative severe pulmonary arterial hypertension with continuous inhaled iloprost in a patient with complex CHD. We found this method of delivering the drug very effective in stabilising haemodynamic swings in the setting of severe pulmonary arterial hypertension.

  7. Nature of unstable insertional mutations and reversions at the cut locus of Drosophila melanogaster: Molecular mechanism for transpositional memory

    International Nuclear Information System (INIS)

    Mizrokhi, L.Yu.; Georgieva, S.G.; Obolenkova, L.A.; Priimyagi, A.F.; Gerasimova, T.I.; Il'in, Yu.V.

    1988-01-01

    A segment of the cut locus containing an mdg4 insertion as a result of ct MR and ct MRp10 mutations was cloned. Clones were obtained for the phenotypically different ct MR2 and ct MRpN10 mutants and for stable and unstable revertants. All mutations studied are associated with mdg4 insertion at an identical nucleotide sequence of the cut locus, the same site at which mdg4 is inserted at the ct 6 allele. The ct MRpN line differs from ct MR2 in that the mobile element jockey (3 kbp) is inserted in mdg4. Jockey is represented by about 1,000 copies per genome; it is homogeneous and lacks long terminal repeats (LTRs). In stable ct + reversions, mdg4 is completely excised. In unstable ct + reversions, in which there is a high degree of reverse directed transposition of mdg4 to the cut locus, an LTR of mdg4 is preserved at the site of the mutation. It is a sequence along which new copies of mdg4 or jockey-containing mdg4 are inserted into the genome. The authors discuss a molecular mechanism for transpositional memory involving homologous recombination of the remnant LTR and circular extrachromosomal copies of mdg4

  8. Schizophrenia: A Pathogenetic Autoimmune Disease Caused by Viruses and Pathogens and Dependent on Genes

    Directory of Open Access Journals (Sweden)

    C. J. Carter

    2011-01-01

    Full Text Available Many genes have been implicated in schizophrenia as have viral prenatal or adult infections and toxoplasmosis or Lyme disease. Several autoantigens also target key pathology-related proteins. These factors are interrelated. Susceptibility genes encode for proteins homologous to those of the pathogens while the autoantigens are homologous to pathogens' proteins, suggesting that the risk-promoting effects of genes and risk factors are conditional upon each other, and dependent upon protein matching between pathogen and susceptibility gene products. Pathogens' proteins may act as dummy ligands, decoy receptors, or via interactome interference. Many such proteins are immunogenic suggesting that antibody mediated knockdown of multiple schizophrenia gene products could contribute to the disease, explaining the immune activation in the brain and lymphocytes in schizophrenia, and the preponderance of immune-related gene variants in the schizophrenia genome. Schizophrenia may thus be a “pathogenetic” autoimmune disorder, caused by pathogens, genes, and the immune system acting together, and perhaps preventable by pathogen elimination, or curable by the removal of culpable antibodies and antigens.

  9. A single gene causes an interspecific difference in pigmentation in Drosophila.

    Science.gov (United States)

    Ahmed-Braimah, Yasir H; Sweigart, Andrea L

    2015-05-01

    The genetic basis of species differences remains understudied. Studies in insects have contributed significantly to our understanding of morphological evolution. Pigmentation traits in particular have received a great deal of attention and several genes in the insect pigmentation pathway have been implicated in inter- and intraspecific differences. Nonetheless, much remains unknown about many of the genes in this pathway and their potential role in understudied taxa. Here we genetically analyze the puparium color difference between members of the virilis group of Drosophila. The puparium of Drosophila virilis is black, while those of D. americana, D. novamexicana, and D. lummei are brown. We used a series of backcross hybrid populations between D. americana and D. virilis to map the genomic interval responsible for the difference between this species pair. First, we show that the pupal case color difference is caused by a single Mendelizing factor, which we ultimately map to an ∼11-kb region on chromosome 5. The mapped interval includes only the first exon and regulatory region(s) of the dopamine N-acetyltransferase gene (Dat). This gene encodes an enzyme that is known to play a part in the insect pigmentation pathway. Second, we show that this gene is highly expressed at the onset of pupation in light brown taxa (D. americana and D. novamexicana) relative to D. virilis, but not in the dark brown D. lummei. Finally, we examine the role of Dat in adult pigmentation between D. americana (heavily melanized) and D. novamexicana (lightly melanized) and find no discernible effect of this gene in adults. Our results demonstrate that a single gene is entirely or almost entirely responsible for a morphological difference between species. Copyright © 2015 by the Genetics Society of America.

  10. TET-mediated oxidation of methylcytosine causes TDG or NEIL glycosylase dependent gene reactivation.

    Science.gov (United States)

    Müller, Udo; Bauer, Christina; Siegl, Michael; Rottach, Andrea; Leonhardt, Heinrich

    2014-07-01

    The discovery of hydroxymethyl-, formyl- and carboxylcytosine, generated through oxidation of methylcytosine by TET dioxygenases, raised the question how these modifications contribute to epigenetic regulation. As they are subjected to complex regulation in vivo, we dissected links to gene expression with in vitro modified reporter constructs. We used an Oct4 promoter-driven reporter gene and demonstrated that in vitro methylation causes gene silencing while subsequent oxidation with purified catalytic domain of TET1 leads to gene reactivation. To identify proteins involved in this pathway we screened for TET interacting factors and identified TDG, PARP1, XRCC1 and LIG3 that are involved in base-excision repair. Knockout and rescue experiments demonstrated that gene reactivation depended on the glycosylase TDG, but not MBD4, while NEIL1, 2 and 3 could partially rescue the loss of TDG. These results clearly show that oxidation of methylcytosine by TET dioxygenases and subsequent removal by TDG or NEIL glycosylases and the BER pathway results in reactivation of epigenetically silenced genes. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  11. Autosomal recessive retinitis pigmentosa caused by mutations in the MAK gene.

    Science.gov (United States)

    Stone, Edwin M; Luo, Xunda; Héon, Elise; Lam, Byron L; Weleber, Richard G; Halder, Jennifer A; Affatigato, Louisa M; Goldberg, Jacqueline B; Sumaroka, Alexander; Schwartz, Sharon B; Cideciyan, Artur V; Jacobson, Samuel G

    2011-12-28

    To determine the disease expression in autosomal recessive (ar) retinitis pigmentosa (RP) caused by mutations in the MAK (male germ cell-associated kinase) gene. Patients with RP and MAK gene mutations (n = 24; age, 32-77 years at first visit) were studied by ocular examination, perimetry, and optical coherence tomography (OCT). All but one MAK patient were homozygous for an identical truncating mutation in exon 9 and had Ashkenazi Jewish heritage. The carrier frequency of this mutation among 1207 unrelated Ashkenazi control subjects was 1 in 55, making it the most common cause of heritable retinal disease in this population and MAK-associated RP the sixth most common Mendelian disease overall in this group. Visual acuities could be normal into the eighth decade of life. Kinetic fields showed early loss in the superior-temporal quadrant. With more advanced disease, superior and midperipheral function was lost, but the nasal field remained. Only a central island was present at late stages. Pigmentary retinopathy was less prominent in the superior nasal quadrant. Rod-mediated vision was abnormal but detectable in the residual field; all patients had rod>cone dysfunction. Photoreceptor layer thickness was normal centrally but decreased with eccentricity. At the stages studied, there was no evidence of photoreceptor ciliary elongation. The patterns of disease expression in the MAK form of arRP showed some resemblance to patterns described in autosomal dominant RP, especially the form caused by RP1 mutations. The similarity in phenotypes is of interest, considering that there is experimental evidence of interaction between Mak and RP1 in the photoreceptor cilium.

  12. A large inversion in the linear chromosome of Streptomyces griseus caused by replicative transposition of a new Tn3 family transposon.

    Science.gov (United States)

    Murata, M; Uchida, T; Yang, Y; Lezhava, A; Kinashi, H

    2011-04-01

    We have comprehensively analyzed the linear chromosomes of Streptomyces griseus mutants constructed and kept in our laboratory. During this study, macrorestriction analysis of AseI and DraI fragments of mutant 402-2 suggested a large chromosomal inversion. The junctions of chromosomal inversion were cloned and sequenced and compared with the corresponding target sequences in the parent strain 2247. Consequently, a transposon-involved mechanism was revealed. Namely, a transposon originally located at the left target site was replicatively transposed to the right target site in an inverted direction, which generated a second copy and at the same time caused a 2.5-Mb chromosomal inversion. The involved transposon named TnSGR was grouped into a new subfamily of the resolvase-encoding Tn3 family transposons based on its gene organization. At the end, terminal diversity of S. griseus chromosomes is discussed by comparing the sequences of strains 2247 and IFO13350.

  13. In vitro fertilization surrogate pregnancy in a patient who underwent radical hysterectomy followed by ovarian transposition, lower abdominal wall radiotherapy, and chemotherapy.

    Science.gov (United States)

    Steigrad, Stephen; Hacker, Neville F; Kolb, Bradford

    2005-05-01

    To describe an IVF surrogate pregnancy from a patient who had a radical hysterectomy followed by excision of a laparoscopic port site implantation with ovarian transposition followed by abdominal wall irradiation and chemotherapy, which resulted in premature ovarian failure from which there was partial recovery. Case report. Tertiary referral university women's hospital in Sydney, Australia and private reproductive medicine clinic in California. A 34-year-old woman who underwent laparoscopy for pelvic pain, shortly afterward followed by radical hysterectomy and pelvic lymph node dissection, who subsequently developed a laparoscopic port site recurrence, which was excised in association with ovarian transposition before abdominal wall irradiation and chemotherapy. Modified IVF treatment, transabdominal oocyte retrieval, embryo cryopreservation in Australia, and transfer to a surrogate mother in the United States. Pregnancy. Miscarriage in the second cycle and a twin pregnancy in the fourth cycle. This is the first case report of ovarian stimulation and oocyte retrieval performed on transposed ovaries after a patient developed premature ovarian failure after radiotherapy and chemotherapy with subsequent partial ovarian recovery.

  14. Gene therapy for the circumvention of inborn errors of metabolism (IEM) caused by single-nucleotide-polymorphisms (SNPs).

    Science.gov (United States)

    Wiseman, Alan

    2004-01-01

    Single nucleotide polymorphisms (SNPs) are the result of point mutations in nuclear (and mitochondrial) DNA. Such localised damage to DNA (and its replicative mechanisms) may not be excised fully by the DNA repair mechanism in the genome: and therefore can become inheritable; subsequently to manifest later as an inborn error of metabolism (IEM). Causes of mutagenic damage to the DNA can include background radiation (such as emitted by radon gas), and by reactive oxygen species (ROS): and also by mutagenic chemicals that occur naturally (inter alia in the diet). Other causes of DNA damage are variable environmental hazards such as solar-derived short wave ultraviolet light A. Gene therapy involves the placement of missing genes into particular tissues by the harnessing of suitable vectors (originally these were animal viruses such as SV40). For example, gene therapy in the rat for diabetes has succeeded by liver-production of insulin (using genes obtained from pancreatic Islets of Langerhans cells). Many inborn errors of metabolism could be treated in this way: examples may include 100 haemoglobinopathies (such as sickle cell anaemia), phenylketonuria; and other diseases caused by lack of tissue-production of a particular enzyme (in its catalytically-active conformation).

  15. [From gene to disease; genetic causes of hearing loss and visual impairment sometimes accompanied by vestibular problems (Usher syndrome)].

    Science.gov (United States)

    Pennings, R J E; Kremer, H; Deutman, A F; Kimberling, W J; Cremers, C W R J

    2002-12-07

    Usher syndrome is an autosomal recessively inherited disease, characterised by sensorineural hearing loss, tapetoretinal degeneration and in some cases vestibular problems. Based on the clinical heterogeneity, the disease can be classified into three clinical types (I, II and III), which have their own genetic subtypes (Usher 1A-Usher IG, Usher 2A-Usher 2C and Usher 3). The majority of the Usher type I cases are caused by mutations in the MYO7A gene (Usher 1B) while mutations in the USH2A gene (Usher 2A) are the cause of most cases of type II. Usher syndrome type III, caused by mutations in the USH3 gene, is frequently seen only in Finland.

  16. XLID-Causing Mutations and Associated Genes Challenged in Light of Data From Large-Scale Human Exome Sequencing

    OpenAIRE

    Piton, Amélie; Redin, Claire; Mandel, Jean-Louis

    2013-01-01

    Because of the unbalanced sex ratio (1.3–1.4 to 1) observed in intellectual disability (ID) and the identification of large ID-affected families showing X-linked segregation, much attention has been focused on the genetics of X-linked ID (XLID). Mutations causing monogenic XLID have now been reported in over 100 genes, most of which are commonly included in XLID diagnostic gene panels. Nonetheless, the boundary between true mutations and rare non-disease-causing variants often remains elusive...

  17. Contiguous gene deletion of chromosome 2p16.3-p21 as a cause of Lynch syndrome.

    Science.gov (United States)

    Salo-Mullen, Erin E; Lynn, Patricio B; Wang, Lu; Walsh, Michael; Gopalan, Anuradha; Shia, Jinru; Tran, Christina; Man, Fung Ying; McBride, Sean; Schattner, Mark; Zhang, Liying; Weiser, Martin R; Stadler, Zsofia K

    2018-01-01

    Lynch syndrome is an autosomal dominant condition caused by pathogenic mutations in the DNA mismatch repair (MMR) genes. Although commonly associated with clinical features such as intellectual disability and congenital anomalies, contiguous gene deletions may also result in cancer predisposition syndromes. We report on a 52-year-old male with Lynch syndrome caused by deletion of chromosome 2p16.3-p21. The patient had intellectual disability and presented with a prostatic adenocarcinoma with an incidentally identified synchronous sigmoid adenocarcinoma that exhibited deficient MMR with an absence of MSH2 and MSH6 protein expression. Family history was unrevealing. Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles. The patient underwent total colectomy with ileorectal anastomosis for a pT3N1 sigmoid adenocarcinoma. Germline genetic testing of the MSH2, MSH6, and EPCAM genes revealed full gene deletions. SNP-array based DNA copy number analysis identified a deletion of 4.8 Mb at 2p16.3-p21. In addition to the three Lynch syndrome associated genes, the deleted chromosomal section encompassed genes including NRXN1, CRIPT, CALM2, FBXO11, LHCGR, MCFD2, TTC7A, EPAS1, PRKCE, and 15 others. Contiguous gene deletions have been described in other inherited cancer predisposition syndromes, such as Familial Adenomatous Polyposis. Our report and review of the literature suggests that contiguous gene deletion within the 2p16-p21 chromosomal region is a rare cause of Lynch syndrome, but presents with distinct phenotypic features, highlighting the need for recognition and awareness of this syndromic entity.

  18. No muscle involvement in myoclonus-dystonia caused by epsilon-sarcoglycan gene mutations1

    DEFF Research Database (Denmark)

    Hjermind, L.E.; Vissing, J.; Asmus, F.

    2008-01-01

    Mutations in the epsilon-sarcoglycan gene (SGCE) can cause autosomal dominant inherited myoclonus-dystonia (M-D). Defects in other sarcoglycans; alpha-, beta-, gamma-, and delta can cause autosomal recessive inherited limb girdle muscular dystrophies. epsilon- and alpha-sarcoglycans are very...... strength and mass showed no difference between M-D patients and controls. Our findings indicate that patients with M-D have no signs or symptoms of muscle disease. This suggests a different role of the sarcoglycan complex epsilonbetagammadelta versus alphabetagammadelta complex in humans, as earlier...

  19. Gene amplification as a cause of inherited thyroxine-binding globulin excess in two Japanese families

    Energy Technology Data Exchange (ETDEWEB)

    Mori, Yuichi; Miura, Yoshitaka; Saito, Hidehiko [Toyota Memorial Hospital (Japan)] [and others

    1995-12-01

    T{sub 4}-binding globulin (TBG) is the major thyroid hormone transport protein in man. Inherited abnormalities in the level of serum TBG have been classified as partial deficiency, complete deficiency, and excess. Sequencing analysis of the TBG gene, located on Xq21-22, has uncovered the molecular defects causing partial and complete deficiency. However, the mechanism leading to inherited TBG excess remains unknown. In this study, two Japanese families, F-A and F-T, with inherited TBG excess were analyzed. Serum TBG levels in hemizygous males were 58 and 44 {mu}g/mL, 3- and 2-fold the normal value, respectively. The molecule had normal properties in terms of heat stability and isoelectric focussing pattern. The sequence of the coding region and the promoter activity of the TBG gene were also indistinguishable between hemizygotes and normal subjects. The gene dosage of TBG relative to that of {beta}-globin, which is located on chromosome 11, and Duchenne muscular dystropy, which is located on Xp, was evaluated by coamplification of these target genes using polymerase chain reaction and subsequent quantitation by HPLC. The TBG/{beta}-globin ratios of the affected male and female of F-A were 3.13 and 4.13 times, respectively, that in the normal males. The TBG/Duchenne muscular dystrophy ratios were 2.92 and 2.09 times the normal value, respectively. These results are compatible with three copies of TBG gene on the affected X-chromosome. Similarly, a 2-fold increase in gene dosage was demonstrated in the affected hemizygote of F-T. A 3-fold tandem amplification of the TBG gene was shown by in situ hybridization of prometaphase and interphase chromosomes from the affected male with a biotinylated genomic TBG probe, confirming the gene dosage results. Gene amplification of TBG is the cause of inherited TBG excess in these two families. 35 refs., 3 figs., 2 tabs.

  20. Masseteric-facial nerve transposition for reanimation of the smile in incomplete facial paralysis.

    Science.gov (United States)

    Hontanilla, Bernardo; Marre, Diego

    2015-12-01

    Incomplete facial paralysis occurs in about a third of patients with Bell's palsy. Although their faces are symmetrical at rest, when they smile they have varying degrees of disfigurement. Currently, cross-face nerve grafting is one of the most useful techniques for reanimation. Transfer of the masseteric nerve, although widely used for complete paralysis, has not to our knowledge been reported for incomplete palsy. Between December 2008 and November 2013, we reanimated the faces of 9 patients (2 men and 7 women) with incomplete unilateral facial paralysis with transposition of the masseteric nerve. Sex, age at operation, cause of paralysis, duration of denervation, recipient nerves used, and duration of follow-up were recorded. Commissural excursion, velocity, and patients' satisfaction were evaluated with the FACIAL CLIMA and a questionnaire, respectively. The mean (SD) age at operation was 39 (±6) years and the duration of denervation was 29 (±19) months. There were no complications that required further intervention. Duration of follow-up ranged from 6-26 months. FACIAL CLIMA showed improvement in both commissural excursion and velocity of more than two thirds in 6 patients, more than one half in 2 patients and less than one half in one. Qualitative evaluation showed a slight or pronounced improvement in 7/9 patients. The masseteric nerve is a reliable alternative for reanimation of the smile in patients with incomplete facial paralysis. Its main advantages include its consistent anatomy, a one-stage operation, and low morbidity at the donor site. Copyright © 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

  1. Long-term results after atrial correction of complete transposition of the great arteries.

    Science.gov (United States)

    Merlo, M; de Tommasi, S M; Brunelli, F; Abbruzzese, P A; Crupi, G; Ghidoni, I; Casari, A; Pitì, A; Mamprin, F; Parenzan, L

    1991-02-01

    This study presents the late results for the first 104 consecutive patients surviving and atrial repair for transposition of the great arteries (TGA) between January 1971 and December 1978 (group 1). Mean follow-up was 12 years (range, 0.1 to 17.7 years). The actuarial survival rate at 18 years was 84.2% (70% confidence limits, 79% to 88%) for simple TGA and 93.7% (70% confidence limits, 84% to 97%) for complex TGA. Nine of the 11 deaths were sudden. Two (2.6%) of the 78 late survivors operated on for simple TGA are in New York Heart Association functional class III or IV versus 4 (26.7%) of the 15 survivors with complex TGA; the other patients are doing very well. To better assess long-term results, we report the findings for randomly obtained electrocardiograms, Holter monitor recordings, radionuclide angiographic studies, and cardiac catheterizations performed in 1987 in a larger group of 159 long-term survivors of atrial repair operated on at Ospedale Riuniti di Bergamo from January 1971 to December 1984 (group 2), which includes all of group 1. The findings confirm that the arterial switch repair is the procedure of choice for complex TGA and that there is a major incidence (approximately 10%) of systemic right ventricular dysfunction and rhythm disturbances after the atrial repair. On the other hand, our late survival rate at 18 years of 84% for simple TGA with 97.5% of the patients in functional class I is a result that should be kept in mind, especially in institutions where the arterial switch is a relatively new approach and presumably is a higher risk to cause early death.

  2. Surgical transposition of the ovaries: imaging findings in 14 patients.

    Science.gov (United States)

    Kier, R; Chambers, S K

    1989-11-01

    Pelvic radiation therapy for cervical or vaginal cancer often leads to ovarian failure. To remove the ovaries from the radiation portal and preserve their function, they can be transposed to the lateral abdomen. Serial imaging studies in 14 patients who had undergone ovarian transposition (five bilateral, nine unilateral) were reviewed. Images obtained included 32 CT scans, 20 sonograms, and one MR image. Most transposed ovaries were located along the paracolic gutters near the iliac crests, creating an extrinsic mass effect on adjacent bowel. Detection of surgical clips on the ovary on CT scans allowed confident recognition of all 19 transposed ovaries. Cysts in the transposed ovaries, noted on most imaging studies, did not correlate with complications of pain or hormonal dysfunction. In one case, a large physiologic cyst in a transposed ovary distorted the cecum and was mistaken for a mucocele of the appendix. In another case, a large ovarian cyst was thought to be tumor recurrence or a lymphocele. These findings indicate that although the transposed ovaries can be recognized on CT scans by the surgical clips attached to the ovaries, the appearance of the ovary does not predict reliably the development of complications.

  3. Surgical transposition of the ovaries: Imaging findings in 14 patients

    International Nuclear Information System (INIS)

    Kier, R.; Chambers, S.K.

    1989-01-01

    Pelvic radiation therapy for cervical or vaginal cancer often leads to ovarian failure. To remove the ovaries from the radiation portal and preserve their function, they can be transposed to the lateral abdomen. Serial imaging studies in 14 patients who had undergone ovarian transposition (five bilateral, nine unilateral) were reviewed. Images obtained included 32 CT scans, 20 sonograms, and one MR image. Most transposed ovaries were located along the paracolic gutters near the iliac crests, creating an extrinsic mass effect on adjacent bowel. Detection of surgical clips on the ovary on CT scans allowed confident recognition of all 19 transposed ovaries. Cysts in the transposed ovaries, noted on most imaging studies, did not correlate with complications of pain or hormonal dysfunction. In one case, a large physiologic cyst in a transposed ovary distorted the cecum and was mistaken for a mucocele of the appendix. In another case, a large ovarian cyst was thought to be tumor recurrence or a lymphocele. These findings indicate that although the transposed ovaries can be recognized on CT scans by the surgical clips attached to the ovaries, the appearance of the ovary does not predict reliably the development of complications

  4. Birth and death of gene overlaps in vertebrates

    Directory of Open Access Journals (Sweden)

    Makałowska Izabela

    2007-10-01

    Full Text Available Abstract Background Between five and fourteen per cent of genes in the vertebrate genomes do overlap sharing some intronic and/or exonic sequence. It was observed that majority of these overlaps are not conserved among vertebrate lineages. Although several mechanisms have been proposed to explain gene overlap origination the evolutionary basis of these phenomenon are still not well understood. Here, we present results of the comparative analysis of several vertebrate genomes. The purpose of this study was to examine overlapping genes in the context of their evolution and mechanisms leading to their origin. Results Based on the presence and arrangement of human overlapping genes orthologs in rodent and fish genomes we developed 15 theoretical scenarios of overlapping genes evolution. Analysis of these theoretical scenarios and close examination of genomic sequences revealed new mechanisms leading to the overlaps evolution and confirmed that many of the vertebrate gene overlaps are not conserved. This study also demonstrates that repetitive elements contribute to the overlapping genes origination and, for the first time, that evolutionary events could lead to the loss of an ancient overlap. Conclusion Birth as well as most probably death of gene overlaps occurred over the entire time of vertebrate evolution and there wasn't any rapid origin or 'big bang' in the course of overlapping genes evolution. The major forces in the gene overlaps origination are transposition and exaptation. Our results also imply that origin of overlapping genes is not an issue of saving space and contracting genomes size.

  5. [Using exon combined target region capture sequencing chip to detect the disease-causing genes of retinitis pigmentosa].

    Science.gov (United States)

    Rong, Weining; Chen, Xuejuan; Li, Huiping; Liu, Yani; Sheng, Xunlun

    2014-06-01

    To detect the disease-causing genes of 10 retinitis pigmentosa pedigrees by using exon combined target region capture sequencing chip. Pedigree investigation study. From October 2010 to December 2013, 10 RP pedigrees were recruited for this study in Ningxia Eye Hospital. All the patients and family members received complete ophthalmic examinations. DNA was abstracted from patients, family members and controls. Using exon combined target region capture sequencing chip to screen the candidate disease-causing mutations. Polymerase chain reaction (PCR) and direct sequencing were used to confirm the disease-causing mutations. Seventy patients and 23 normal family members were recruited from 10 pedigrees. Among 10 RP pedigrees, 1 was autosomal dominant pedigrees and 9 were autosomal recessive pedigrees. 7 mutations related to 5 genes of 5 pedigrees were detected. A frameshift mutation on BBS7 gene was detected in No.2 pedigree, the patients of this pedigree combined with central obesity, polydactyly and mental handicap. No.2 pedigree was diagnosed as Bardet-Biedl syndrome finally. A missense mutation was detected in No.7 and No.10 pedigrees respectively. Because the patients suffered deafness meanwhile, the final diagnosis was Usher syndrome. A missense mutation on C3 gene related to age-related macular degeneration was also detected in No. 7 pedigrees. A nonsense mutation and a missense mutation on CRB1 gene were detected in No. 1 pedigree and a splicesite mutation on PROM1 gene was detected in No. 5 pedigree. Retinitis pigmentosa is a kind of genetic eye disease with diversity clinical phenotypes. Rapid and effective genetic diagnosis technology combined with clinical characteristics analysis is helpful to improve the level of clinical diagnosis of RP.

  6. Optimization of the representativeness and transposition approach, for the neutronic design of experimental programs in critical mock-up

    International Nuclear Information System (INIS)

    Dos-Santos, N.

    2013-01-01

    The work performed during this thesis focused on uncertainty propagation (nuclear data, technological uncertainties, calculation biases,...) on integral parameters, and the development of a novel approach enabling to reduce this uncertainty a priori directly from the design phase of a new experimental program. This approach is based on a multi-parameter multi-criteria extension of representativeness and transposition theories. The first part of this PhD work covers an optimization study of sensitivity and uncertainty calculation schemes to different modeling scales (cell, assembly and whole core) for LWRs and FBRs. A degraded scheme, based on standard and generalized perturbation theories, has been validated for the calculation of uncertainty propagation to various integral quantities of interest. It demonstrated the good a posteriori representativeness of the EPICURE experiment for the validation of mixed UOX-MOX loadings, as the importance of some nuclear data in the power tilt phenomenon in large LWR cores. The second part of this work was devoted to methods and tools development for the optimized design of experimental programs in ZPRs. Those methods are based on multi-parameters representativeness using simultaneously various quantities of interest. Finally, an original study has been conducted on the rigorous estimation of correlations between experimental programs in the transposition process. The coupling of experimental correlations and multi-parametric representativeness approach enables to efficiently design new programs, able to answer additional qualification requirements on calculation tools. (author) [fr

  7. Orthodontic management of bilateral maxillary canine-first premolar transposition and bilateral agenesis of maxillary lateral incisors: a case report.

    Science.gov (United States)

    Di Palma, Elena; Di Giuseppe, Biagio; Tepedino, Michele; Chimenti, Claudio

    2015-01-01

    Maxillary canine-first premolar transposition (Mx.C.P1) is an uncommon dental positional anomaly that may create many orthodontic problems from both esthetic and functional points of view. In this report we show the orthodontic management of a case of Mx.C.P1 associated with bilateral maxillary lateral incisor agenesis and unilateral mandibular second premolar agenesis The patient was treated with a multibracket appliance and the extraction of the lower premolar. treatment was completed without the need for any prosthetic replacement.

  8. The Arabidopsis thaliana mobilome and its impact at the species level.

    Science.gov (United States)

    Quadrana, Leandro; Bortolini Silveira, Amanda; Mayhew, George F; LeBlanc, Chantal; Martienssen, Robert A; Jeddeloh, Jeffrey A; Colot, Vincent

    2016-06-03

    Transposable elements (TEs) are powerful motors of genome evolution yet a comprehensive assessment of recent transposition activity at the species level is lacking for most organisms. Here, using genome sequencing data for 211 Arabidopsis thaliana accessions taken from across the globe, we identify thousands of recent transposition events involving half of the 326 TE families annotated in this plant species. We further show that the composition and activity of the 'mobilome' vary extensively between accessions in relation to climate and genetic factors. Moreover, TEs insert equally throughout the genome and are rapidly purged by natural selection from gene-rich regions because they frequently affect genes, in multiple ways. Remarkably, loci controlling adaptive responses to the environment are the most frequent transposition targets observed. These findings demonstrate the pervasive, species-wide impact that a rich mobilome can have and the importance of transposition as a recurrent generator of large-effect alleles.

  9. [Reconstruction of the extensor pollicis longus tendon by transposition of the extensor indicis tendon].

    Science.gov (United States)

    Loos, A; Kalb, K; Van Schoonhoven, J; Landsleitner Dagger, B

    2003-12-01

    Rupture of the extensor pollicis longus-tendon (EPL) is a frequent complication after distal radius fractures. Other traumatic and non-traumatic reasons for this tendon lesion are known, including a theory about a disorder in the blood supply to the tendon itself. We examined 40 patients after reconstruction of the EPL-tendon in a mean follow-up time of 30 months. All patients were clinically examined and a DASH questionnaire was answered by all patients. The method to reconstruct the EPL-tendon was the transposition of the extensor indicis-tendon. After the operations the thumb was put in a splint for four weeks in a "hitch-hiker's-position". 31 ruptures of the tendon (77.5 %) were a result of trauma. In 20 of them (50 %) a distal radius fracture had occurred. Clinical examination included measurements of the movement of the thumb- and index-finger joints, the grip strength and the maximal span of the hand. Significant differences were not found. The isolated extension of the index finger was possible in all patients. But it was reduced in ten cases which represent 25 %. Our results were evaluated by the Geldmacher score to evaluate the reconstruction of the EPL-tendon. 20 % excellent, 65 % good, 12.5 % fair and 2.5 % poor results were reached. The Geldmacher score was used critically. We suggest its modification for the evaluation of thumb abduction. The DASH score reached a functional value of ten points which represents a very good result. In conclusion the extensor indicis-transposition is a safe method to reconstruct the EPL-tendon. Its substantial advantage is taking a healthy muscle as the motor, thereby avoiding the risk of using a degenerated muscle in late tendon reconstruction. A powerful extension of the index finger will be maintained by physical education. Generally, the loss of the extension of the index finger is negligible. It does not disturb the patients. But it has to be discussed with the patient before the operation.

  10. Splicing defect in FKBP10 gene causes autosomal recessive osteogenesis imperfecta disease: a case report.

    Science.gov (United States)

    Maghami, Fatemeh; Tabei, Seyed Mohammad Bagher; Moravej, Hossein; Dastsooz, Hassan; Modarresi, Farzaneh; Silawi, Mohammad; Faghihi, Mohammad Ali

    2018-05-25

    Osteogenesis imperfecta (OI) is a group of connective tissue disorder caused by mutations of genes involved in the production of collagen and its supporting proteins. Although the majority of reported OI variants are in COL1A1 and COL1A2 genes, recent reports have shown problems in other non-collagenous genes involved in the post translational modifications, folding and transport, transcription and proliferation of osteoblasts, bone mineralization, and cell signaling. Up to now, 17 types of OI have been reported in which types I to IV are the most frequent cases with autosomal dominant pattern of inheritance. Here we report an 8- year- old boy with OI who has had multiple fractures since birth and now he is wheelchair-dependent. To identify genetic cause of OI in our patient, whole exome sequencing (WES) was carried out and it revealed a novel deleterious homozygote splice acceptor site mutation (c.1257-2A > G, IVS7-2A > G) in FKBP10 gene in the patient. Then, the identified mutation was confirmed using Sanger sequencing in the proband as homozygous and in his parents as heterozygous, indicating its autosomal recessive pattern of inheritance. In addition, we performed RT-PCR on RNA transcripts originated from skin fibroblast of the proband to analyze the functional effect of the mutation on splicing pattern of FKBP10 gene and it showed skipping of the exon 8 of this gene. Moreover, Real-Time PCR was carried out to quantify the expression level of FKBP10 in the proband and his family members in which it revealed nearly the full decrease in the level of FKBP10 expression in the proband and around 75% decrease in its level in the carriers of the mutation, strongly suggesting the pathogenicity of the mutation. Our study identified, for the first time, a private pathogenic splice site mutation in FKBP10 gene and further prove the involvement of this gene in the rare cases of autosomal recessive OI type XI with distinguished clinical manifestations.

  11. Conditional gene expression in the mouse using a Sleeping Beauty gene-trap transposon

    Directory of Open Access Journals (Sweden)

    Hackett Perry B

    2006-06-01

    Full Text Available Abstract Background Insertional mutagenesis techniques with transposable elements have been popular among geneticists studying model organisms from E. coli to Drosophila and, more recently, the mouse. One such element is the Sleeping Beauty (SB transposon that has been shown in several studies to be an effective insertional mutagen in the mouse germline. SB transposon vector studies have employed different functional elements and reporter molecules to disrupt and report the expression of endogenous mouse genes. We sought to generate a transposon system that would be capable of reporting the expression pattern of a mouse gene while allowing for conditional expression of a gene of interest in a tissue- or temporal-specific pattern. Results Here we report the systematic development and testing of a transposon-based gene-trap system incorporating the doxycycline-repressible Tet-Off (tTA system that is capable of activating the expression of genes under control of a Tet response element (TRE promoter. We demonstrate that the gene trap system is fully functional in vitro by introducing the "gene-trap tTA" vector into human cells by transposition and identifying clones that activate expression of a TRE-luciferase transgene in a doxycycline-dependent manner. In transgenic mice, we mobilize gene-trap tTA vectors, discover parameters that can affect germline mobilization rates, and identify candidate gene insertions to demonstrate the in vivo functionality of the vector system. We further demonstrate that the gene-trap can act as a reporter of endogenous gene expression and it can be coupled with bioluminescent imaging to identify genes with tissue-specific expression patterns. Conclusion Akin to the GAL4/UAS system used in the fly, we have made progress developing a tool for mutating and revealing the expression of mouse genes by generating the tTA transactivator in the presence of a secondary TRE-regulated reporter molecule. A vector like the gene

  12. Familial Dilated Cardiomyopathy Caused by a Novel Frameshift in the BAG3 Gene.

    Directory of Open Access Journals (Sweden)

    Rocio Toro

    Full Text Available Dilated cardiomyopathy, a major cause of chronic heart failure and cardiac transplantation, is characterized by left ventricular or biventricular heart dilatation. In nearly 50% of cases the pathology is inherited, and more than 60 genes have been reported as disease-causing. However, in 30% of familial cases the mutation remains unidentified even after comprehensive genetic analysis. This study clinically and genetically assessed a large Spanish family affected by dilated cardiomyopathy to search for novel variations.Our study included a total of 100 family members. Clinical assessment was performed in alive, and genetic analysis was also performed in alive and 1 deceased relative. Genetic screening included resequencing of 55 genes associated with sudden cardiac death, and Sanger sequencing of main disease-associated genes. Genetic analysis identified a frame-shift variation in BAG3 (p.H243Tfr*64 in 32 patients. Genotype-phenotype correlation identified substantial heterogeneity in disease expression. Of 32 genetic carriers (one deceased, 21 relatives were clinically affected, and 10 were asymptomatic. Seventeen of the symptomatic genetic carriers exhibited proto-diastolic septal knock by echocardiographic assessment.We report p.H243Tfr*64_BAG3 as a novel pathogenic variation responsible for familial dilated cardiomyopathy. This variation correlates with a more severe phenotype of the disease, mainly in younger individuals. Genetic analysis in families, even asymptomatic individuals, enables early identification of individuals at risk and allows implementation of preventive measures.

  13. Gene expression profiling: cell cycle deregulation and aneuploidy do not cause breast cancer formation in WAP-SVT/t transgenic animals.

    Science.gov (United States)

    Klein, Andreas; Guhl, Eva; Zollinger, Raphael; Tzeng, Yin-Jeh; Wessel, Ralf; Hummel, Michael; Graessmann, Monika; Graessmann, Adolf

    2005-05-01

    Microarray studies revealed that as a first hit the SV40 T/t antigen causes deregulation of 462 genes in mammary gland cells (ME cells) of WAP-SVT/t transgenic animals. The majority of deregulated genes are cell proliferation specific and Rb-E2F dependent, causing ME cell proliferation and gland hyperplasia but not breast cancer formation. In the breast tumor cells a further 207 genes are differentially expressed, most of them belonging to the cell communication category. In tissue culture breast tumor cells frequently switch off WAP-SVT/t transgene expression and regain the morphology and growth characteristics of normal ME cells, although the tumor-revertant cells are aneuploid and only 114 genes regain the expression level of normal ME cells. The profile of retransformants shows that only 38 deregulated genes are tumor-specific, and that none of them is considered to be a typical breast cancer gene.

  14. Methamphetamine causes differential alterations in gene expression and patterns of histone acetylation/hypoacetylation in the rat nucleus accumbens.

    Directory of Open Access Journals (Sweden)

    Tracey A Martin

    Full Text Available Methamphetamine (METH addiction is associated with several neuropsychiatric symptoms. Little is known about the effects of METH on gene expression and epigenetic modifications in the rat nucleus accumbens (NAC. Our study investigated the effects of a non-toxic METH injection (20 mg/kg on gene expression, histone acetylation, and the expression of the histone acetyltransferase (HAT, ATF2, and of the histone deacetylases (HDACs, HDAC1 and HDAC2, in that structure. Microarray analyses done at 1, 8, 16 and 24 hrs after the METH injection identified METH-induced changes in the expression of genes previously implicated in the acute and longterm effects of psychostimulants, including immediate early genes and corticotropin-releasing factor (Crf. In contrast, the METH injection caused time-dependent decreases in the expression of other genes including Npas4 and cholecystokinin (Cck. Pathway analyses showed that genes with altered expression participated in behavioral performance, cell-to-cell signaling, and regulation of gene expression. PCR analyses confirmed the changes in the expression of c-fos, fosB, Crf, Cck, and Npas4 transcripts. To determine if the METH injection caused post-translational changes in histone markers, we used western blot analyses and identified METH-mediated decreases in histone H3 acetylated at lysine 9 (H3K9ac and lysine 18 (H3K18ac in nuclear sub-fractions. In contrast, the METH injection caused time-dependent increases in acetylated H4K5 and H4K8. The changes in histone acetylation were accompanied by decreased expression of HDAC1 but increased expression of HDAC2 protein levels. The histone acetyltransferase, ATF2, showed significant METH-induced increased in protein expression. These results suggest that METH-induced alterations in global gene expression seen in rat NAC might be related, in part, to METH-induced changes in histone acetylation secondary to changes in HAT and HDAC expression. The causal role that HATs and

  15. Neonatal Marfan syndrome caused by an exon 25 mutation of the fibrillin-1 gene.

    Science.gov (United States)

    Elçioglu, N H; Akalin, F; Elçioglu, M; Comeglio, P; Child, A H

    2004-01-01

    Neonatal Marfan syndrome caused by an exon 25 mutation of the Fibrillin-1 gene: We describe a male infant with severe arachnodactyly, hypermobility of the fingers, flexion contractures of elbows, wrists, hips, and knees, microretrognathia, crumpled ears, rockerbottom feet, loose redundant skin, and lens dislocations. Cardiac valve insufficiency and aortic dilatation resulted in cardiac failure, decompensated with digitalisation and death occurred at the age of 4 months. This case represents the severe end of the clinical spectrum of Marfan syndrome, namely neonatal Marfan syndrome. Molecular diagnostic analyses confirmed a de novo exon 25 mutation in the FBN1 gene.

  16. Evolution of European Union legislation of herbal medicinal products and its transposition to national legislation in 1965-2007: case Finland.

    Science.gov (United States)

    Koski, Sari M; Laitinen-Parkkonen, Pirjo; Airaksinen, Marja

    2015-01-01

    The study aim was to explore the progress of legislation relating to herbal medicinal products in the European Union and compare it with the corresponding progress of the legislation in Finland in 1965-2007. The study was carried out using content analysis. Data were searched from publicly available European Union directives and national acts. All definitions and safety-related requirements for herbal medicinal products were identified. The transposition of safety-related requirements into the national legislation was studied. Medicinal products from plant origins have been part of the European Union legislation since 1965. Most plant-based products have not initially been regarded as medicinal products but rather as some kind of medicine-like products. The official definition of herbal medicinal products was introduced in Directive 2004/24/EC and implemented into the Finnish legislation with the terminology to recognise herbal medicinal products as part of medicinal products. The current safety-related requirements of medicinal products concern analogously herbal medicinal products. Herbal medicinal products have had different definitions in pharmaceutical legislation over the study period in the European Union and Finland. The current definition places herbal medicinal products more clearly under the medicinal products' legislation. Safety-related requirements are now practically identical for all medicinal products. Transposition of the European Union legislation into the national legislation in Finland is apparent. Copyright © 2013 John Wiley & Sons, Ltd.

  17. Genes and Gut Bacteria Involved in Luminal Butyrate Reduction Caused by Diet and Loperamide.

    Science.gov (United States)

    Hwang, Nakwon; Eom, Taekil; Gupta, Sachin K; Jeong, Seong-Yeop; Jeong, Do-Youn; Kim, Yong Sung; Lee, Ji-Hoon; Sadowsky, Michael J; Unno, Tatsuya

    2017-11-28

    Unbalanced dietary habits and gut dysmotility are causative factors in metabolic and functional gut disorders, including obesity, diabetes, and constipation. Reduction in luminal butyrate synthesis is known to be associated with gut dysbioses, and studies have suggested that restoring butyrate formation in the colon may improve gut health. In contrast, shifts in different types of gut microbiota may inhibit luminal butyrate synthesis, requiring different treatments to restore colonic bacterial butyrate synthesis. We investigated the influence of high-fat diets (HFD) and low-fiber diets (LFD), and loperamide (LPM) administration, on key bacteria and genes involved in reduction of butyrate synthesis in mice. MiSeq-based microbiota analysis and HiSeq-based differential gene analysis indicated that different types of bacteria and genes were involved in butyrate metabolism in each treatment. Dietary modulation depleted butyrate kinase and phosphate butyryl transferase by decreasing members of the Bacteroidales and Parabacteroides . The HFD also depleted genes involved in succinate synthesis by decreasing Lactobacillus . The LFD and LPM treatments depleted genes involved in crotonoyl-CoA synthesis by decreasing Roseburia and Oscilllibacter . Taken together, our results suggest that different types of bacteria and genes were involved in gut dysbiosis, and that selected treatments may be needed depending on the cause of gut dysfunction.

  18. Development of in vitro transposon assisted signal sequence trapping and its use in screening Bacillus halodurans C125 and Sulfolobus solfataricus P2 gene libraries

    DEFF Research Database (Denmark)

    Becker, F.; Schnorr, K.; Wilting, R.

    2004-01-01

    To identify genes encoding extracytosolic proteins, a minitransposon, TnSig, containing a signal-less beta-lactamase ('bla) as reporter gene, was constructed and used for in vitro transposition of genomic libraries made in Escherichia coli. The 'bla gene was cloned into a bacteriophage MU...... minitransposon enabling translational fusions between 'bla and target genes. Fusion of TnSig in the correct reading frame to a protein carrying transmembrane domains or signal peptides resulted in ampicillin resistance of the corresponding clone. Prokaryotic gene libraries from the alkaliphilic bacterium...... Bacillus halodurans C125 and the hyperthermophilic archaeon Sulfolobus solfataricus P2 were tagged with TnSig. The genomic sequences, which are publicly available (EMBL BA000004 and EMBL AE006641), were used for rapid open reading frame (ORF) identification and prediction of protein localisation...

  19. The Arabidopsis thaliana mobilome and its impact at the species level

    Science.gov (United States)

    Quadrana, Leandro; Bortolini Silveira, Amanda; Mayhew, George F; LeBlanc, Chantal; Martienssen, Robert A; Jeddeloh, Jeffrey A; Colot, Vincent

    2016-01-01

    Transposable elements (TEs) are powerful motors of genome evolution yet a comprehensive assessment of recent transposition activity at the species level is lacking for most organisms. Here, using genome sequencing data for 211 Arabidopsis thaliana accessions taken from across the globe, we identify thousands of recent transposition events involving half of the 326 TE families annotated in this plant species. We further show that the composition and activity of the 'mobilome' vary extensively between accessions in relation to climate and genetic factors. Moreover, TEs insert equally throughout the genome and are rapidly purged by natural selection from gene-rich regions because they frequently affect genes, in multiple ways. Remarkably, loci controlling adaptive responses to the environment are the most frequent transposition targets observed. These findings demonstrate the pervasive, species-wide impact that a rich mobilome can have and the importance of transposition as a recurrent generator of large-effect alleles. DOI: http://dx.doi.org/10.7554/eLife.15716.001 PMID:27258693

  20. Screening for mutations in the androgen receptor gene (AR) causing infertility in Syrian men using real-time PCR

    International Nuclear Information System (INIS)

    Madania, A.; Ghouri, I.; Abou-Alshamat, Gh.; Issa, M.; Al-Halabi, M.

    2012-01-01

    14 known point mutations in the androgen receptor gene (AR) causing male infertility were screened by real time PCR and by DNA sequencing, in order to identify point mutations in the AR gene causing infertility in azoospermic men. We screened 110 Syrian patients suffering from non-obstructive azoospermia with no chromosomal aberrations or AZF micro deletions. We discovered a new AR mutation, del 57Leu, described for the first time as a possible cause of male infertility. Furthermore, we found two patients with the Ala474Val mutation and one patient bearing the Pro390Ser mutation. Our results indicate that these mutations are significant markers for idiopathic male infertility in the Syrian society and in Mediterranean populations in general. (author)

  1. «Вольное переложение» Жития Феодора Студита"Free transposition" of The Life of Theodore Studite

    Directory of Open Access Journals (Sweden)

    Tamara P. Lönngren

    2012-01-01

    Full Text Available This article deals with the manuscript tradition named "free transposition" applied to The Life of Theodore Studite in Old Russian literature. Evidence is presented that the author of this "free transposition" was indeed Nil Sorskij. The investigation of eight recently discovered copies has made it possible to establish their mutual interdependence and to construct the corresponding stemma.

  2. First contiguous gene deletion causing biotinidase deficiency: The enzyme deficiency in three Sri Lankan children

    Directory of Open Access Journals (Sweden)

    Danika Nadeen Senanayake

    2015-03-01

    Full Text Available We report three symptomatic children with profound biotinidase deficiency from Sri Lanka. All three children presented with typical clinical features of the disorder. The first is homozygous for a missense mutation in the BTD gene (c.98_104 del7insTCC; p.Cys33PhefsX36 that is commonly seen in the western countries, the second is homozygous for a novel missense mutation (p.Ala439Asp, and the third is the first reported instance of a contiguous gene deletion causing the enzyme deficiency. In addition, this latter finding exemplifies the importance of considering a deletion within the BTD gene for reconciling enzymatic activity with genotype, which can occur in asymptomatic children who are identified by newborn screening.

  3. Radiological findings after transposition of the stomach for replacement of long oesophageal segments

    Energy Technology Data Exchange (ETDEWEB)

    Lechner, G.; Roka, R.; Niederle, B.; Waneck, R.

    1982-10-01

    Thirty-seven patients, in whom the stomach had been transposed in order to replace a long segment of the oesophagus, were studied. Radiologically important early complications and the late results of this surgical technique were correlated. Twenty-five patients were observed radiologically and clinically for a period of three to 20 months. The study was directed at the morphology of the transposed stomach and of the anastomosis, and particularly at the problem of gastro-oesophageal reflux. Knowledge of the operation site is essential for evaluating the transplant (pleura defect). Radiological examination is the most suitable method for evaluating the cervical extra-thoracic anastomosis in the early post-operative phase (six to ten days). It is also effective at a later stage for the early recognition of fibrotic stenosis which will require treatment. An attempt has been made to define an ideal situation following gastric transposition which will usually correspond with a good clinical result.

  4. A Gaijin-like miniature inverted repeat transposable element is mobilized in rice during cell differentiation

    Directory of Open Access Journals (Sweden)

    Dong Hai-Tao

    2012-04-01

    Full Text Available Abstract Background Miniature inverted repeat transposable element (MITE is one type of transposable element (TE, which is largely found in eukaryotic genomes and involved in a wide variety of biological events. However, only few MITEs were proved to be currently active and their physiological function remains largely unknown. Results We found that the amplicon discrepancy of a gene locus LOC_Os01g0420 in different rice cultivar genomes was resulted from the existence of a member of Gaijin-like MITEs (mGing. This result indicated that mGing transposition was occurred at this gene locus. By using a modified transposon display (TD analysis, the active transpositions of mGing were detected in rice Jiahua No. 1 genome under three conditions: in seedlings germinated from the seeds received a high dose γ-ray irradiation, in plantlets regenerated from anther-derived calli and from scutellum-derived calli, and were confirmed by PCR validation and sequencing. Sequence analysis revealed that single nucleotide polymorphisms (SNPs or short additional DNA sequences at transposition sites post mGing transposition. It suggested that sequence modification was possibly taken place during mGing transposition. Furthermore, cell re-differentiation experiment showed that active transpositions of both mGing and mPing (another well studied MITE were identified only in regenerated plantlets. Conclusions It is for the first time that mGing active transposition was demonstrated under γ-ray irradiation or in cell re-differentiation process in rice. This newly identified active MITE will provide a foundation for further analysis of the roles of MITEs in biological process.

  5. Environmental genomics of "Haloquadratum walsbyi" in a saltern crystallizer indicates a large pool of accessory genes in an otherwise coherent species

    Directory of Open Access Journals (Sweden)

    Bolhuis Henk

    2006-07-01

    Full Text Available Abstract Background Mature saturated brine (crystallizers communities are largely dominated (>80% of cells by the square halophilic archaeon "Haloquadratum walsbyi". The recent cultivation of the strain HBSQ001 and thesequencing of its genome allows comparison with the metagenome of this taxonomically simplified environment. Similar studies carried out in other extreme environments have revealed very little diversity in gene content among the cell lineages present. Results The metagenome of the microbial community of a crystallizer pond has been analyzed by end sequencing a 2000 clone fosmid library and comparing the sequences obtained with the genome sequence of "Haloquadratum walsbyi". The genome of the sequenced strain was retrieved nearly complete within this environmental DNA library. However, many ORF's that could be ascribed to the "Haloquadratum" metapopulation by common genome characteristics or scaffolding to the strain genome were not present in the specific sequenced isolate. Particularly, three regions of the sequenced genome were associated with multiple rearrangements and the presence of different genes from the metapopulation. Many transposition and phage related genes were found within this pool which, together with the associated atypical GC content in these areas, supports lateral gene transfer mediated by these elements as the most probable genetic cause of this variability. Additionally, these sequences were highly enriched in putative regulatory and signal transduction functions. Conclusion These results point to a large pan-genome (total gene repertoire of the genus/species even in this highly specialized extremophile and at a single geographic location. The extensive gene repertoire is what might be expected of a population that exploits a diverse nutrient pool, resulting from the degradation of biomass produced at lower salinities.

  6. Hypomorphic mutation in mouse Nppc gene causes retarded bone growth due to impaired endochondral ossification

    International Nuclear Information System (INIS)

    Tsuji, Takehito; Kondo, Eri; Yasoda, Akihiro; Inamoto, Masataka; Kiyosu, Chiyo; Nakao, Kazuwa; Kunieda, Tetsuo

    2008-01-01

    Long bone abnormality (lbab/lbab) is a spontaneous mutant mouse characterized by dwarfism with shorter long bones. A missense mutation was reported in the Nppc gene, which encodes C-type natriuretic peptide (CNP), but it has not been confirmed whether this mutation is responsible for the dwarf phenotype. To verify that the mutation causes the dwarfism of lbab/lbab mice, we first investigated the effect of CNP in lbab/lbab mice. By transgenic rescue with chondrocyte-specific expression of CNP, the dwarf phenotype in lbab/lbab mice was completely compensated. Next, we revealed that CNP derived from the lbab allele retained only slight activity to induce cGMP production through its receptor. Histological analysis showed that both proliferative and hypertrophic zones of chondrocytes in the growth plate of lbab/lbab mice were markedly reduced. Our results demonstrate that lbab/lbab mice have a hypomorphic mutation in the Nppc gene that is responsible for dwarfism caused by impaired endochondral ossification

  7. Alu-mediated large deletion of the CDSN gene as a cause of peeling skin disease.

    Science.gov (United States)

    Wada, T; Matsuda, Y; Muraoka, M; Toma, T; Takehara, K; Fujimoto, M; Yachie, A

    2014-10-01

    Peeling skin disease (PSD) is an autosomal recessive skin disorder caused by mutations in CDSN and is characterized by superficial peeling of the upper epidermis. Corneodesmosin (CDSN) is a major component of corneodesmosomes that plays an important role in maintaining epidermis integrity. Herein, we report a patient with PSD caused by a novel homozygous large deletion in the 6p21.3 region encompassing the CDSN gene, which abrogates CDSN expression. Several genes including C6orf15, PSORS1C1, PSORS1C2, CCHCR1, and TCF19 were also deleted, however, the patient showed only clinical features typical of PSD. The deletion size was 59.1 kb. Analysis of the sequence surrounding the breakpoint showed that both telomeric and centromeric breakpoints existed within Alu-S sequences that were oriented in opposite directions. These results suggest an Alu-mediated recombination event as the mechanism underlying the deletion in our patient. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Gene Therapy for the Retinal Degeneration of Usher Syndrome Caused by Mutations in MYO7A.

    Science.gov (United States)

    Lopes, Vanda S; Williams, David S

    2015-01-20

    Usher syndrome is a deaf-blindness disorder. One of the subtypes, Usher 1B, is caused by loss of function of the gene encoding the unconventional myosin, MYO7A. A variety of different viral-based delivery approaches have been tested for retinal gene therapy to prevent the blindness of Usher 1B, and a clinical trial based on one of these approaches has begun. This review evaluates the different approaches. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

  9. Waardenburg syndrome type II in a Chinese patient caused by a novel nonsense mutation in the SOX10 gene.

    Science.gov (United States)

    Ma, Jing; Zhang, Tie-Song; Lin, Ken; Sun, Hao; Jiang, Hong-Chao; Yang, Yan-Li; Low, Fan; Gao, Ying-Qin; Ruan, Biao

    2016-06-01

    Waardenburg syndrome is a congenital genetic disorder. It is the most common type of syndromic hearing impairment with highly genetic heterogeneity and proved to be related by 6 genes as follows: PAX3, MITF, SNAI2, EDN3, EDNRB and SOX10. This article aims to identify the genetic causes of a Chinese WS child patient. A Chinese WS child was collected for clinical data collection by questionnaire survey. DNA samples of proband and his parents were extracted from peripheral blood samples. Six candidate genes were sequenced by the Trusight One sequencing panel on the illumina NextSeq 500 platform. A novel nonsense heterozygous mutation was found in the coding region of exon 2 in the SOX10 gene of proband. The novel nonsense heterozygous mutation could cause the replacement of the 55th lysine codon by stop codon (484T > C, C142R) and further more possibly cause terminating the protein translation in advance. However, both proband's parents had no mutation of genes above mentioned. The gene mutation of SOX10 [NM_006941.3 c.163A > T] is a novel nonsense mutation. No record of this mutation has been found in dbSNP, HGMD, 1000 Genomes Project, ClinVar and ESP6500 databases. It meets the condition of PS2 of strong evidence in 2015 ACMG Standards and Guidelines. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Development of quality metrics for ambulatory pediatric cardiology: Transposition of the great arteries after arterial switch operation.

    Science.gov (United States)

    Baker-Smith, Carissa M; Carlson, Karina; Ettedgui, Jose; Tsuda, Takeshi; Jayakumar, K Anitha; Park, Matthew; Tede, Nikola; Uzark, Karen; Fleishman, Craig; Connuck, David; Likes, Maggie; Penny, Daniel J

    2018-01-01

    To develop quality metrics (QMs) for the ambulatory care of patients with transposition of the great arteries following arterial switch operation (TGA/ASO). Under the auspices of the American College of Cardiology Adult Congenital and Pediatric Cardiology (ACPC) Steering committee, the TGA/ASO team generated candidate QMs related to TGA/ASO ambulatory care. Candidate QMs were submitted to the ACPC Steering Committee and were reviewed for validity and feasibility using individual expert panel member scoring according to the RAND-UCLA methodology. QMs were then made available for review by the entire ACC ACPC during an "open comment period." Final approval of each QM was provided by a vote of the ACC ACPC Council. Patients with TGA who had undergone an ASO were included. Patients with complex transposition were excluded. Twelve candidate QMs were generated. Seven metrics passed the RAND-UCLA process. Four passed the "open comment period" and were ultimately approved by the Council. These included: (1) at least 1 echocardiogram performed during the first year of life reporting on the function, aortic dimension, degree of neoaortic valve insufficiency, the patency of the systemic and pulmonary outflows, the patency of the branch pulmonary arteries and coronary arteries, (2) neurodevelopmental (ND) assessment after ASO; (3) lipid profile by age 11 years; and (4) documentation of a transition of care plan to an adult congenital heart disease (CHD) provider by 18 years of age. Application of the RAND-UCLA methodology and linkage of this methodology to the ACPC approval process led to successful generation of 4 QMs relevant to the care of TGA/ASO pediatric patients in the ambulatory setting. These metrics have now been incorporated into the ACPC Quality Network providing guidance for the care of TGA/ASO patients across 30 CHD centers. © 2017 Wiley Periodicals, Inc.

  11. Origins of amino acid transporter loci in trypanosomatid parasites

    Directory of Open Access Journals (Sweden)

    Jackson Andrew P

    2007-02-01

    Full Text Available Abstract Background Large amino acid transporter gene families were identified from the genome sequences of three parasitic protists, Trypanosoma brucei, Trypanosoma cruzi and Leishmania major. These genes encode molecular sensors of the external host environment for trypanosomatid cells and are crucial to modulation of gene expression as the parasite passes through different life stages. This study provides a comprehensive phylogenetic account of the origins of these genes, redefining each locus according to a positional criterion, through the integration of phyletic identity with comparative gene order information. Results Each locus was individually specified by its surrounding gene order and associated with homologs showing the same position ('homoeologs' in other species, where available. Bayesian and maximum likelihood phylogenies were in general agreement on systematic relationships and confirmed several 'orthology sets' of genes retained since divergence from the common ancestor. Reconciliation analysis quantified the scale of duplication and gene loss, as well as identifying further apparent orthology sets, which lacked conservation of genomic position. These instances suggested substantial genomic restructuring or transposition. Other analyses identified clear instances of evolutionary rate changes post-duplication, the effects of concerted evolution within tandem gene arrays and gene conversion events between syntenic loci. Conclusion Despite their importance to cell function and parasite development, the repertoires of AAT loci in trypanosomatid parasites are relatively fluid in both complement and gene dosage. Some loci are ubiquitous and, after an ancient origin through transposition, originated through descent from the ancestral trypanosomatid. However, reconciliation analysis demonstrated that unilateral expansions of gene number through tandem gene duplication, transposition of gene duplicates to otherwise well conserved genomic

  12. Differences in acidity of apples are probably mainly caused by a malic acid transporter gene on LG16

    NARCIS (Netherlands)

    Khan, S.A.; Beekwilder, J.; Schaart, J.G.; Mumm, R.; Soriano, J.M.; Jacobsen, E.; Schouten, H.J.

    2013-01-01

    Acidity has profound effects on the taste of apples (Malus × domestica). Malic acid is the predominant organic acid in apples. Differences in malic acid content are caused by differences in accumulation of malic acid in the vacuole. This accumulation may be caused by a gene that is responsible for

  13. Ribosomal protein gene knockdown causes developmental defects in zebrafish.

    Directory of Open Access Journals (Sweden)

    Tamayo Uechi

    Full Text Available The ribosomal proteins (RPs form the majority of cellular proteins and are mandatory for cellular growth. RP genes have been linked, either directly or indirectly, to various diseases in humans. Mutations in RP genes are also associated with tissue-specific phenotypes, suggesting a possible role in organ development during early embryogenesis. However, it is not yet known how mutations in a particular RP gene result in specific cellular changes, or how RP genes might contribute to human diseases. The development of animal models with defects in RP genes will be essential for studying these questions. In this study, we knocked down 21 RP genes in zebrafish by using morpholino antisense oligos to inhibit their translation. Of these 21, knockdown of 19 RPs resulted in the development of morphants with obvious deformities. Although mutations in RP genes, like other housekeeping genes, would be expected to result in nonspecific developmental defects with widespread phenotypes, we found that knockdown of some RP genes resulted in phenotypes specific to each gene, with varying degrees of abnormality in the brain, body trunk, eyes, and ears at about 25 hours post fertilization. We focused further on the organogenesis of the brain. Each knocked-down gene that affected the morphogenesis of the brain produced a different pattern of abnormality. Among the 7 RP genes whose knockdown produced severe brain phenotypes, 3 human orthologs are located within chromosomal regions that have been linked to brain-associated diseases, suggesting a possible involvement of RP genes in brain or neurological diseases. The RP gene knockdown system developed in this study could be a powerful tool for studying the roles of ribosomes in human diseases.

  14. Chromosomal evolution of the PKD1 gene family in primates

    Directory of Open Access Journals (Sweden)

    Krawczak Michael

    2008-09-01

    Full Text Available Abstract Background The autosomal dominant polycystic kidney disease (ADPKD is mostly caused by mutations in the PKD1 (polycystic kidney disease 1 gene located in 16p13.3. Moreover, there are six pseudogenes of PKD1 that are located proximal to the master gene in 16p13.1. In contrast, no pseudogene could be detected in the mouse genome, only a single copy gene on chromosome 17. The question arises how the human situation originated phylogenetically. To address this question we applied comparative FISH-mapping of a human PKD1-containing genomic BAC clone and a PKD1-cDNA clone to chromosomes of a variety of primate species and the dog as a non-primate outgroup species. Results Comparative FISH with the PKD1-cDNA clone clearly shows that in all primate species studied distinct single signals map in subtelomeric chromosomal positions orthologous to the short arm of human chromosome 16 harbouring the master PKD1 gene. Only in human and African great apes, but not in orangutan, FISH with both BAC and cDNA clones reveals additional signal clusters located proximal of and clearly separated from the PKD1 master genes indicating the chromosomal position of PKD1 pseudogenes in 16p of these species, respectively. Indeed, this is in accordance with sequencing data in human, chimpanzee and orangutan. Apart from the master PKD1 gene, six pseudogenes are identified in both, human and chimpanzee, while only a single-copy gene is present in the whole-genome sequence of orangutan. The phylogenetic reconstruction of the PKD1-tree reveals that all human pseudogenes are closely related to the human PKD1 gene, and all chimpanzee pseudogenes are closely related to the chimpanzee PKD1 gene. However, our statistical analyses provide strong indication that gene conversion events may have occurred within the PKD1 family members of human and chimpanzee, respectively. Conclusion PKD1 must have undergone amplification very recently in hominid evolution. Duplicative

  15. A novel mutation in the SH3BP2 gene causes cherubism: case report

    Directory of Open Access Journals (Sweden)

    Yu Shi-Feng

    2006-12-01

    Full Text Available Abstract Background Cherubism is a rare hereditary multi-cystic disease of the jaws, characterized by its typical appearance in early childhood, and stabilization and remission after puberty. It is genetically transmitted in an autosomal dominant fashion and the gene coding for SH3-binding protein 2 (SH3BP2 may be involved. Case presentation We investigated a family consisting of 21 members with 3 female affected individuals with cherubism from Northern China. Of these 21 family members, 17 were recruited for the genetic analysis. We conducted the direct sequence analysis of the SH3BP2 gene among these 17 family members. A disease-causing mutation was identified in exon 9 of the gene. It was an A1517G base change, which leads to a D419G amino acid substitution. Conclusion To our knowledge, the A1517G mutation has not been reported previously in cherubism. This finding is novel.

  16. [Surrogate mothers and ovarian transposition: two attitudes to be considered in young women with cervical carcinoma. A case report].

    Science.gov (United States)

    Giacalone, P L; Sobierajksi, J; Benos, P; Giovannini, N; Laffargue, F; Hédon, B

    2003-02-01

    In cases of cervical cancer, there are 2 major advantages to preserving the ovaries, with or without transposition: hormone function is maintained during subsequent cancer treatment and patient quality of life is improved. We report the first case of pregnancy in a surrogate mother following stimulation of a transposed ovary before irradiation and chemotherapy for a squamous cell carcinoma of the uterine cervix. Because of the wide dissemination of information on the technical progress in this area, patients are now in a position to make therapeutic choices that are no longer guided by strictly medical considerations.

  17. Multiple organ gigantism caused by mutation in VmPPD gene in blackgram (Vigna mungo).

    Science.gov (United States)

    Naito, Ken; Takahashi, Yu; Chaitieng, Bubpa; Hirano, Kumi; Kaga, Akito; Takagi, Kyoko; Ogiso-Tanaka, Eri; Thavarasook, Charaspon; Ishimoto, Masao; Tomooka, Norihiko

    2017-03-01

    Seed size is one of the most important traits in leguminous crops. We obtained a recessive mutant of blackgram that had greatly enlarged leaves, stems and seeds. The mutant produced 100% bigger leaves, 50% more biomass and 70% larger seeds though it produced 40% less number of seeds. We designated the mutant as multiple-organ-gigantism ( mog ) and found the mog phenotype was due to increase in cell numbers but not in cell size. We also found the mog mutant showed a rippled leaf ( rl ) phenotype, which was probably caused by a pleiotropic effect of the mutation. We performed a map-based cloning and successfully identified an 8 bp deletion in the coding sequence of VmPPD gene, an orthologue of Arabidopsis PEAPOD ( PPD ) that regulates arrest of cell divisions in meristematic cells . We found no other mutations in the neighboring genes between the mutant and the wild type. We also knocked down GmPPD genes and reproduced both the mog and rl phenotypes in soybean. Controlling PPD genes to produce the mog phenotype is highly valuable for breeding since larger seed size could directly increase the commercial values of grain legumes.

  18. Induced pluripotent stem cells derived from a patient with autosomal dominant familial neurohypophyseal diabetes insipidus caused by a variant in the AVP gene

    DEFF Research Database (Denmark)

    Toustrup, Lise Bols; Zhou, Yan; Kvistgaard, Helene

    2017-01-01

    Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is caused by variants in the arginine vasopressin (AVP) gene. Here we report the generation of induced pluripotent stem cells (iPSCs) from a 42-year-old man carrying an adFNDI causing variant in exon 1 of the AVP gene using...

  19. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome.

    Science.gov (United States)

    Santen, Gijs W E; Aten, Emmelien; Sun, Yu; Almomani, Rowida; Gilissen, Christian; Nielsen, Maartje; Kant, Sarina G; Snoeck, Irina N; Peeters, Els A J; Hilhorst-Hofstee, Yvonne; Wessels, Marja W; den Hollander, Nicolette S; Ruivenkamp, Claudia A L; van Ommen, Gert-Jan B; Breuning, Martijn H; den Dunnen, Johan T; van Haeringen, Arie; Kriek, Marjolein

    2012-03-18

    We identified de novo truncating mutations in ARID1B in three individuals with Coffin-Siris syndrome (CSS) by exome sequencing. Array-based copy-number variation (CNV) analysis in 2,000 individuals with intellectual disability revealed deletions encompassing ARID1B in 3 subjects with phenotypes partially overlapping that of CSS. Taken together with published data, these results indicate that haploinsufficiency of the ARID1B gene, which encodes an epigenetic modifier of chromatin structure, is an important cause of CSS and is potentially a common cause of intellectual disability and speech impairment.

  20. c.376G>A mutation in WFS1 gene causes Wolfram syndrome without deafness.

    Science.gov (United States)

    Safarpour Lima, Behnam; Ghaedi, Hamid; Daftarian, Narsis; Ahmadieh, Hamid; Jamshidi, Javad; Khorrami, Mehdi; Noroozi, Rezvan; Sohrabifar, Nasim; Assarzadegan, Farhad; Hesami, Omid; Taghavi, Shaghayegh; Ahmadifard, Azadeh; Atakhorrami, Minoo; Rahimi-Aliabadi, Simin; Shahmohammadibeni, Neda; Alehabib, Elham; Andarva, Monavvar; Darvish, Hossein; Emamalizadeh, Babak

    2016-02-01

    Wolfram syndrome is one of the rare autosomal recessive, progressive, neurodegenerative disorders, characterized by diabetes mellitus and optic atrophy. Several other features are observed in patients including deafness, ataxia, and peripheral neuropathy. A gene called WFS1 is identified on chromosome 4p, responsible for Wolfram syndrome. We investigated a family consisted of parents and 8 children, which 5 of them have been diagnosed for Wolfram syndrome. WFS1 gene in all family members was sequenced for causative mutations. A mutation (c.376G>A, p.A126T) was found in all affected members in homozygous state and in both parents in heterozygous state. The bioinformatics analysis showed the deleterious effects of this nucleotide change on the structure and function of the protein product. As all of the patients in the family showed the homozygote mutation, and parents were both heterozygote, this mutation is probably the cause of the disease. We identified this mutation in homozygous state for the first time as Wolfram syndrome causation. We also showed that this mutation probably doesn't cause deafness in affected individuals. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. RNA-seq de novo Assembly Reveals Differential Gene Expression in Glossina palpalis gambiensis Infected with Trypanosoma brucei gambiense vs. Non-Infected and Self-Cured Flies.

    Science.gov (United States)

    Hamidou Soumana, Illiassou; Klopp, Christophe; Ravel, Sophie; Nabihoudine, Ibouniyamine; Tchicaya, Bernadette; Parrinello, Hugues; Abate, Luc; Rialle, Stéphanie; Geiger, Anne

    2015-01-01

    Trypanosoma brucei gambiense (Tbg), causing the sleeping sickness chronic form, completes its developmental cycle within the tsetse fly vector Glossina palpalis gambiensis (Gpg) before its transmission to humans. Within the framework of an anti-vector disease control strategy, a global gene expression profiling of trypanosome infected (susceptible), non-infected, and self-cured (refractory) tsetse flies was performed, on their midguts, to determine differential genes expression resulting from in vivo trypanosomes, tsetse flies (and their microbiome) interactions. An RNAseq de novo assembly was achieved. The assembled transcripts were mapped to reference sequences for functional annotation. Twenty-four percent of the 16,936 contigs could not be annotated, possibly representing untranslated mRNA regions, or Gpg- or Tbg-specific ORFs. The remaining contigs were classified into 65 functional groups. Only a few transposable elements were present in the Gpg midgut transcriptome, which may represent active transpositions and play regulatory roles. One thousand three hundred and seventy three genes differentially expressed (DEGs) between stimulated and non-stimulated flies were identified at day-3 post-feeding; 52 and 1025 between infected and self-cured flies at 10 and 20 days post-feeding, respectively. The possible roles of several DEGs regarding fly susceptibility and refractoriness are discussed. The results provide new means to decipher fly infection mechanisms, crucial to develop anti-vector control strategies.

  2. A single point-mutation within the melanophilin gene causes the lavender plumage colour dilution phenotype in the chicken

    Directory of Open Access Journals (Sweden)

    Tixier-Boichard Michèle

    2008-01-01

    Full Text Available Abstract Background The lavender phenotype in the chicken causes the dilution of both black (eumelanin and red/brown (phaeomelanin pigments. Defects in three genes involved in intracellular melanosomal transport, previously described in mammals, give rise to similar diluted pigmentation phenotypes as those seen in lavender chickens. Results We have used a candidate-gene approach based on an expectation of homology with mammals to isolate a gene involved in pigmentation in chicken. Comparative sequence analysis of candidate genes in the chicken identified a strong association between a mutation in the MLPH gene and the diluted pigmentation phenotype. This mutation results in the amino acid change R35W, at a site also associated with similar phenotypes in mice, humans and cats. Conclusion This is the first time that an avian species with a mutation in the MLPH gene has been reported.

  3. Recurrent invasion and extinction of a selfish gene.

    Science.gov (United States)

    Goddard, M R; Burt, A

    1999-11-23

    Homing endonuclease genes show super-Mendelian inheritance, which allows them to spread in populations even when they are of no benefit to the host organism. To test the idea that regular horizontal transmission is necessary for the long-term persistence of these genes, we surveyed 20 species of yeasts for the omega-homing endonuclease gene and associated group I intron. The status of omega could be categorized into three states (functional, nonfunctional, or absent), and status was not clustered on the host phylogeny. Moreover, the phylogeny of omega differed significantly from that of the host, strong evidence of horizontal transmission. Further analyses indicate that horizontal transmission is more common than transposition, and that it occurs preferentially between closely related species. Parsimony analysis and coalescent theory suggest that there have been 15 horizontal transmission events in the ancestry of our yeast species, through simulations indicate that this value is probably an underestimate. Overall, the data support a cyclical model of invasion, degeneration, and loss, followed by reinvasion, and each of these transitions is estimated to occur about once every 2 million years. The data are thus consistent with the idea that frequent horizontal transmission is necessary for the long-term persistence of homing endonuclease genes, and further, that this requirement limits these genes to organisms with easily accessible germ lines. The data also show that mitochondrial DNA sequences are transferred intact between yeast species; if other genes do not show such high levels of horizontal transmission, it would be due to lack of selection, rather than lack of opportunity.

  4. Identification of Two Disease-causing Genes TJP2 and GJB2 in a Chinese Family with Unconditional Autosomal Dominant Nonsyndromic Hereditary Hearing Impairment

    Directory of Open Access Journals (Sweden)

    Hong-Yang Wang

    2015-01-01

    Full Text Available Background: There are more than 300 genetic loci that have been found to be related to hereditary hearing impairment (HHI, including 92 causative genes for nonsyndromic hearing loss, among which 34 genes are related to autosomal dominant nonsyndromic HHI (ADNSHHI. Traditional linkage analysis and candidate gene sequencing are not effective at detecting the ADNSHHI, especially for the unconditional families that may have more than one pathogenic cause. This study identified two disease-causing genes TJP2 and GJB2 in a Chinese family with unconditional ADNSHHI. Methods: To decipher the genetic code of a Chinese family (family 686 with ADNSHHI, different gene screening techniques have been performed, including linkage analysis, candidate genes screening, high-throughput sequencing and Sanger sequencing. These techniques were done on samples obtained from this family over a period of 10 years. Results: We identified a pathogenic missense mutation, c. 2081G>A (p.G694E, in TJP2, a gene that plays a crucial role in apoptosis and age-related hearing loss (ARHL. The mutation was co-segregated in this pedigree in all, but not in the two patients who presented with different phenotypes from the other affected family members. In one of the two patients, we confirmed that the compound heterozygosity for p.Y136FNx01 and p.G45E in the GJB2 gene may account for the phenotype shown in this patient. Conclusions: We identified the co-occurrence of two genetic causes in family 686. The possible disease-causing missense mutation of TJP2 in family 686 presents an opportunity for further investigation into ARHL. It is necessary to combine various genes screening methods, especially for some unconventional cases.

  5. Ogura-CMS in Chinese cabbage (Brassica rapa ssp. pekinensis) causes delayed expression of many nuclear genes.

    Science.gov (United States)

    Dong, Xiangshu; Kim, Wan Kyu; Lim, Yong-Pyo; Kim, Yeon-Ki; Hur, Yoonkang

    2013-02-01

    We investigated the mechanism regulating cytoplasmic male sterility (CMS) in Brassica rapa ssp. pekinensis using floral bud transcriptome analyses of Ogura-CMS Chinese cabbage and its maintainer line in B. rapa 300-K oligomeric probe (Br300K) microarrays. Ogura-CMS Chinese cabbage produced few and infertile pollen grains on indehiscent anthers. Compared to the maintainer line, CMS plants had shorter filaments and plant growth, and delayed flowering and pollen development. In microarray analysis, 4646 genes showed different expression, depending on floral bud size, between Ogura-CMS and its maintainer line. We found 108 and 62 genes specifically expressed in Ogura-CMS and its maintainer line, respectively. Ogura-CMS line-specific genes included stress-related, redox-related, and B. rapa novel genes. In the maintainer line, genes related to pollen coat and germination were specifically expressed in floral buds longer than 3mm, suggesting insufficient expression of these genes in Ogura-CMS is directly related to dysfunctional pollen. In addition, many nuclear genes associated with auxin response, ATP synthesis, pollen development and stress response had delayed expression in Ogura-CMS plants compared to the maintainer line, which is consistent with the delay in growth and development of Ogura-CMS plants. Delayed expression may reduce pollen grain production and/or cause sterility, implying that mitochondrial, retrograde signaling delays nuclear gene expression. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  6. Rapid characterization of disease-causing mutations in the low density lipoprotein receptor (LDL-R) gene by overexpression in COS cells

    DEFF Research Database (Denmark)

    Jensen, T G; Andresen, B S; Jensen, H K

    1996-01-01

    To characterize disease-causing mutations in the low density lipoprotein receptor (LDL-R) gene, COS cells are transfected with the mutant gene in an EBV-based expression vector and characterized by flow cytometry. Using antibodies against the LDL-receptor the amount of receptor protein on the cel...

  7. Normalization of Overexpressed α-Synuclein Causing Parkinson's Disease By a Moderate Gene Silencing With RNA Interference

    Directory of Open Access Journals (Sweden)

    Masaki Takahashi

    2015-01-01

    Full Text Available The α-synuclein (SNCA gene is a responsible gene for Parkinson's disease (PD; and not only nucleotide variations but also overexpression of SNCA appears to be involved in the pathogenesis of PD. A specific inhibition against mutant SNCA genes carrying nucleotide variations may be feasible by a specific silencing such as an allele-specific RNA interference (RNAi; however, there is no method for restoring the SNCA overexpression to a normal level. Here, we show that an atypical RNAi using small interfering RNAs (siRNAs that confer a moderate level of gene silencing is capable of controlling overexpressed SNCA genes to return to a normal level; named “expression-control RNAi” (ExCont-RNAi. ExCont-RNAi exhibited little or no significant off-target effects in its treated PD patient's fibroblasts that carry SNCA triplication. To further assess the therapeutic effect of ExCont-RNAi, PD-model flies that carried the human SNCA gene underwent an ExCont-RNAi treatment. The treated PD-flies demonstrated a significant improvement in their motor function. Our current findings suggested that ExCont-RNAi might be capable of becoming a novel therapeutic procedure for PD with the SNCA overexpression, and that siRNAs conferring a moderate level of gene silencing to target genes, which have been abandoned as useless siRNAs so far, might be available for controlling abnormally expressed disease-causing genes without producing adverse effects.

  8. Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome.

    Science.gov (United States)

    Lynch, Danielle C; Revil, Timothée; Schwartzentruber, Jeremy; Bhoj, Elizabeth J; Innes, A Micheil; Lamont, Ryan E; Lemire, Edmond G; Chodirker, Bernard N; Taylor, Juliet P; Zackai, Elaine H; McLeod, D Ross; Kirk, Edwin P; Hoover-Fong, Julie; Fleming, Leah; Savarirayan, Ravi; Majewski, Jacek; Jerome-Majewska, Loydie A; Parboosingh, Jillian S; Bernier, Francois P

    2014-07-22

    Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro-costo-mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development.

  9. Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro–costo–mandibular syndrome

    Science.gov (United States)

    Lynch, Danielle C.; Revil, Timothée; Schwartzentruber, Jeremy; Bhoj, Elizabeth J.; Innes, A. Micheil; Lamont, Ryan E.; Lemire, Edmond G.; Chodirker, Bernard N.; Taylor, Juliet P.; Zackai, Elaine H.; McLeod, D. Ross; Kirk, Edwin P.; Hoover-Fong, Julie; Fleming, Leah; Savarirayan, Ravi; Boycott, Kym; MacKenzie, Alex; Brudno, Michael; Bulman, Dennis; Dyment, David; Majewski, Jacek; Jerome-Majewska, Loydie A.; Parboosingh, Jillian S.; Bernier, Francois P.

    2014-01-01

    Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro–costo–mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development. PMID:25047197

  10. Alu element insertion in PKLR gene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients.

    Science.gov (United States)

    Lesmana, Harry; Dyer, Lisa; Li, Xia; Denton, James; Griffiths, Jenna; Chonat, Satheesh; Seu, Katie G; Heeney, Matthew M; Zhang, Kejian; Hopkin, Robert J; Kalfa, Theodosia A

    2018-03-01

    Pyruvate kinase deficiency (PKD) is the most frequent red blood cell enzyme abnormality of the glycolytic pathway and the most common cause of hereditary nonspherocytic hemolytic anemia. Over 250 PKLR-gene mutations have been described, including missense/nonsense, splicing and regulatory mutations, small insertions, small and gross deletions, causing PKD and hemolytic anemia of variable severity. Alu retrotransposons are the most abundant mobile DNA sequences in the human genome, contributing to almost 11% of its mass. Alu insertions have been associated with a number of human diseases either by disrupting a coding region or a splice signal. Here, we report on two unrelated Middle Eastern patients, both born from consanguineous parents, with transfusion-dependent hemolytic anemia, where sequence analysis revealed a homozygous insertion of AluYb9 within exon 6 of the PKLR gene, causing precipitous decrease of PKLR RNA levels. This Alu element insertion consists a previously unrecognized mechanism underlying pathogenesis of PKD. © 2017 Wiley Periodicals, Inc.

  11. Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

    Science.gov (United States)

    Klevering, B Jeroen; Blankenagel, Anita; Maugeri, Alessandra; Cremers, Frans P M; Hoyng, Carel B; Rohrschneider, Klaus

    2002-06-01

    To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were reviewed after molecular analysis revealed mutations in the ABCA4 gene. In two of the patients both the photopic and scotopic electroretinogram were nonrecordable. In the remainder, the photopic cone b-wave amplitudes appeared to be more seriously affected than the scotopic rod b-wave amplitudes. Although the clinical presentation was heterogeneous, all patients experienced visual loss early in life, impaired color vision, and a central scotoma. Fundoscopy revealed evidence of early-onset maculopathy, sometimes accompanied by involvement of the retinal periphery in the later stages of the disease. Mutations in the ABCA4 gene are the pathologic cause of the CRD-like dystrophy in these patients, and the resultant clinical pictures are complex and heterogeneous. Given this wide clinical spectrum of CRD-like phenotypes associated with ABCA4 mutations, detailed clinical subclassifications are difficult and may not be very useful.

  12. Frequent gain and loss of introns in fungal cytochrome b genes.

    Directory of Open Access Journals (Sweden)

    Liang-Fen Yin

    Full Text Available In this study, all available cytochrome b (Cyt b genes from the GOBASE database were compiled and the evolutionary dynamics of the Cyt b gene introns was assessed. Cyt b gene introns were frequently present in the fungal kingdom and some lower plants, but generally absent or rare in Chromista, Protozoa, and Animalia. Fungal Cyt b introns were found at 35 positions in Cyt b genes and the number of introns varied at individual positions from a single representative to 32 different introns at position 131, showing a wide and patchy distribution. Many homologous introns were present at the same position in distantly related species but absent in closely related species, suggesting that introns of the Cyt b genes were frequently lost. On the other hand, highly similar intron sequences were observed in some distantly related species rather than in closely related species, suggesting that these introns were gained independently, likely through lateral transfers. The intron loss-and-gain events could be mediated by transpositions that might have occurred between nuclear and mitochondria. Southern hybridization analysis confirmed that some introns contained repetitive sequences and might be transposable elements. An intron gain in Botryotinia fuckeliana prevented the development of QoI fungicide resistance, suggesting that intron loss-and-gain events were not necessarily beneficial to their host organisms.

  13. Mutations in the ABCA4 (ABCR) Gene Are the Major Cause of Autosomal Recessive Cone-Rod Dystrophy

    OpenAIRE

    Maugeri, Alessandra; Klevering, B. Jeroen; Rohrschneider, Klaus; Blankenagel, Anita; Brunner, Han G.; Deutman, August F.; Hoyng, Carel B.; Cremers, Frans P. M.

    2000-01-01

    The photoreceptor cell–specific ATP-binding cassette transporter gene (ABCA4; previously denoted “ABCR”) is mutated in most patients with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients with isolated CRD, all fro...

  14. Gitelman or Bartter type 3 syndrome? A case of distal convoluted tubulopathy caused by CLCNKB gene mutation.

    Science.gov (United States)

    Cruz, António José; Castro, Alexandra

    2013-01-22

    A 32-year-old woman with no significant medical history was sent to our consultation due to hypokalaemia (syndrome (GS) came negative. CLCNKB gene mutation analysis present in both GS and Bartter (BS) type 3 syndromes was positive. The patient is now being treated with potassium and magnesium oral supplements, ramipril and spironolactone with stable near-normal potassium and magnesium levels. This article presents the case of a patient with hypokalaemia caused by CLCNKB gene mutation hard to categorise as GS or BS type 3.

  15. FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Rene L. Begay, BS

    2016-08-01

    Full Text Available A genetic etiology has been identified in 30% to 40% of dilated cardiomyopathy (DCM patients, yet only 50% of these cases are associated with a known causative gene variant. Thus, in order to understand the pathophysiology of DCM, it is necessary to identify and characterize additional genes. In this study, whole exome sequencing in combination with segregation analysis was used to identify mutations in a novel gene, filamin C (FLNC, resulting in a cardiac-restricted DCM pathology. Here we provide functional data via zebrafish studies and protein analysis to support a model implicating FLNC haploinsufficiency as a mechanism of DCM.

  16. GENETIC TRANSFORMATION AND ANALYSIS OF WHEAT TRANSGENIC CELL LINES BY IRAP-PCR

    Directory of Open Access Journals (Sweden)

    Bavol A. V.

    2013-12-01

    Full Text Available The transgenic wheat cell lines were obtained via biolistic transformation of the callus cultures initiated from the 3-day-old sterile seedling shoot apexes. The pAHC25 vector construction used for 14- and 28-day-old callus cultures transformation carried the selective phosphinothricin-N-acetyltransferase (bar gene and reporter ?-glucuronidase gene. The cell line selection was carried out on the media with phosphinothricin by means of graduated cell selection. The transgenic status of the obtained forms was proved by PCR-analysis. The presence of new relatively high molecular (more than 1 000 bp amplicons were found out for three transformed lines by means of IRAP PCRanalysis with the primers coding for long termainal repeats sequences of SIRE 1 retrotransposon. This fact may prove transposition of this mobile genetic element. The new DNA fragments were detected for three of the seven analyzed lines but for the control callus. It is possible to assume at induction of SIRE 1 transposition bis probably caused by the genomic stress of foreign DNA inserting or associated with the transformation process (mechanical wounding, cultivation on selective media.

  17. Acute Type A Aortic Dissection Successfully Managed with One-stage Surgery of Total Aortic Arch Replacement with Supra-aortic Transposition Plus Frozen Elephant Trunk Technique

    Directory of Open Access Journals (Sweden)

    Meng-Lin Lee

    2014-09-01

    Full Text Available Acute type A aortic dissection has long been a challenging issue. The surgical techniques traditionally vary with the anatomic extent of the aortic dissection. Simple ascending aortic grafting can be lifesaving, but the lesions beyond the aorta, which include the arch vessels and descending aorta, remain potential hazards. In this paper, we present a patient in which acute type A aortic dissection with lesions extending into descending thoracic aorta was successfully managed by total arch replacement with supra-aortic transposition plus the frozen elephant trunk technique to the descending aorta. A 67-year-old gentleman presented with severe tearing pain from the anterior to posterior chest. Computed tomography confirmed the diagnosis of acute type A dissection extending to the level of the right common iliac artery. An emergent operation was performed as in the aforementioned technique. The surgery went well and the patient was discharged without comorbidities on postoperative day 25. The patient had regular outpatient clinical follow-up. The follow-up computed tomography images showed adequate results with the obliteration of the false lumen. In conclusion, total aortic arch replacement with supra-aortic transposition plus frozen elephant trunk technique is a safe and feasible operative method for patients with detrimental acute type A aortic dissection.

  18. Human case of bacteremia caused by Streptococcus canis sequence type 9 harboring the scm gene.

    Science.gov (United States)

    Taniyama, Daisuke; Abe, Yoshihiko; Sakai, Tetsuya; Kikuchi, Takahide; Takahashi, Takashi

    2017-01-01

    Streptococcus canis (Sc) is a zoonotic pathogen that is transferred mainly from companion animals to humans. One of the major virulence factors in Sc is the M-like protein encoded by the scm gene, which is involved in anti-phagocytic activities, as well as the recruitment of plasminogen to the bacterial surface in cooperation with enolase, and the consequent enhancement of bacterial transmigration and survival. This is the first reported human case of uncomplicated bacteremia following a dog bite, caused by Streptococcus canis harboring the scm gene. The similarity of the 16S rRNA from the infecting species to that of the Sc type strain, as well as the amplification of the species-specific cfg gene, encoding a co-hemolysin, was used to confirm the species identity. Furthermore, the isolate was confirmed as sequence type 9. The partial scm gene sequence harbored by the isolate was closely related to those of other two Sc strains. While this isolate did not possess the erm (A), erm (B), or mef (A), macrolide/lincosamide resistance genes, it was not susceptible to azithromycin: its susceptibility was intermediate. Even though human Sc bacteremia is rare, clinicians should be aware of this microorganism, as well as Pasteurella sp., Prevotella sp., and Capnocytophaga sp., when examining and treating patients with fever who maintain close contact with companion animals.

  19. APPENDIX – Mircea Eliade: Preamble to the Hermeneutics of Reception. The Transposition of Eliade’s Literary Works into Other Artistic Languages. A Short History

    OpenAIRE

    Cristina SCARLAT

    2011-01-01

    The material published in “Postmodern Openings”, Iasi, year 2, no. 7, September 2011, pp.75 – 98, Mircea Eliade: Preamble to the Hermeneutics of Reception. The Transposition of Eliade’s Literary Works into other Artistic Languages. A Short History represents an illustration of these aspects – at a first statistical level. We signaled in that material the artistic versions having Eliadian literary work as their starting point. Now, we are coming with this Appendix elaborated through correspond...

  20. Double Copies of bla(KPC-3)::Tn4401a on an IncX3 Plasmid in Klebsiella pneumoniae Successful Clone ST512 from Italy.

    Science.gov (United States)

    Fortini, Daniela; Villa, Laura; Feudi, Claudia; Pires, João; Bonura, Celestino; Mammina, Caterina; Endimiani, Andrea; Carattoli, Alessandra

    2016-01-01

    A carbapenem-resistant sequence type 512 (ST512) Klebsiella pneumoniae carbapenemase 3 (KPC-3)-producing K. pneumoniae strain showing a novel variant plasmid content was isolated in Palermo, Italy, in 2014. ST512 is a worldwide successful clone associated with the spread of bla(KPC) genes located on the IncFIIk pKpQIL plasmid. In our ST512 strain, the bla(KPC-3) gene was unusually located on an IncX3 plasmid, whose complete sequence was determined. Two copies of bla(KPC-3)::Tn4401a caused by intramolecular transposition events were detected in the plasmid. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  1. Identification of new IS711 insertion sites in Brucella abortus field isolates.

    Science.gov (United States)

    Mancilla, Marcos; Ulloa, Marcos; López-Goñi, Ignacio; Moriyón, Ignacio; María Zárraga, Ana

    2011-08-03

    Brucellosis is a zoonosis caused by Brucella spp., a group of highly homogeneous bacteria. The insertion sequence IS711 is characteristic of these bacteria, and occurs in variable numbers and positions, but always constant within a given species. This species-associated polymorphism is used in molecular typing and identification. Field isolates of B. abortus, the most common species infecting cattle, typically carry seven IS711 copies (one truncated). Thus far, IS711 transposition has only been shown in vitro and only for B. ovis and B. pinnipedialis, two species carrying a high number of IS711 copies, but never in other Brucella species, neither in vitro nor in field strains. We found several B. abortus strains isolated from milk and aborted fetuses that carried additional IS711 copies in two hitherto undescribed insertion sites: one in an intergenic region near to the 3' end of a putative lactate permease gene and the other interrupting the sequence of a marR transcriptional regulator gene. Interestingly, the second type of insertion was identified in isolates obtained repeatedly from the same herd after successive brucellosis outbreaks, an observation that proves the stability and virulence of the new genotype under natural conditions. Sequence analyses revealed that the new copies probably resulted from the transposition of a single IS711 copy common to all Brucella species sequenced so far. Our results show that the replicative transposition of IS711 can occur under field conditions. Therefore, it represents an active mechanism for the emergence of genetic diversity in B. abortus thus contributing to intra-species genetic polymorphism.

  2. Campylobacter jejuni, an uncommon cause of splenic abscess diagnosed by 16S rRNA gene sequencing

    Directory of Open Access Journals (Sweden)

    Piseth Seng

    2014-12-01

    Full Text Available Splenic abscess is a rare disease that primarily occurs in patients with splenic trauma, endocarditis, sickle cell anemia, or other diseases that compromise the immune system. This report describes a culture-negative splenic abscess in an immunocompetent patient caused by Campylobacter jejuni, as determined by 16S rRNA gene sequencing.

  3. Venezuelan equine encephalitis virus infection causes modulation of inflammatory and immune response genes in mouse brain

    Directory of Open Access Journals (Sweden)

    Puri Raj K

    2008-06-01

    Full Text Available Abstract Background Neurovirulent Venezuelan equine encephalitis virus (VEEV causes lethal encephalitis in equines and is transmitted to humans by mosquitoes. VEEV is highly infectious when transmitted by aerosol and has been developed as a bio-warfare agent, making it an important pathogen to study from a military and civilian standpoint. Molecular mechanisms of VEE pathogenesis are poorly understood. To study these, the gene expression profile of VEEV infected mouse brains was investigated. Changes in gene expression were correlated with histological changes in the brain. In addition, a molecular framework of changes in gene expression associated with progression of the disease was studied. Results Our results demonstrate that genes related to important immune pathways such as antigen presentation, inflammation, apoptosis and response to virus (Cxcl10, CxCl11, Ccl5, Ifr7, Ifi27 Oas1b, Fcerg1,Mif, Clusterin and MHC class II were upregulated as a result of virus infection. The number of over-expressed genes (>1.5-fold level increased as the disease progressed (from 197, 296, 400, to 1086 at 24, 48, 72 and 96 hours post infection, respectively. Conclusion Identification of differentially expressed genes in brain will help in the understanding of VEEV-induced pathogenesis and selection of biomarkers for diagnosis and targeted therapy of VEEV-induced neurodegeneration.

  4. Ileal Transposition Surgery Decreases Fat Mass and Improves Glucose Metabolism in Diabetic GK Rats: Possible Involvement of FGF21

    Directory of Open Access Journals (Sweden)

    Kemin Yan

    2018-03-01

    Full Text Available Objective: Ileal transposition (IT surgery has been reported to improve glucose and lipid metabolism, and fibroblast growth factor 21 (FGF21 is a powerful metabolic regulator. In the present study, we aimed to investigate the effects of IT surgery on metabolism and its possible relationship with the FGF21 signaling pathway in diabetic Goto-Kakizaki (GK rats.Methods: Ten-week-old male GK rats were subjected to IT surgery with translocation of a 10 cm ileal segment to the proximal jejunum (IT group or sham surgery without the ileum transposition (Sham-IT group. Rats in the no surgery group did not receive any surgical intervention. Six weeks later, body weight, fat mass, fasting blood glucose (FBG, and serum levels of FGF21 and leptin were measured. The expression of the FGF21 signaling pathway and white adipose tissue (WAT browning-related genes in the WAT and liver were evaluated by real-time reverse transcription polymerase chain reaction (RT-qPCR and western blot.Results: IT surgery significantly decreased the body weights and FBG levels and increased the insulin sensitivity of GK rats. The total WAT mass of the IT rats showed a 41.5% reduction compared with the Sham-IT rats, and serum levels of FGF21 and leptin of the IT rats decreased by 26.3 and 61.7%, respectively (all P < 0.05. The mRNA levels of fibroblast growth factor receptor 1 (FGFR1 and its co-receptor β klotho (KLB in the perirenal WAT (pWAT of the IT rats were 1.4- and 2.4-fold that of the Sham-IT rats, respectively, and the FGFR1 protein levels were 1.7-fold of the Sham-IT rats (all P < 0.05. In accordance with the pWAT, the protein levels of FGFR1 and KLB in the epididymal WAT (eWAT of the IT rats notably increased to 3.0- and 3.9-fold of the Sham-IT rats (P < 0.05. Furthermore, uncoupling protein 1 (UCP1 protein levels in the eWAT and pWAT of the IT rats also increased to 2.2- and 2.3-fold of the Sham-IT rats (P < 0.05. However, the protein levels of FGFR1 and KLB in the

  5. Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

    NARCIS (Netherlands)

    Klevering, B.J.; Blankenagel, A.; Maugeri, A.; Cremers, F.P.M.; Hoyng, C.B.; Rohrschneider, K.

    2002-01-01

    PURPOSE: To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. METHODS: The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were

  6. The Managerial Reduction in the Management Technologies Transposition Process to Public Organizations

    Directory of Open Access Journals (Sweden)

    Sandro Trescastro Bergue

    2010-04-01

    Full Text Available This essay discusses the phenomenon of the implementation of technologies designed in the management business, with emphasis on relations with public organizations. It proposes a reflection on the concept of sociological reduction by Guerreiro Ramos, recovering its roots in Husserl and Heidegger and their relationship with the concepts of creative adaptation and the translation of managerial issues. Contextualized in the paradigm of new public management and the list of values and assumptions on which this movement is based, the analysis of the reproduction of practices known in private organizations by public ones seeking their legitimacy has revealed the formality and ceremonial aspect of this contemporary phenomenon. The importance of bringing knowledge from the organizational field that subsidizes management as well as the coherence of these cultural objects in terms of concepts and assumptions of organization are highlighted here. The process of transpositions, contrasting with reproducible traits of Brazilian managerial culture that are historically constructed but consistent with the notion of sociological reduction, requires a critical, conscious and engaged attitude on the part of members of the organization not only regarding the relevance of the imported content but also giving new meaning to the concepts underlying the management technologies.

  7. Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes.

    Science.gov (United States)

    Torsvik, Janniche; Johansson, Stefan; Johansen, Anders; Ek, Jakob; Minton, Jayne; Raeder, Helge; Ellard, Sian; Hattersley, Andrew; Pedersen, Oluf; Hansen, Torben; Molven, Anders; Njølstad, Pål R

    2010-01-01

    We have previously shown that heterozygous single-base deletions in the carboxyl-ester lipase (CEL) gene cause exocrine and endocrine pancreatic dysfunction in two multigenerational families. These deletions were found in the first and fourth repeats of a variable number of tandem repeats (VNTR), which has proven challenging to sequence due to high GC-content and considerable length variation. We have therefore developed a screening method consisting of a multiplex PCR followed by fragment analysis. The method detected putative disease-causing insertions and deletions in the proximal repeats of the VNTR, and determined the VNTR-length of each allele. When blindly testing 56 members of the two families with known single-base deletions in the CEL VNTR, the method correctly assessed the mutation carriers. Screening of 241 probands from suspected maturity-onset diabetes of the young (MODY) families negative for mutations in known MODY genes (95 individuals from Denmark and 146 individuals from UK) revealed no deletions in the proximal repeats of the CEL VNTR. However, we found one Danish patient with a short, novel CEL allele containing only three VNTR repeats (normal range 7-23 in healthy controls). This allele co-segregated with diabetes or impaired glucose tolerance in the patient's family as six of seven mutation carriers were affected. We also identified individuals who had three copies of a complete CEL VNTR. In conclusion, the CEL gene is highly polymorphic, but mutations in CEL are likely to be a rare cause of monogenic diabetes.

  8. Early-Onset Severe Encephalopathy with Epilepsy: The BRAT1 Gene Should Be Added to the List of Causes.

    Science.gov (United States)

    van de Pol, Laura A; Wolf, Nicole I; van Weissenbruch, Mirjam M; Stam, Cornelie J; Weiss, Janneke M; Waisfisz, Quinten; Kevelam, Sietske H; Bugiani, Mariana; van de Kamp, Jiddeke M; van der Knaap, Marjo S

    2015-12-01

    A variety of pathologies can underlie early-onset severe encephalopathy with epilepsy. To aid the diagnostic process in such patients we present an overview of causes, including the rapidly expanding list of genes involved. When no explanation is found, whole-exome sequencing (WES) can be used in an attempt to identify gene defects in patients suspected to suffer from a genetic form. We describe three siblings, born to consanguineous parents, with a lethal severe epileptic encephalopathy with early-infantile onset, including their magnetic resonance imaging, electroencephalography and, in one case, neuropathological findings. Using WES a homozygous frameshift mutation in the BRAT1 gene, c.638dup p.(Val214Glyfs*189), was identified. We present our cases in the context of all published cases with mutations in the BRAT1 gene and conclude that BRAT1 should be added to the growing list of genes related to early-onset severe encephalopathy with epilepsy. Georg Thieme Verlag KG Stuttgart · New York.

  9. XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing.

    Science.gov (United States)

    Piton, Amélie; Redin, Claire; Mandel, Jean-Louis

    2013-08-08

    Because of the unbalanced sex ratio (1.3-1.4 to 1) observed in intellectual disability (ID) and the identification of large ID-affected families showing X-linked segregation, much attention has been focused on the genetics of X-linked ID (XLID). Mutations causing monogenic XLID have now been reported in over 100 genes, most of which are commonly included in XLID diagnostic gene panels. Nonetheless, the boundary between true mutations and rare non-disease-causing variants often remains elusive. The sequencing of a large number of control X chromosomes, required for avoiding false-positive results, was not systematically possible in the past. Such information is now available thanks to large-scale sequencing projects such as the National Heart, Lung, and Blood (NHLBI) Exome Sequencing Project, which provides variation information on 10,563 X chromosomes from the general population. We used this NHLBI cohort to systematically reassess the implication of 106 genes proposed to be involved in monogenic forms of XLID. We particularly question the implication in XLID of ten of them (AGTR2, MAGT1, ZNF674, SRPX2, ATP6AP2, ARHGEF6, NXF5, ZCCHC12, ZNF41, and ZNF81), in which truncating variants or previously published mutations are observed at a relatively high frequency within this cohort. We also highlight 15 other genes (CCDC22, CLIC2, CNKSR2, FRMPD4, HCFC1, IGBP1, KIAA2022, KLF8, MAOA, NAA10, NLGN3, RPL10, SHROOM4, ZDHHC15, and ZNF261) for which replication studies are warranted. We propose that similar reassessment of reported mutations (and genes) with the use of data from large-scale human exome sequencing would be relevant for a wide range of other genetic diseases. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  10. Induced pluripotent stem cells derived from a patient with autosomal dominant familial neurohypophyseal diabetes insipidus caused by a variant in the AVP gene

    Directory of Open Access Journals (Sweden)

    Lise Bols Toustrup

    2017-03-01

    Full Text Available Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI is caused by variants in the arginine vasopressin (AVP gene. Here we report the generation of induced pluripotent stem cells (iPSCs from a 42-year-old man carrying an adFNDI causing variant in exon 1 of the AVP gene using lentivirus-mediated nuclear reprogramming. The iPSCs carried the expected variant in the AVP gene. Furthermore, the iPSCs expressed pluripotency markers; displayed in vitro differentiation potential to the three germ layers and had a normal karyotype consistent with the original fibroblasts. This iPSC line is useful in future studies focusing on the pathogenesis of adFNDI.

  11. Patient’s Cross-border Mobility Directive: Application, Performance and Perceptions Two Years after Transposition

    Directory of Open Access Journals (Sweden)

    Riedel Rafał

    2016-10-01

    Full Text Available This paper seeks to analyse the directive on the application of patients’ rights in cross-border healthcare. Two years after the transposition, it is time for first evaluations of its application, performance and perception. The analysis consists of three major elements: reconstruction of the legal scope and subject matter of the new legislation, conclusions of the evaluative reports monitoring its implementation and performance as well as the public opinion polls revealing the EU citizens’ perception of its details. These three components combined together deliver a picture of the state of play about the pan-European cross-border patients’ mobility. The bottomline conclusions negatively verify the supposition present in some earlier literature on patients’ cross-border mobility that the directive has a transformative potential leading towards the creation of truly competitive pan-European medical market. After two years of its operation, there is still no increased patients’ mobility across EU internal borders observed. As regards the speculations for the future, there are only some weak symptoms identified and they may result in intensified cross-border mobility for healthcare.

  12. Metabolic alterations and neurodevelopmental outcome of infants with transposition of the great arteries.

    Science.gov (United States)

    Park, I Sook; Yoon, S Young; Min, J Yeon; Kim, Y Hwue; Ko, J Kok; Kim, K Soo; Seo, D Man; Lee, J Hee

    2006-01-01

    Abnormal neurodevelopment has been reported for infants who were born with transposition of the great arteries (TGA) and underwent arterial switch operation (ASO). This study evaluates the cerebral metabolism of TGA infants at birth and before ASO and neurodevelopment 1 year after ASO. Proton magnetic resonance spectroscopy (1H-MRS) was performed on 16 full-term TGA brains before ASO within 3-6 days after birth. The brain metabolite ratios of [NAA/Cr], [Cho/Cr], and [mI/Cr] evaluated measured. Ten infants were evaluated at 1 year using the Bayley Scales of Infants Development II (BSED II). Cerebral metabolism of infants with TGA was altered in parietal white matter (PWM) and occipital gray matter (OGM) at birth before ASO. One year after ASO, [Cho/Cr] in PWM remained altered, but all metabolic ratios in OGM were normal. The results of BSID II at 1 year showed delayed mental and psychomotor development. This delayed neurodevelopmental outcome may reflect consequences of the altered cerebral metabolism in PWM measured by 1H-MRS. It is speculated that the abnormal hemodynamics due to TGA in utero may be responsible for the impaired cerebral metabolism and the subsequent neurodevelopmental deficit.

  13. The reverse boomerang sign: a marker for first-trimester transposition of great arteries.

    Science.gov (United States)

    Bravo-Valenzuela, Nathalie Jeanne; Peixoto, Alberto Borges; Araujo Júnior, Edward; Da Silva Costa, Fabricio; Meagher, Simon

    2017-10-12

    To describe a new sonographic marker of transposition of great arteries (TGA) during the first-trimester screening. We reviewed six cases of TGA from 2013 to 2016 in which an antenatal diagnosis of TGA at first-trimester screening (11-13 + 6 weeks of gestation) was confirmed postnatally. We specifically assessed images obtained by scanning the fetal heart in three vessels (3V) and three-vessel with trachea (3VT) views using color Doppler. The "reverse boomerang" sign was defined as a reverse curvature of right ventricle outflow tract (RVOT) at level of the 3VT view. We described six cases of confirmed TGA, five singletons and one twin pregnancy, among which only two vessels and the reverse curvature of RVOT (reverse boomerang sign) was demonstrated in the first-trimester screening at level of 3VT view. Ventricular septal defects were observed in three cases, and double outlet right ventricle in one case. No other cardiac or extracardiac anomalies were identified. Termination of pregnancy was not performed in any case. Our series case suggests that the reverse boomerang sign may improve the early prenatal screening for TGA.

  14. MASA syndrome is caused by mutations in the neural cell adhesion gene, L1CAM

    Energy Technology Data Exchange (ETDEWEB)

    Schwartz, C.E.; Wang, Y.; Schroer, R.J.; Stevenson, R.E. [Greenwood Genetic Center, SC (United States)

    1994-09-01

    The MASA syndrome is a recessive X-linked disorder characterized by Mental retardation, Adducted thumbs, Shuffling gait and Aphasia. Recently we found that MASA in one family was likely caused by a point mutation in exon 6 of the L1CAM gene. This gene has also been shown to be involved in X-linked hydrocephalus (HSAS). We have screened 60 patients with either sporadic HSAS or MASA as well as two additional families with MASA. For the screening, we initially utilized 3 cDNA probes for the L1CAM gene. In one of the MASA families, K8310, two affected males were found to have an altered BglII band. The band was present in their carrier mother but not in their normal brothers. This band was detected by the entire cDNA probe as well as the cDNA probe for 3{prime} end of the gene. Analysis of the L1CAM sequence indicated the altered BglII site is distal to the exon 28 but proximal to the punative poly A signal site. It is hypothesized that this point mutation alters the stability of the L1CAM mRNA. This is being tested using cell lines established from the two affected males.

  15. Deletion of ETS-1, a gene in the Jacobsen syndrome critical region, causes ventricular septal defects and abnormal ventricular morphology in mice

    Science.gov (United States)

    Ye, Maoqing; Coldren, Chris; Liang, Xingqun; Mattina, Teresa; Goldmuntz, Elizabeth; Benson, D. Woodrow; Ivy, Dunbar; Perryman, M.B.; Garrett-Sinha, Lee Ann; Grossfeld, Paul

    2010-01-01

    Congenital heart defects comprise the most common form of major birth defects, affecting 0.7% of all newborn infants. Jacobsen syndrome (11q-) is a rare chromosomal disorder caused by deletions in distal 11q. We have previously determined that a wide spectrum of the most common congenital heart defects occur in 11q-, including an unprecedented high frequency of hypoplastic left heart syndrome (HLHS). We identified an ∼7 Mb ‘cardiac critical region’ in distal 11q that contains a putative causative gene(s) for congenital heart disease. In this study, we utilized chromosomal microarray mapping to characterize three patients with 11q- and congenital heart defects that carry interstitial deletions overlapping the 7 Mb cardiac critical region. We propose that this 1.2 Mb region of overlap harbors a gene(s) that causes at least a subset of the congenital heart defects that occur in 11q-. We demonstrate that one gene in this region, ETS-1 (a member of the ETS family of transcription factors), is expressed in the endocardium and neural crest during early mouse heart development. Gene-targeted deletion of ETS-1 in mice in a C57/B6 background causes, with high penetrance, large membranous ventricular septal defects and a bifid cardiac apex, and less frequently a non-apex-forming left ventricle (one of the hallmarks of HLHS). Our results implicate an important role for the ETS-1 transcription factor in mammalian heart development and should provide important insights into some of the most common forms of congenital heart disease. PMID:19942620

  16. Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease.

    Science.gov (United States)

    Faucz, Fabio R; Tirosh, Amit; Tatsi, Christina; Berthon, Annabel; Hernández-Ramírez, Laura C; Settas, Nikolaos; Angelousi, Anna; Correa, Ricardo; Papadakis, Georgios Z; Chittiboina, Prashant; Quezado, Martha; Pankratz, Nathan; Lane, John; Dimopoulos, Aggeliki; Mills, James L; Lodish, Maya; Stratakis, Constantine A

    2017-08-01

    Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have been recently identified as the most common genetic alteration in patients with Cushing disease (CD). However, the frequency of these mutations in the pediatric population has not been extensively assessed. We investigated the status of the USP8 gene at the somatic level in a cohort of pediatric patients with corticotroph adenomas. The USP8 gene was fully sequenced in both germline and tumor DNA samples from 42 pediatric patients with CD. Clinical, biochemical, and imaging data were compared between patients with and without somatic USP8 mutations. Five different USP8 mutations (three missense, one frameshift, and one in-frame deletion) were identified in 13 patients (31%), all of them located in exon 14 at the previously described mutational hotspot, affecting the 14-3-3 binding motif of the protein. Patients with somatic mutations were older at disease presentation [mean 5.1 ± 2.1 standard deviation (SD) vs 13.1 ± 3.6 years, P = 0.03]. Levels of urinary free cortisol, midnight serum cortisol, and adrenocorticotropic hormone, as well as tumor size and frequency of invasion of the cavernous sinus, were not significantly different between the two groups. However, patients harboring somatic USP8 mutations had a higher likelihood of recurrence compared with patients without mutations (46.2% vs 10.3%, P = 0.009). Somatic USP8 gene mutations are a common cause of pediatric CD. Patients harboring a somatic mutation had a higher likelihood of tumor recurrence, highlighting the potential importance of this molecular defect for the disease prognosis and the development of targeted therapeutic options. Copyright © 2017 Endocrine Society

  17. An innovative strategy to clone positive modifier genes of defects caused by mtDNA mutations: MRPS18C as suppressor gene of m.3946G>A mutation in MT-ND1 gene.

    Science.gov (United States)

    Rodríguez-García, María Elena; Cotrina-Vinagre, Francisco Javier; Carnicero-Rodríguez, Patricia; Martínez-Azorín, Francisco

    2017-07-01

    We have developed a new functional complementation approach to clone modifier genes which overexpression is able to suppress the biochemical defects caused by mtDNA mutations (suppressor genes). This strategy consists in transferring human genes into respiratory chain-deficient fibroblasts, followed by a metabolic selection in a highly selective medium. We used a normalized expression cDNA library in an episomal vector (pREP4) to transfect the fibroblasts, and a medium with glutamine and devoid of any carbohydrate source to select metabolically. Growing the patient's fibroblasts in this selective medium, the deficient cells rapidly disappear unless they are rescued by the cDNA of a suppressor gene. The use of an episomal vector allows us to carry out several rounds of transfection/selection (cyclical phenotypic rescue) to enrich the rescue with true clones of suppressor genes. Using fibroblasts from a patient with epileptic encephalopathy with the m.3946G>A (p.E214K) mutation in the MT-ND1 gene, several candidate genes were identified and one of them was characterized functionally. Thus, overexpression of MRPS18C gene (that encode for bS18m protein) suppressed the molecular defects produced by this mtDNA mutation, recovering the complex I activity and reducing the ROS produced by this complex to normal levels. We suggest that modulation of bS18m expression may be an effective therapeutic strategy for the patients with this mutation.

  18. North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene.

    Science.gov (United States)

    Bowne, Sara J; Sullivan, Lori S; Wheaton, Dianna K; Locke, Kirsten G; Jones, Kaylie D; Koboldt, Daniel C; Fulton, Robert S; Wilson, Richard K; Blanton, Susan H; Birch, David G; Daiger, Stephen P

    2016-01-01

    To identify the underlying cause of disease in a large family with North Carolina macular dystrophy (NCMD). A large four-generation family (RFS355) with an autosomal dominant form of NCMD was ascertained. Family members underwent comprehensive visual function evaluations. Blood or saliva from six affected family members and three unaffected spouses was collected and DNA tested for linkage to the MCDR1 locus on chromosome 6q12. Three affected family members and two unaffected spouses underwent whole exome sequencing (WES) and subsequently, custom capture of the linkage region followed by next-generation sequencing (NGS). Standard PCR and dideoxy sequencing were used to further characterize the mutation. Of the 12 eyes examined in six affected individuals, all but two had Gass grade 3 macular degeneration features. Large central excavation of the retinal and choroid layers, referred to as a macular caldera, was seen in an age-independent manner in the grade 3 eyes. The calderas are unique to affected individuals with MCDR1. Genome-wide linkage mapping and haplotype analysis of markers from the chromosome 6q region were consistent with linkage to the MCDR1 locus. Whole exome sequencing and custom-capture NGS failed to reveal any rare coding variants segregating with the phenotype. Analysis of the custom-capture NGS sequencing data for copy number variants uncovered a tandem duplication of approximately 60 kb on chromosome 6q. This region contains two genes, CCNC and PRDM13 . The duplication creates a partial copy of CCNC and a complete copy of PRDM13 . The duplication was found in all affected members of the family and is not present in any unaffected members. The duplication was not seen in 200 ethnically matched normal chromosomes. The cause of disease in the original family with MCDR1 and several others has been recently reported to be dysregulation of the PRDM13 gene, caused by either single base substitutions in a DNase 1 hypersensitive site upstream of the CCNC

  19. Telomeric repeat-containing RNA/G-quadruplex-forming sequences cause genome-wide alteration of gene expression in human cancer cells in vivo.

    Science.gov (United States)

    Hirashima, Kyotaro; Seimiya, Hiroyuki

    2015-02-27

    Telomere erosion causes cell mortality, suggesting that longer telomeres enable more cell divisions. In telomerase-positive human cancer cells, however, telomeres are often kept shorter than those of surrounding normal tissues. Recently, we showed that cancer cell telomere elongation represses innate immune genes and promotes their differentiation in vivo. This implies that short telomeres contribute to cancer malignancy, but it is unclear how such genetic repression is caused by elongated telomeres. Here, we report that telomeric repeat-containing RNA (TERRA) induces a genome-wide alteration of gene expression in telomere-elongated cancer cells. Using three different cell lines, we found that telomere elongation up-regulates TERRA signal and down-regulates innate immune genes such as STAT1, ISG15 and OAS3 in vivo. Ectopic TERRA oligonucleotides repressed these genes even in cells with short telomeres under three-dimensional culture conditions. This appeared to occur from the action of G-quadruplexes (G4) in TERRA, because control oligonucleotides had no effect and a nontelomeric G4-forming oligonucleotide phenocopied the TERRA oligonucleotide. Telomere elongation and G4-forming oligonucleotides showed similar gene expression signatures. Most of the commonly suppressed genes were involved in the innate immune system and were up-regulated in various cancers. We propose that TERRA G4 counteracts cancer malignancy by suppressing innate immune genes. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  20. A new mutation of the fukutin gene causing late-onset limb girdle muscular dystrophy

    DEFF Research Database (Denmark)

    Riisager, Maria; Duno, M; Hansen, Flemming Juul

    2013-01-01

    to aberrations of FKTN is rare, with only eight reported cases of limb girdle phenotype (LGMD2M). We describe the mildest affected patient outside Japan with genetically confirmed LGMD2M and onset of symptoms at age 14. She was brought to medical attention at age 12, not because of muscle weakness, but due...... to episodes of tachycardia caused by Wolff-Parkinson-White syndrome. On examination, she had rigid spine syndrome, a typical limb girdle dystrophy pattern of muscle weakness, cardiomyopathy, and serum CK levels >2000 IU/L (normal G; p.Y306C mutation in the FKTN gene was found. The case confirms FKTN mutations...... as a cause of LGMD2M without mental retardation and expands the phenotypic spectrum for LGMD2M to include cardiomyopathy and rigid spine syndrome in the mildest affected non-Japanese patient reported so far....

  1. Generation and analysis of knock-in mice carrying pseudohypoaldosteronism type II-causing mutations in the cullin 3 gene.

    Science.gov (United States)

    Araki, Yuya; Rai, Tatemitsu; Sohara, Eisei; Mori, Takayasu; Inoue, Yuichi; Isobe, Kiyoshi; Kikuchi, Eriko; Ohta, Akihito; Sasaki, Sei; Uchida, Shinichi

    2015-10-21

    Pseudohypoaldosteronism type II (PHAII) is a hereditary hypertensive disease caused by mutations in four different genes: with-no-lysine kinases (WNK) 1 and 4, Kelch-like family member 3 (KLHL3), and cullin 3 (Cul3). Cul3 and KLHL3 form an E3 ligase complex that ubiquitinates and reduces the expression level of WNK4. PHAII-causing mutations in WNK4 and KLHL3 impair WNK4 ubiquitination. However, the molecular pathogenesis of PHAII caused by Cul3 mutations is unclear. In cultured cells and human leukocytes, PHAII-causing Cul3 mutations result in the skipping of exon 9, producing mutant Cul3 protein lacking 57 amino acids. However, whether this phenomenon occurs in the kidneys and is responsible for the pathogenesis of PHAII in vivo is unknown. We generated knock-in mice carrying a mutation in the C-terminus of intron 8 of Cul3, c.1207-1G>A, which corresponds to a PHAII-causing mutation in the human Cul3 gene. Heterozygous Cul3(G(-1)A/+) knock-in mice did not exhibit PHAII phenotypes, and the skipping of exon 9 was not evident in their kidneys. However, the level of Cul3 mRNA expression in the kidneys of heterozygous knock-in mice was approximately half that of wild-type mice. Furthermore, homozygous knock-in mice were nonviable. It suggested that the mutant allele behaved like a knockout allele and did not produce Cul3 mRNA lacking exon 9. A reduction in Cul3 expression alone was not sufficient to develop PHAII in the knock-in mice. Our findings highlighted the pathogenic role of mutant Cul3 protein and provided insight to explain why PHAII-causing mutations in Cul3 cause kidney-predominant PHAII phenotypes. © 2015. Published by The Company of Biologists Ltd.

  2. Development of a high-frequency in vivo transposon mutagenesis system for Synechocystis sp. PCC 6803 and Synechococcus elongatus PCC 7942.

    Science.gov (United States)

    Watabe, Kazuyuki; Mimuro, Mamoru; Tsuchiya, Tohru

    2014-11-01

    Synechocystis sp. PCC 6803 (Synechocystis) is the first sequenced photosynthetic organism and has two advantages: natural transformation and light-activated heterotrophic growth. Such characteristics have mainly promoted reverse genetic analysis in this organism, however, to date approximately 50% of genes are still annotated as 'unknown protein' or 'hypothetical protein'. Therefore, forward genetic analysis is required for the identification of significant genes responsible for photosynthesis and other physiological phenomena among the genes of unknown function. The in vivo transposon mutagenesis system is one of the major methods for random mutagenesis. However, present in vivo transposon mutagenesis systems for cyanobacteria face problems such as relatively low frequency of transposition and repeated transposition in the host cells. In this study, we constructed vectors based on a mini-Tn5-derived vector that was designed to prevent repeated transposition. Our vectors carry a hyperactive transposase and optimized recognition sequence of transposase, which were reported to enhance frequency of transposition. Using the vector, we succeeded in highly frequent transposition (9×10(-3) per recipient cell) in Synechocystis. Transposon insertion sites of 10 randomly selected mutants indicated that the insertion sites spread throughout the genome with low sequence dependency. Furthermore, one of the 10 mutants exhibited the slow-growing phenotype, and the mutant was functionally complemented by using our expression vector. Our system also worked with another model cyanobacterium, Synechococcus elongatus PCC 7942, with high frequency. These results indicate that the developed system can be applied to the forward genetic analysis of a broad range of cyanobacteria. © The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  3. Verticillium dahliae-Arabidopsis Interaction Causes Changes in Gene Expression Profiles and Jasmonate Levels on Different Time Scales

    Directory of Open Access Journals (Sweden)

    Sandra S. Scholz

    2018-02-01

    Full Text Available Verticillium dahliae is a soil-borne vascular pathogen that causes severe wilt symptoms in a wide range of plants. Co-culture of the fungus with Arabidopsis roots for 24 h induces many changes in the gene expression profiles of both partners, even before defense-related phytohormone levels are induced in the plant. Both partners reprogram sugar and amino acid metabolism, activate genes for signal perception and transduction, and induce defense- and stress-responsive genes. Furthermore, analysis of Arabidopsis expression profiles suggests a redirection from growth to defense. After 3 weeks, severe disease symptoms can be detected for wild-type plants while mutants impaired in jasmonate synthesis and perception perform much better. Thus, plant jasmonates have an important influence on the interaction, which is already visible at the mRNA level before hormone changes occur. The plant and fungal genes that rapidly respond to the presence of the partner might be crucial for early recognition steps and the future development of the interaction. Thus they are potential targets for the control of V. dahliae-induced wilt diseases.

  4. Spontaneous Pancreatitis Caused by Tissue-Specific Gene Ablation of Hhex in MiceSummary

    Directory of Open Access Journals (Sweden)

    Mark J. Ferreira

    2015-09-01

    Full Text Available Background & Aims: Perturbations in pancreatic ductal bicarbonate secretion cause chronic pancreatitis. The physiologic mechanism of ductal secretion is known, but its transcriptional control is not. We determine the role of the transcription factor hematopoietically expressed homeobox protein (Hhex in ductal secretion and pancreatitis. Methods: We derived mice with pancreas-specific, Cre-mediated Hhex gene ablation to determine the requirement of Hhex in the pancreatic duct in early life and in adult stages. Histologic and immunostaining analyses were used to detect the presence of pathology. Pancreatic primary ductal cells were isolated to discover differentially expressed transcripts upon acute Hhex ablation on a cell autonomous level. Results: Hhex protein was detected throughout the embryonic and adult ductal trees. Ablation of Hhex in pancreatic progenitors resulted in postnatal ductal ectasia associated with acinar-to-ductal metaplasia, a progressive phenotype that ultimately resulted in chronic pancreatitis. Hhex ablation in adult mice, however, did not cause any detectable pathology. Ductal ectasia in young mice did not result from perturbation of expression of Hnf6, Hnf1β, or the primary cilia genes. RNA-seq analysis of Hhex-ablated pancreatic primary ductal cells showed mRNA levels of the G-protein coupled receptor natriuretic peptide receptor 3 (Npr3, implicated in paracrine signaling, up-regulated by 4.70-fold. Conclusions: Although Hhex is dispensable for ductal cell function in the adult, ablation of Hhex in pancreatic progenitors results in pancreatitis. Our data highlight the critical role of Hhex in maintaining ductal homeostasis in early life and support ductal hypersecretion as a novel etiology of pediatric chronic pancreatitis. Keywords: Npr3, Pancreatic Ducts, Primary Cilia

  5. Gene Therapy

    Science.gov (United States)

    Gene therapy Overview Gene therapy involves altering the genes inside your body's cells in an effort to treat or stop disease. Genes contain your ... that don't work properly can cause disease. Gene therapy replaces a faulty gene or adds a new ...

  6. Phenylalanine hydroxylase deficiency caused by a single base substitution in an exon of the human phenylalanine hydroxylase gene

    International Nuclear Information System (INIS)

    Lichter-Konecki, U.; Konecki, D.S.; DiLella, A.G.; Brayton, K.; Marvit, J.; Hahn, T.M.; Trefz, E.K.; Woo, S.L.C.

    1988-01-01

    A novel restriction fragment length polymorphism in the phenylalanine hydroxylase (PAH) locus generated by the restriction endonuclease MspI was observed in a German phenylketonuria (PKU) patient. Molecular cloning and DNA sequence analyses revealed that the MspI polymorphism was created by a T to C transition in exon 9 of the human PAH gene, which also resulted in the conversion of a leucine codon to proline codon. The effect of the amino acid substitution was investigated by creating a corresponding mutation in a full-length human PAD cDNA by site-directed mutagenesis followed by expression analysis in cultured mammalian cells. Results demonstrate that the mutation in the gene causes the synthesis of an unstable protein in the cell corresponding to a CRM - phenotype. Together with the other mutations recently reported in the PAH gene,the data support previous biochemical and clinical observations that PKU is a heterogeneous disorder at the gene level

  7. Phenylalanine hydroxylase deficiency caused by a single base substitution in an exon of the human phenylalanine hydroxylase gene

    Energy Technology Data Exchange (ETDEWEB)

    Lichter-Konecki, U.; Konecki, D.S.; DiLella, A.G.; Brayton, K.; Marvit, J.; Hahn, T.M.; Trefz, E.K.; Woo, S.L.C.

    1988-04-19

    A novel restriction fragment length polymorphism in the phenylalanine hydroxylase (PAH) locus generated by the restriction endonuclease MspI was observed in a German phenylketonuria (PKU) patient. Molecular cloning and DNA sequence analyses revealed that the MspI polymorphism was created by a T to C transition in exon 9 of the human PAH gene, which also resulted in the conversion of a leucine codon to proline codon. The effect of the amino acid substitution was investigated by creating a corresponding mutation in a full-length human PAD cDNA by site-directed mutagenesis followed by expression analysis in cultured mammalian cells. Results demonstrate that the mutation in the gene causes the synthesis of an unstable protein in the cell corresponding to a CRM/sup -/ phenotype. Together with the other mutations recently reported in the PAH gene,the data support previous biochemical and clinical observations that PKU is a heterogeneous disorder at the gene level.

  8. Conditional ablation of the choroideremia gene causes age-related changes in mouse retinal pigment epithelium.

    Science.gov (United States)

    Wavre-Shapton, Silène T; Tolmachova, Tanya; Lopes da Silva, Mafalda; da Silva, Mafalda Lopes; Futter, Clare E; Seabra, Miguel C

    2013-01-01

    The retinal pigment epithelium (RPE) is a pigmented monolayer of cells lying between the photoreceptors and a layer of fenestrated capillaries, the choriocapillaris. Choroideremia (CHM) is an X-linked progressive degeneration of these three layers caused by the loss of function of Rab Escort protein-1 (REP1). REP1 is involved in the prenylation of Rab proteins, key regulators of membrane trafficking. To study the pathological consequences of chronic disruption of membrane traffic in the RPE we used a cell type-specific knock-out mouse model of the disease, where the Chm/Rep1 gene is deleted only in pigmented cells (Chm(Flox), Tyr-Cre+). Transmission electron microscopy (TEM) was used to quantitate the melanosome distribution in the RPE and immunofluorescent staining of rhodopsin was used to quantitate phagocytosed rod outer segments in retinal sections. The ultrastructure of the RPE and Bruch's membrane at different ages was characterised by TEM to analyse age-related changes occurring as a result of defects in membrane traffic pathways. Chm/Rep1 gene knockout in RPE cells resulted in reduced numbers of melanosomes in the apical processes and delayed phagosome degradation. In addition, the RPE accumulated pathological changes at 5-6 months of age similar to those observed in 2-year old controls. These included the intracellular accumulation of lipofuscin-containing deposits, disorganised basal infoldings and the extracellular accumulation of basal laminar and basal linear deposits. The phenotype of the Chm(Flox), Tyr-Cre+ mice suggests that loss of the Chm/Rep1 gene causes premature accumulation of features of aging in the RPE. Furthermore, the striking similarities between the present observations and some of the phenotypes reported in age-related macular degeneration (AMD) suggest that membrane traffic defects may contribute to the pathogenesis of AMD.

  9. Conditional ablation of the choroideremia gene causes age-related changes in mouse retinal pigment epithelium.

    Directory of Open Access Journals (Sweden)

    Silène T Wavre-Shapton

    Full Text Available The retinal pigment epithelium (RPE is a pigmented monolayer of cells lying between the photoreceptors and a layer of fenestrated capillaries, the choriocapillaris. Choroideremia (CHM is an X-linked progressive degeneration of these three layers caused by the loss of function of Rab Escort protein-1 (REP1. REP1 is involved in the prenylation of Rab proteins, key regulators of membrane trafficking. To study the pathological consequences of chronic disruption of membrane traffic in the RPE we used a cell type-specific knock-out mouse model of the disease, where the Chm/Rep1 gene is deleted only in pigmented cells (Chm(Flox, Tyr-Cre+. Transmission electron microscopy (TEM was used to quantitate the melanosome distribution in the RPE and immunofluorescent staining of rhodopsin was used to quantitate phagocytosed rod outer segments in retinal sections. The ultrastructure of the RPE and Bruch's membrane at different ages was characterised by TEM to analyse age-related changes occurring as a result of defects in membrane traffic pathways. Chm/Rep1 gene knockout in RPE cells resulted in reduced numbers of melanosomes in the apical processes and delayed phagosome degradation. In addition, the RPE accumulated pathological changes at 5-6 months of age similar to those observed in 2-year old controls. These included the intracellular accumulation of lipofuscin-containing deposits, disorganised basal infoldings and the extracellular accumulation of basal laminar and basal linear deposits. The phenotype of the Chm(Flox, Tyr-Cre+ mice suggests that loss of the Chm/Rep1 gene causes premature accumulation of features of aging in the RPE. Furthermore, the striking similarities between the present observations and some of the phenotypes reported in age-related macular degeneration (AMD suggest that membrane traffic defects may contribute to the pathogenesis of AMD.

  10. VIP Gene Deletion in Mice Causes Cardiomyopathy Associated with Upregulation of Heart Failure Genes

    Energy Technology Data Exchange (ETDEWEB)

    Szema, Anthony M.; Hamidi, Sayyed A.; Smith, S. David; Benveniste, Helene; Katare, Rajesh Gopalrao

    2013-05-20

    Vasoactive Intestinal Peptide (VIP), a pulmonary vasodilator and inhibitor of vascular smooth muscle proliferation, is absent in pulmonary arteries of patients with idiopathic pulmonary arterial hypertension (PAH). We previously determined that targeted deletion of the VIP gene in mice leads to PAH with pulmonary vascular remodeling and right ventricular (RV) dilatation. Whether the left ventricle is also affected by VIP gene deletion is unknown. In the current study, we examined if VIP knockout mice (VIP-/-) develop both right (RV) and left ventricular (LV) cardiomyopathy, manifested by LV dilatation and systolic dysfunction, as well as overexpression of genes conducive to heart failure.

  11. Vector modifications to eliminate transposase expression following piggyBac-mediated transgenesis

    Science.gov (United States)

    Chakraborty, Syandan; Ji, HaYeun; Chen, Jack; Gersbach, Charles A.; Leong, Kam W.

    2014-01-01

    Transgene insertion plays an important role in gene therapy and in biological studies. Transposon-based systems that integrate transgenes by transposase-catalyzed “cut-and-paste” mechanism have emerged as an attractive system for transgenesis. Hyperactive piggyBac transposon is particularly promising due to its ability to integrate large transgenes with high efficiency. However, prolonged expression of transposase can become a potential source of genotoxic effects due to uncontrolled transposition of the integrated transgene from one chromosomal locus to another. In this study we propose a vector design to decrease post-transposition expression of transposase and to eliminate the cells that have residual transposase expression. We design a single plasmid construct that combines the transposase and the transpositioning transgene element to share a single polyA sequence for termination. Consequently, the separation of the transposase element from the polyA sequence after transposition leads to its deactivation. We also co-express Herpes Simplex Virus thymidine kinase (HSV-tk) with the transposase. Therefore, cells having residual transposase expression can be eliminated by the administration of ganciclovir. We demonstrate the utility of this combination transposon system by integrating and expressing a model therapeutic gene, human coagulation Factor IX, in HEK293T cells. PMID:25492703

  12. Heart failure and sudden cardiac death in heritable thoracic aortic disease caused by pathogenic variants in the SMAD3 gene.

    Science.gov (United States)

    Backer, Julie De; Braverman, Alan C

    2018-05-01

    Predominant cardiovascular manifestations in the spectrum of Heritable Thoracic Aortic Disease include by default aortic root aneurysms- and dissections, which may be associated with aortic valve disease. Mitral- and tricuspid valve prolapse are other commonly recognized features. Myocardial disease, characterized by heart failure and/or malignant arrhythmias has been reported in humans and in animal models harboring pathogenic variants in the Fibrillin1 gene. Description of clinical history of three cases from one family in Ghent (Belgium) and one family in St. Louis (US). We report on three cases from two families presenting end-stage heart failure (in two) and lethal arrhythmias associated with moderate left ventricular dilatation (in one). All three cases harbor a pathogenic variant in the SMAD3 gene, known to cause aneurysm osteoarthritis syndrome, Loeys-Dietz syndrome type 3 or isolated Heritable Thoracic Aortic Disease. These unusual presentations warrant awareness for myocardial disease in patients harboring pathogenic variants in genes causing Heritable Thoracic Aortic Disease and indicate the need for prospective studies in larger cohorts. © 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

  13. Early-Onset Severe Encephalopathy with Epilepsy: The BRAT1 Gene Should Be Added to the List of Causes

    NARCIS (Netherlands)

    van de Pol, L.A.; Wolf, N.I.; van Weissenbruch, M.M.; Stam, C.J.; Weiss, M.M.; Waisfisz, Q.; Kevelam, S.H.; Bugiani, M.; van de Kamp, J.M.; Knaap, M.

    2015-01-01

    A variety of pathologies can underlie early-onset severe encephalopathy with epilepsy. To aid the diagnostic process in such patients we present an overview of causes, including the rapidly expanding list of genes involved. When no explanation is found, whole-exome sequencing (WES) can be used in an

  14. Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a mutation in the arginine-vasopressin II gene in four generations of a Korean family

    Directory of Open Access Journals (Sweden)

    Myo-Jing Kim

    2014-12-01

    Full Text Available Autosomal dominant neurohypophyseal diabetes insipidus is a rare form of central diabetes insipidus that is caused by mutations in the vasopressin-neurophysin II (AVP-NPII gene. It is characterized by persistent polydipsia and polyuria induced by deficient or absent secretion of arginine vasopressin (AVP. Here we report a case of familial neurohypophyseal diabetes insipidus in four generations of a Korean family, caused by heterozygous missense mutation in exon 2 of the AVP-NPII gene (c.286G>T. This is the first report of such a case in Korea.

  15. Identification of new IS711 insertion sites in Brucella abortus field isolates

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    Moriyón Ignacio

    2011-08-01

    Full Text Available Abstract Background Brucellosis is a zoonosis caused by Brucella spp., a group of highly homogeneous bacteria. The insertion sequence IS711 is characteristic of these bacteria, and occurs in variable numbers and positions, but always constant within a given species. This species-associated polymorphism is used in molecular typing and identification. Field isolates of B. abortus, the most common species infecting cattle, typically carry seven IS711 copies (one truncated. Thus far, IS711 transposition has only been shown in vitro and only for B. ovis and B. pinnipedialis, two species carrying a high number of IS711 copies, but never in other Brucella species, neither in vitro nor in field strains. Results We found several B. abortus strains isolated from milk and aborted fetuses that carried additional IS711 copies in two hitherto undescribed insertion sites: one in an intergenic region near to the 3' end of a putative lactate permease gene and the other interrupting the sequence of a marR transcriptional regulator gene. Interestingly, the second type of insertion was identified in isolates obtained repeatedly from the same herd after successive brucellosis outbreaks, an observation that proves the stability and virulence of the new genotype under natural conditions. Sequence analyses revealed that the new copies probably resulted from the transposition of a single IS711 copy common to all Brucella species sequenced so far. Conclusions Our results show that the replicative transposition of IS711 can occur under field conditions. Therefore, it represents an active mechanism for the emergence of genetic diversity in B. abortus thus contributing to intra-species genetic polymorphism.

  16. Letter-transposition effects are not universal: The impact of transposing letters in Hebrew.

    Science.gov (United States)

    Velan, Hadas; Frost, Ram

    2009-10-01

    We examined the effects of letter transposition in Hebrew in three masked-priming experiments. Hebrew, like English has an alphabetic orthography where sequential and contiguous letter strings represent phonemes. However, being a Semitic language it has a non-concatenated morphology that is based on root derivations. Experiment 1 showed that transposed-letter (TL) root primes inhibited responses to targets derived from the non-transposed root letters, and that this inhibition was unrelated to relative root frequency. Experiment 2 replicated this result and showed that if the transposed letters of the root created a nonsense-root that had no lexical representation, then no inhibition and no facilitation were obtained. Finally, Experiment 3 demonstrated that in contrast to English, French, or Spanish, TL nonword primes did not facilitate recognition of targets, and when the root letters embedded in them consisted of a legal root morpheme, they produced inhibition. These results suggest that lexical space in alphabetic orthographies may be structured very differently in different languages if their morphological structure diverges qualitatively. In Hebrew, lexical space is organized according to root families rather than simple orthographic structure, so that all words derived from the same root are interconnected or clustered together, independent of overall orthographic similarity.

  17. Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings.

    Science.gov (United States)

    Ben-Salem, Salma; Sobreira, Nara; Akawi, Nadia A; Al-Shamsi, Aisha M; John, Anne; Pramathan, Thachillath; Valle, David; Ali, Bassam R; Al-Gazali, Lihadh

    2016-01-01

    The gene encoding the AT-rich interaction domain-containing protein 1B (ARID1B) has recently been shown to be one of the most frequently mutated genes in patients with intellectual disability (ID). The phenotypic spectrums associated with variants in this gene vary widely ranging for mild to severe non-specific ID to Coffin-Siris syndrome. In this study, we evaluated three children from a consanguineous Emirati family affected with ID and dysmorphic features. Genomic DNA from all affected siblings was analyzed using CGH array and whole-exome sequencing (WES). Based on a recessive mode of inheritance, homozygous or compound heterozygous variants shared among all three affected children could not be identified. However, further analysis revealed a heterozygous variant (c.4318C>T; p.Q1440*) in the three affected children in an autosomal dominant ID causing gene, ARID1B. This variant was absent in peripheral blood samples obtained from both parents and unaffected siblings. Therefore, we propose that the most likely explanation for this situation is that one of the parents is a gonadal mosaic for the variant. To the best of our knowledge, this is the first report of a gonadal mosaicism inheritance of an ARID1B variant leading to familial ID recurrence. © 2015 Wiley Periodicals, Inc.

  18. Inactivation of the Tumor Suppressor Genes Causing the Hereditary Syndromes Predisposing to Head and Neck Cancer via Promoter Hypermethylation in Sporadic Head and Neck Cancers

    OpenAIRE

    Smith, Ian M.; Mithani, Suhail K.; Mydlarz, Wojciech K.; Chang, Steven S.; Califano, Joseph A.

    2010-01-01

    Fanconi anemia (FA) and dyskeratosis congenita (DC) are rare inherited syndromes that cause head and neck squamous cell cancer (HNSCC). Prior studies of inherited forms of cancer have been extremely important in elucidating tumor suppressor genes inactivated in sporadic tumors. Here, we studied whether sporadic tumors have epigenetic silencing of the genes causing the inherited forms of HNSCC. Using bisulfite sequencing, we investigated the incidence of promoter hypermethylation of the 17 Fan...

  19. Echocardiographic knowledge-based reconstruction for quantification of the systemic right ventricle in young adults with repaired D-transposition of great arteries.

    Science.gov (United States)

    Kutty, Shelby; Li, Ling; Polak, Amanda; Gribben, Paul; Danford, David A

    2012-03-15

    The systemic right ventricle (RV) in congenital heart disease is susceptible to progressive dilation and dysfunction. A 2-dimensional echocardiographic means for serial monitoring of the RV would be of great value in this clinical setting. We used 2-dimensional echocardiography with knowledge-based reconstruction (2DE-KBR) for evaluation of systemic RV. Patients with d-transposition of great arteries repaired with an atrial switch and without implanted pacemakers were prospectively recruited for same-day 2DE-KBR and cardiac magnetic resonance (CMR) imaging. RV images were acquired in various 2-dimensional imaging planes using a 3-dimensional space-localizing device attached to the imaging transducer and 3-dimensional reconstruction was performed. RV end-diastolic volume, end-systolic volume, and ejection fraction (EF) were calculated and compared to volumetric CMR analysis. Fifteen patients (7 women, 8 men, 24 ± 7 years old, weight 67 ± 12 kg) were studied. There was good agreement of 2DE-KBR and CMR measurements. Mean RV end-diastolic volume was 221 ± 39 ml with 2DE-KBR and 231 ± 35 ml with CMR (r = 0.80); mean end-systolic volume was 129 ± 35 ml with KBR and 132 ± 30 ml with CMR (r = 0.82), and EF was 42 ± 10% with KBR and 43 ± 7% with CMR (r = 0.86). For 2DE-KBR mean interobserver variabilities were 4.6%, 2.6%, and 4.3%; intraobserver variabilities were 3.2%, 3.1%, and 2.3%, respectively, for end-diastolic volume, end-systolic volume, and EF. In conclusion, this study demonstrates the clinical feasibility of quantifying systemic RV volumes and function using 2DE-KBR in adolescents and young adults with repaired d-transposition of great arteries and good agreement of measurements with CMR. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. A novel recessive mutation in the gene ELOVL4 causes a neuro-ichthyotic disorder with variable expressivity

    Science.gov (United States)

    2014-01-01

    Background A rare neuro-ichthyotic disorder characterized by ichthyosis, spastic quadriplegia and intellectual disability and caused by recessive mutations in ELOVL4, encoding elongase-4 protein has recently been described. The objective of the study was to search for sequence variants in the gene ELOVL4 in three affected individuals of a consanguineous Pakistani family exhibiting features of neuro-ichthyotic disorder. Methods Linkage in the family was searched by genotyping microsatellite markers linked to the gene ELOVL4, mapped at chromosome 6p14.1. Exons and splice junction sites of the gene ELOVL4 were polymerase chain reaction amplified and sequenced in an automated DNA sequencer. Results DNA sequence analysis revealed a novel homozygous nonsense mutation (c.78C > G; p.Tyr26*). Conclusions Our report further confirms the recently described ELOVL4-related neuro-ichthyosis and shows that the neurological phenotype can be absent in some individuals. PMID:24571530

  1. Suppression of different classes of somatic mutations in Arabidopsis by vir gene-expressing Agrobacterium strains.

    Science.gov (United States)

    Shah, Jasmine M; Ramakrishnan, Anantha Maharasi; Singh, Amit Kumar; Ramachandran, Subalakshmi; Unniyampurath, Unnikrishnan; Jayshankar, Ajitha; Balasundaram, Nithya; Dhanapal, Shanmuhapreya; Hyde, Geoff; Baskar, Ramamurthy

    2015-08-26

    Agrobacterium infection, which is widely used to generate transgenic plants, is often accompanied by T-DNA-linked mutations and transpositions in flowering plants. It is not known if Agrobacterium infection also affects the rates of point mutations, somatic homologous recombinations (SHR) and frame-shift mutations (FSM). We examined the effects of Agrobacterium infection on five types of somatic mutations using a set of mutation detector lines of Arabidopsis thaliana. To verify the effect of secreted factors, we exposed the plants to different Agrobacterium strains, including wild type (Ach5), its derivatives lacking vir genes, oncogenes or T-DNA, and the heat-killed form for 48 h post-infection; also, for a smaller set of strains, we examined the rates of three types of mutations at multiple time-points. The mutation detector lines carried a non-functional β-glucuronidase gene (GUS) and a reversion of mutated GUS to its functional form resulted in blue spots. Based on the number of blue spots visible in plants grown for a further two weeks, we estimated the mutation frequencies. For plants co-cultivated for 48 h with Agrobacterium, if the strain contained vir genes, then the rates of transversions, SHRs and FSMs (measured 2 weeks later) were lower than those of uninfected controls. In contrast, co-cultivation for 48 h with any of the Agrobacterium strains raised the transposition rates above control levels. The multiple time-point study showed that in seedlings co-cultivated with wild type Ach5, the reduced rates of transversions and SHRs after 48 h co-cultivation represent an apparent suppression of an earlier short-lived increase in mutation rates (peaking for plants co-cultivated for 3 h). An increase after 3 h co-cultivation was also seen for rates of transversions (but not SHR) in seedlings exposed to the strain lacking vir genes, oncogenes and T-DNA. However, the mutation rates in plants co-cultivated for longer times with this strain subsequently

  2. The expanding universe of transposon technologies for gene and cell engineering

    Directory of Open Access Journals (Sweden)

    Ivics Zoltán

    2010-12-01

    Full Text Available Abstract Transposable elements can be viewed as natural DNA transfer vehicles that, similar to integrating viruses, are capable of efficient genomic insertion. The mobility of class II transposable elements (DNA transposons can be controlled by conditionally providing the transposase component of the transposition reaction. Thus, a DNA of interest (be it a fluorescent marker, a small hairpin (shRNA expression cassette, a mutagenic gene trap or a therapeutic gene construct cloned between the inverted repeat sequences of a transposon-based vector can be used for stable genomic insertion in a regulated and highly efficient manner. This methodological paradigm opened up a number of avenues for genome manipulations in vertebrates, including transgenesis for the generation of transgenic cells in tissue culture, the production of germline transgenic animals for basic and applied research, forward genetic screens for functional gene annotation in model species, and therapy of genetic disorders in humans. Sleeping Beauty (SB was the first transposon shown to be capable of gene transfer in vertebrate cells, and recent results confirm that SB supports a full spectrum of genetic engineering including transgenesis, insertional mutagenesis, and therapeutic somatic gene transfer both ex vivo and in vivo. The first clinical application of the SB system will help to validate both the safety and efficacy of this approach. In this review, we describe the major transposon systems currently available (with special emphasis on SB, discuss the various parameters and considerations pertinent to their experimental use, and highlight the state of the art in transposon technology in diverse genetic applications.

  3. The expanding universe of transposon technologies for gene and cell engineering.

    Science.gov (United States)

    Ivics, Zoltán; Izsvák, Zsuzsanna

    2010-12-07

    Transposable elements can be viewed as natural DNA transfer vehicles that, similar to integrating viruses, are capable of efficient genomic insertion. The mobility of class II transposable elements (DNA transposons) can be controlled by conditionally providing the transposase component of the transposition reaction. Thus, a DNA of interest (be it a fluorescent marker, a small hairpin (sh)RNA expression cassette, a mutagenic gene trap or a therapeutic gene construct) cloned between the inverted repeat sequences of a transposon-based vector can be used for stable genomic insertion in a regulated and highly efficient manner. This methodological paradigm opened up a number of avenues for genome manipulations in vertebrates, including transgenesis for the generation of transgenic cells in tissue culture, the production of germline transgenic animals for basic and applied research, forward genetic screens for functional gene annotation in model species, and therapy of genetic disorders in humans. Sleeping Beauty (SB) was the first transposon shown to be capable of gene transfer in vertebrate cells, and recent results confirm that SB supports a full spectrum of genetic engineering including transgenesis, insertional mutagenesis, and therapeutic somatic gene transfer both ex vivo and in vivo. The first clinical application of the SB system will help to validate both the safety and efficacy of this approach. In this review, we describe the major transposon systems currently available (with special emphasis on SB), discuss the various parameters and considerations pertinent to their experimental use, and highlight the state of the art in transposon technology in diverse genetic applications.

  4. Comparative effectiveness of one-stage versus two-stage basilic vein transposition arteriovenous fistulas.

    Science.gov (United States)

    Ghaffarian, Amir A; Griffin, Claire L; Kraiss, Larry W; Sarfati, Mark R; Brooke, Benjamin S

    2018-02-01

    Basilic vein transposition (BVT) fistulas may be performed as either a one-stage or two-stage operation, although there is debate as to which technique is superior. This study was designed to evaluate the comparative clinical efficacy and cost-effectiveness of one-stage vs two-stage BVT. We identified all patients at a single large academic hospital who had undergone creation of either a one-stage or two-stage BVT between January 2007 and January 2015. Data evaluated included patient demographics, comorbidities, medication use, reasons for abandonment, and interventions performed to maintain patency. Costs were derived from the literature, and effectiveness was expressed in quality-adjusted life-years (QALYs). We analyzed primary and secondary functional patency outcomes as well as survival during follow-up between one-stage and two-stage BVT procedures using multivariate Cox proportional hazards models and Kaplan-Meier analysis with log-rank tests. The incremental cost-effectiveness ratio was used to determine cost savings. We identified 131 patients in whom 57 (44%) one-stage BVT and 74 (56%) two-stage BVT fistulas were created among 8 different vascular surgeons during the study period that each performed both procedures. There was no significant difference in the mean age, male gender, white race, diabetes, coronary disease, or medication profile among patients undergoing one- vs two-stage BVT. After fistula transposition, the median follow-up time was 8.3 months (interquartile range, 3-21 months). Primary patency rates of one-stage BVT were 56% at 12-month follow-up, whereas primary patency rates of two-stage BVT were 72% at 12-month follow-up. Patients undergoing two-stage BVT also had significantly higher rates of secondary functional patency at 12 months (57% for one-stage BVT vs 80% for two-stage BVT) and 24 months (44% for one-stage BVT vs 73% for two-stage BVT) of follow-up (P < .001 using log-rank test). However, there was no significant difference

  5. A novel mutation in PGAP2 gene causes developmental delay, intellectual disability, epilepsy and microcephaly in consanguineous Saudi family.

    Science.gov (United States)

    Naseer, Muhammad Imran; Rasool, Mahmood; Jan, Mohammed M; Chaudhary, Adeel G; Pushparaj, Peter Natesan; Abuzenadah, Adel M; Al-Qahtani, Mohammad H

    2016-12-15

    PGAP2 (Post-GPI Attachment to Proteins 2) gene is involved in lipid remodeling steps of Glycosylphosphatidylinositol (GPI)-anchor maturation. At the surface of the cell this gene is required for proper expression of GPI-anchored proteins. Hyperphosphatasia with mental retardation syndrome-3 is an autosomal recessive disorder usually characterized by severe mental retardation. Mutations in the PGAP2 gene cause hyperphosphatasia mental retardation syndrome-3. We have identified a large consanguineous family from Saudi origin segregating developmental delay, intellectual disability, epilepsy and microcephaly. Whole exome sequencing with 100× coverage was performed on two affected siblings of the family. Data analysis in the patient revealed a novel missense mutation c.191C>T in PGAP2 gene resulting in Alanine to Valine substitution (Ala64Val). The mutation was reconfirmed and validated by subsequent Sanger sequencing method. The mutation was ruled out in 100 unrelated healthy controls. We suggest that this pathogenic mutation disrupts the proper function of the gene proteins resulting in the disease state. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Point mutation in the MITF gene causing Waardenburg syndrome type II in a three-generation Indian family.

    Science.gov (United States)

    Lalwani, A K; Attaie, A; Randolph, F T; Deshmukh, D; Wang, C; Mhatre, A; Wilcox, E

    1998-12-04

    Waardenburg syndrome (WS) is an autosomal-dominant neural crest cell disorder phenotypically characterized by hearing impairment and disturbance of pigmentation. A presence of dystopia canthorum is indicative of WS type 1, caused by loss of function mutation in the PAX3 gene. In contrast, type 2 WS (WS2) is characterized by normally placed medial canthi and is genetically heterogeneous; mutations in MITF (microphthalmia associated transcription factor) associated with WS2 have been identified in some but not all affected families. Here, we report on a three-generation Indian family with a point mutation in the MITF gene causing WS2. This mutation, initially reported in a Northern European family, creates a stop codon in exon 7 and is predicted to result in a truncated protein lacking the HLH-Zip or Zip structure necessary for normal interaction with its target DNA motif. Comparison of the phenotype between the two families demonstrates a significant difference in pigmentary disturbance of the eye. This family, with the first documented case of two unrelated WS2 families harboring identical mutations, provides additional evidence for the importance of genetic background on the clinical phenotype.

  7. Aorto-Right Ventricular Tunnel in Transposition of the Great Arteries

    Directory of Open Access Journals (Sweden)

    Antonio F. Corno

    2018-02-01

    Full Text Available Aorto-ventricular tunnel is an extremely rare congenital heart defect, consisting of failure of attachment of an aortic leaflet along the semilunar hinge. In all published reports the leaflet involved was either the right coronary leaflet, most frequently, or the left coronary leaflet, in most of the cases opening toward the left ventricle, with only one-eighth of the reported cases communicating with the right ventricle. Treatment of the aorto-ventricular tunnel has been anecdotally reported by interventional closure with a device and more frequently with surgical approach, either as an isolated malformation or as associated lesions. To the best of our knowledge, the presence of an aorto-ventricular tunnel of the non-adjacent aortic leaflet in transposition of the great arteries has never been reported. We have observed an aorto-ventricular tunnel involving the non-adjacent leaflet of the aortic root, which after arterial switch became the pulmonary root. The patient presented 18 years after the arterial switch with progressive dilatation of the right ventricle due to severe degree of pulmonary valve regurgitation, confirmed by echocardiography and cardiac MRI. Indication for surgery was given with the plan for a pulmonary valve implantation. Because of the intra-operative finding of disconnection of the anterior leaflet of the pulmonary valve (former aortic valve along the semilunar hinge, the surgical plan was modified and the anterior leaflet was attached to the valve annulus, with subsequent plasty in correspondence with the right and left commissurae to reduce the size of the dilated annulus to normal diameter. The post-operative course was uneventful, with extubation after few hours and discharge 4 days after surgery, with echocardiography showing trivial degree of pulmonary valve regurgitation. The patient remains in good conditions 6 months after surgery.

  8. A novel frameshift deletion in the albumin gene causes analbuminemia in a young Turkish woman.

    Science.gov (United States)

    Dagnino, Monica; Caridi, Gianluca; Aydin, Zeki; Ozturk, Savas; Karaali, Zeynep; Kazancioglu, Rumeyza; Cefle, Kivanc; Gursu, Meltem; Campagnoli, Monica; Galliano, Monica; Minchiotti, Lorenzo

    2010-11-11

    Analbuminemia is a rare autosomal recessive disorder manifested by the absence, or severe reduction, of circulating serum albumin. The analbuminemic trait was diagnosed in a young Turkish woman on the basis of her clinical symptoms (bilateral lower limb edema) and biochemical findings (minimal albumin amount and variable increases in other protein fractions). Total DNA from the analbuminemic proband and her parents was PCR-amplified using oligonucleotide primers designed to amplify the 14 exons of the albumin gene (ALB) and the flanking intron regions. The products were screened for mutations by single-strand conformation polymorphism (SSCP) and heteroduplex analyses (HA). HA allowed the identification of the mutation site in exon 12. Direct DNA sequencing of this abnormal fragment revealed that the analbuminemic trait was caused by a homozygous CA deletion at nucleotide positions c. 1614-1615 in the codons for Cys538 and Thr539. The subsequent frameshift should give rise to a putative truncated albumin variant in which the sequence Cys(538)-Thr-Leu-Ser has been changed to Cys(538)-Thr-Phe-Stop. The parents were heterozygous for the same mutation. Gel-based mutation detection and DNA sequencing substantiate the clinical diagnosis of congenital analbuminemia in our patient and show that the condition is caused by a novel mutation within the ALB gene. These results contribute to shed light on the molecular basis of this rare condition. 2010 Elsevier B.V. All rights reserved.

  9. Case reports of juvenile GM1 gangliosidosisis type II caused by mutation in GLB1 gene.

    Science.gov (United States)

    Karimzadeh, Parvaneh; Naderi, Samaneh; Modarresi, Farzaneh; Dastsooz, Hassan; Nemati, Hamid; Farokhashtiani, Tayebeh; Shamsian, Bibi Shahin; Inaloo, Soroor; Faghihi, Mohammad Ali

    2017-07-17

    Type II or juvenile GM1-gangliosidosis is an autosomal recessive lysosomal storage disorder, which is clinically distinct from infantile form of the disease by the lack of characteristic cherry-red spot and hepatosplenomegaly. The disease is characterized by slowly progressive neurodegeneration and mild skeletal changes. Due to the later age of onset and uncharacteristic presentation, diagnosis is frequently puzzled with other ataxic and purely neurological disorders. Up to now, 3-4 types of GM1-gangliosidosis have been reported and among them type I is the most common phenotype with the age of onset around 6 months. Various forms of GM1-gangliosidosis are caused by GLB1 gene mutations but severity of the disease and age of onset are directly related to the position and the nature of deleterious mutations. However, due to its unique genetic cause and overlapping clinical features, some researchers believe that GM1 gangliosidosis represents an overlapped disease spectrum instead of four distinct types. Here, we report a less frequent type of autosomal recessive GM1 gangliosidosis with perplexing clinical presentation in three families in the southwest part of Iran, who are unrelated but all from "Lurs" ethnic background. To identify disease-causing mutations, Whole Exome Sequencing (WES) utilizing next generation sequencing was performed. Four patients from three families were investigated with the age of onset around 3 years old. Clinical presentations were ataxia, gate disturbances and dystonia leading to wheelchair-dependent disability, regression of intellectual abilities, and general developmental regression. They all were born in consanguineous families with no previous documented similar disease in their parents. A homozygote missense mutation in GLB1 gene (c. 601 G > A, p.R201C) was found in all patients. Using Sanger sequencing this identified mutation was confirmed in the proband, their parents, grandparents, and extended family members, confirming

  10. Contemporary management and outcomes in congenitally corrected transposition of the great arteries.

    Science.gov (United States)

    Kutty, Shelby; Danford, David A; Diller, Gerhard-Paul; Tutarel, Oktay

    2018-01-11

    Congenitally corrected transposition of the great arteries (ccTGA) can occur in isolation, or in combination with other structural cardiac anomalies, most commonly ventricular septal defect, pulmonary stenosis and tricuspid valve disease. Clinical recognition can be challenging, so echocardiography is often the means by which definitive diagnosis is made. The tricuspid valve and right ventricle are on the systemic arterial side of the ccTGA circulation, and are therefore subject to progressive functional deterioration. The natural history of ccTGA is also greatly influenced by the nature and severity of accompanying lesions, some of which require surgical repair. Some management strategies leave the right ventricle as the systemic arterial pump, but carry the risk of worsening heart failure. More complex 'double switch' repairs establish the left ventricle as the systemic pump, and include an atrial baffle to redirect venous return in combination with either arterial switch or Rastelli operation (if a suitable ventricular septal defect permits). Occasionally, the anatomic peculiarities of ccTGA do not allow straightforward biventricular repair, and Fontan palliation is a reasonable option. Regardless of the approach selected, late cardiovascular complications are relatively common, so ongoing outpatient surveillance should be established in an age-appropriate facility with expertise in congenital heart disease care. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  11. Digital gene expression analysis of corky split vein caused by boron deficiency in 'Newhall' Navel Orange (Citrus sinensis Osbeck for selecting differentially expressed genes related to vascular hypertrophy.

    Directory of Open Access Journals (Sweden)

    Cheng-Quan Yang

    Full Text Available Corky split vein caused by boron (B deficiency in 'Newhall' Navel Orange was studied in the present research. The boron-deficient citrus exhibited a symptom of corky split vein in mature leaves. Morphologic and anatomical surveys at four representative phases of corky split veins showed that the symptom was the result of vascular hypertrophy. Digital gene expression (DGE analysis was performed based on the Illumina HiSeq™ 2000 platform, which was applied to analyze the gene expression profilings of corky split veins at four morphologic phases. Over 5.3 million clean reads per library were successfully mapped to the reference database and more than 22897 mapped genes per library were simultaneously obtained. Analysis of the differentially expressed genes (DEGs revealed that the expressions of genes associated with cytokinin signal transduction, cell division, vascular development, lignin biosynthesis and photosynthesis in corky split veins were all affected. The expressions of WOL and ARR12 involved in the cytokinin signal transduction pathway were up-regulated at 1(st phase of corky split vein development. Furthermore, the expressions of some cell cycle genes, CYCs and CDKB, and vascular development genes, WOX4 and VND7, were up-regulated at the following 2(nd and 3(rd phases. These findings indicated that the cytokinin signal transduction pathway may play a role in initiating symptom observed in our study.

  12. [Association between S100B gene polymorphisms and hand, foot and mouth disease caused by enterovirus 71 infection].

    Science.gov (United States)

    Li, Jing; Shan, Ruo-Bing; Liu, Rui-Hai; Xu, Ying-Jun; Qu, Ni-Yan; Pan, Gui-Mei; Zhang, Na; Yang, Na; Chen, Zhen-Zhen; Zhang, Wen-Xiang; Li, Zi-Pu

    2017-08-01

    To investigate the association between rs9722 polymorphisms in the S100B gene and hand, foot and mouth disease (HFMD) caused by enterovirus 71. A total of 124 HFMD children with enterovirus 71 infection were enrolled as subjects, and 56 healthy children were enrolled as control group. The rs9722 polymorphisms in the S100B gene were detected for both groups, and the serum level of S100B protein was measured for 74 HFMD children. The rs9722 locus of the S100B gene had three genotypes, CC, CT, and TT, and the genotype frequencies were in accordance with Hardy-Weinberg equilibrium. Compared with the control group, the HFMD group had significant increases in the frequencies of TT genotype and T allele (Penterovirus 71 infection had significantly higher frequencies of TT genotype and T allele than those with moderate or mild HFMD (Penterovirus 71 infection.

  13. Correlating gene expression with deformities caused by aryl hydrocarbon receptor agonists in zebrafish (Danio rerio)

    Energy Technology Data Exchange (ETDEWEB)

    Bugiak, B.; Weber, L. [Saskatchewan Univ., Saskatoon, SK (Canada)

    2009-07-01

    Exposure to aryl hydrocarbon receptor (AhR) agonists in fish causes lethal disturbances in fish development, but the effects of acute AhR agonist exposure on the cardiovascular system and deformities remain unclear. This study addressed this issue by performing a series of experiments on zebrafish (Danio rerio). The authors hypothesized that genes needed for cardiovascular regulation (PTGS) would exhibit a stronger link to deformities than detoxification enzymes (CYPs). Zebrafish eggs were exposed aqueously until 4 days post-fertilization (dpf) to the AhR agonists benzo(a)pyrene (BaP) or 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD) alone and in combination with the putative AhR antagonists resveratrol or alpha-naphthoflavone (ANF). Gene expression was measured using real-time, reverse transcriptase PCR in zebrafish at 5 and 10 dpf. Although the mortalities did not differ considerably among groups at 10 dpf, the deformities increased significantly after BaP-ANF at 5 dpf and after BaP at 10 dpf, but not after TCDD treatment. CYP and PTGS isozymes exhibited small, but statistically significant changes at 5 dpf. By 10 dpf, the expression returned to control values. In general, CYP1A and PTGS-1 expression at 5 dpf were positively correlated with deformities, while all other genes were negatively correlated with deformities. It was concluded that changes in CYP1A, CYP1C2, and PTGS-1 gene expression at 5 dpf are associated with developmental deformities, but additional work is needed to determine which has the most important mechanistic link.

  14. DS read-out transcription in transgenic tomato plants

    NARCIS (Netherlands)

    Rudenko, George N.; Nijkamp, H. John J.; Hille, Jacques

    1994-01-01

    To select for Ds transposition in transgenic tomato plants a phenotypic excision assay, based on restoration of hygromycin phosphotransferase (HPT II) gene expression, was employed. Some tomato plants, however, expressed the marker gene even though the Ds had not excised. Read-out transcriptional

  15. A partial gene deletion of SLC45A2 causes oculocutaneous albinism in Doberman pinscher dogs.

    Directory of Open Access Journals (Sweden)

    Paige A Winkler

    Full Text Available The first white Doberman pinscher (WDP dog was registered by the American Kennel Club in 1976. The novelty of the white coat color resulted in extensive line breeding of this dog and her offspring. The WDP phenotype closely resembles human oculocutaneous albinism (OCA and clinicians noticed a seemingly high prevalence of pigmented masses on these dogs. This study had three specific aims: (1 produce a detailed description of the ocular phenotype of WDPs, (2 objectively determine if an increased prevalence of ocular and cutaneous melanocytic tumors was present in WDPs, and (3 determine if a genetic mutation in any of the genes known to cause human OCA is causal for the WDP phenotype. WDPs have a consistent ocular phenotype of photophobia, hypopigmented adnexal structures, blue irides with a tan periphery and hypopigmented retinal pigment epithelium and choroid. WDPs have a higher prevalence of cutaneous melanocytic neoplasms compared with control standard color Doberman pinschers (SDPs; cutaneous tumors were noted in 12/20 WDP (5 years of age: 8/8 and 1/20 SDPs (p<0.00001. Using exclusion analysis, four OCA causative genes were investigated for their association with WDP phenotype; TYR, OCA2, TYRP1 and SLC45A2. SLC45A2 was found to be linked to the phenotype and gene sequencing revealed a 4,081 base pair deletion resulting in loss of the terminus of exon seven of SLC45A2 (chr4∶77,062,968-77,067,051. This mutation is highly likely to be the cause of the WDP phenotype and is supported by a lack of detectable SLC45A2 transcript levels by reverse transcriptase PCR. The WDP provides a valuable model for studying OCA4 visual disturbances and melanocytic neoplasms in a large animal model.

  16. Transposition of the Scientific Elements in Hiroshi Teshigahara’s Adaptation of Kobo Abe’s the Face of Another

    Directory of Open Access Journals (Sweden)

    Anton Sutandio

    2017-01-01

    Full Text Available This article focuses on Hiroshi Teshigahara’s film adaptation of the famous Kobo Abe’s The Face of Another with special attention on the transposition of the scientific elements of the novel in the film. This article observes how Teshigahara, through cinematic techniques, transposes Abe’s scientific language into visual forms. Abe himself involved in the film adaptation by writing the screenplay, in which he prioritized the literary aspects over the filmic aspect. This makes the adaptation become more interesting because Teshigahara is known as a stylish filmmaker. Another noteworthy aspect is the internal dialogues domination within the novel narration. It is written in an epistolary-like narration, placing the protagonist as a single narrator which consequently raises subjectivity. The way Teshigahara externalizes the stream-of-consciousness narration-like into the medium of film is another significant topic of this essay.

  17. In vitro evaluation of physiological spiral anastomoses for the arterial switch operation in simple transposition of the great arteries: a first step towards a surgical alternative?

    Science.gov (United States)

    Sievers, Hans-Hinrich; Scharfschwerdt, Michael; Putman, Léon M

    2015-08-01

    The currently most frequently used technique for the arterial switch operation (ASO) in simple transposition of the great arteries (TGA) includes the transposition of the pulmonary artery anterior to the ascending aorta. This arterial arrangement is less anatomical, and although the initial results are excellent, some long-term data are indicating a certain risk of morbidity, encouraging the search for more physiological techniques. As a first step, we studied the feasibility of anatomical spiral anastomoses of the great vessels in vitro. A TGA model was constructed to simulate the different spatial positions of the great arteries followed by ASO with physiological spiral connections of the great arteries. It was possible to perform a physiological spiral connection of the great arteries without tension or torsion when the roots of the great vessels were arranged anterior-posterior and with up to 35° rotation of the aortic root to the right around the pulmonary root. With further rotation of the aorta, patch plasties were required for pulmonary artery elongation. The maximal width of the patch was 5 mm. In this TGA model, it was possible to perform tension- and torsion-free arterial anastomoses for ASO without artificial material, when the aortic root was positioned from 0° up to 35° to the right of the pulmonary root. Evaluation of coronary transfer is the next step. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  18. Homozygosity mapping reveals new nonsense mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in a Palestinian family.

    Science.gov (United States)

    Zobor, Ditta; Balousha, Ghassan; Baumann, Britta; Wissinger, Bernd

    2014-01-01

    Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 45 genes. Recently, the FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP. We performed a clinical and molecular genetic study of a consanguineous Palestinian family with two three siblings affected with retinitis pigmentosa. DNA samples were collected from the index patient, his father, his affected sister, and two non-affected brothers. DNA sample from the index was subjected to high resolution genome-wide SNP array. Assuming identity-by-descent in this consanguineous family we applied homozygosity mapping to identify disease causing genes. The index patient reported night blindness since the age of 20 years, followed by moderate disease progression with decrease of peripheral vision, the development of photophobia and later on reduced central vision. At the age of 40 his visual acuity was counting fingers (CF) for both eyes, color discrimination was not possible and his visual fields were severely constricted. Funduscopic examination revealed a typical appearance of advanced RP with optic disc pallor, narrowed retinal vessels, bone-spicule like pigmentary changes in the mid-periphery and atrophic changes in the macula. His younger affected brother (37 years) was reported with overall milder symptoms, while the youngest sister (21 years) reported problems only with night vision. Applying high-density SNP arrays we identified several homozygous genomic regions one of which included the recently identified FAM161A gene mutated in RP28-linked autosomal recessive RP. Sequencing analysis revealed the presence of a novel homozygous nonsense mutation, c.1003C>T/p.R335X in the index patient and the affected sister. We identified an RP28-linked RP family in the Palestinian population caused by a novel nonsense mutation in FAM161A. RP in this family shows a typical disease onset with moderate to rapid progression

  19. Judicial Protection in the Field of Public Procurement: The Transposition into Dutch Law of Directive 2007/66/EC Amending the Remedies Directives

    Directory of Open Access Journals (Sweden)

    Wouter-Jan Berends

    2010-08-01

    Full Text Available Public procurement procedures in the EU are coordinated by Directives 2004/17/EC and 2004/18/EC. The acquis communautaire provides minimum requirements for review procedures against public procurement decisions in order to ensure access to effective remedies for economic operators. These minimum requirements are established in Directives 89/665/ EEC and 92/13/EEC and recently amended by Directive 2007/66/EC. The Helby report identified several substantive concerns over the Dutch proposal on the implementation the of the Remedies Directive; Wet implementatie rechtsbeschermingsrichtlijnen. Although the transposition target date has not been met, the Dutch legislature has succeeded to transpose Directive 2007/66/EC into Dutch law while addressing the concerns of the Helby report.

  20. Hyperthyroidism caused by a germline activating mutation of the thyrotropin receptor gene: difficulties in diagnosis and therapy.

    Science.gov (United States)

    Bertalan, Rita; Sallai, Agnes; Sólyom, János; Lotz, Gábor; Szabó, István; Kovács, Balázs; Szabó, Eva; Patócs, Attila; Rácz, Károly

    2010-03-01

    Germline activating mutations of the thyrotropin receptor (TSHR) gene have been considered as the only known cause of sporadic nonautoimmune hyperthyroidism in the pediatric population. Here we describe the long-term follow-up and evaluation of a patient with sporadic nonautoimmune primary hyperthyroidism who was found to have a de novo germline activating mutation of the TSHR gene. The patient was an infant who presented at the age of 10 months in an unconscious state with exsiccation, wet skin, fever, and tachycardia. Nonautoimmune primary hyperthyroidism was diagnosed, and brain magnetic resonance imaging and computed tomography showed also Arnold-Chiari malformation type I. Continuous propylthiouracil treatment resulted in a prolonged clinical cure lasting for 10 years. At the age of 11 years and 5 months the patient underwent subtotal thyroidectomy because of symptoms of trachea compression caused by a progressive multinodular goiter. However, 2 months after surgery, hormonal evaluation indicated recurrent hyperthyroidism and the patient was treated with propylthiouracil during the next 4 years. At the age of 15 years the patient again developed symptoms of trachea compression. Radioiodine treatment resulted in a regression of the recurrent goiter and a permanent cure of hyperthyroidism without relapse during the last 3 years of his follow-up. Sequencing of exon 10 of the TSHR gene showed a de novo heterozygous germline I630L mutation, which has been previously described as activating mutation at somatic level in toxic thyroid nodules. The I630L mutation of the TSHR gene occurs not only at somatic level in toxic thyroid nodules, but also its presence in germline is associated with nonautoimmune primary hyperthyroidism. Our case report demonstrates that in this disorder a continuous growth of the thyroid occurs without any evidence of elevated TSH due to antithyroid drug overdosing. This may justify previous recommendations for early treatment of affected

  1. Two-stage anatomical repair of “simple” transposition of great arteries in neonates with extracardiac perinatal complications

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    O. Yu. Kornoukhov

    2017-07-01

    Full Text Available Aim. This study was designed to analyse the results of two-stage arterial switch operation (ASO of “simple” transposition of great arteries in patients with infection, neurological problems or necrotizing enterocolitis, which preclude neonatal surgery. Methods. Transthoracic echocardiography data and outcomes of surgery were investigated in 19 patients (study group; #1 after two-stage ASO and 67 patients (control group; #2 after a single-stage ASO. Age of patients at the first stage was 27 (8–55 days and at the second stage 172 (92–256 days. Patients in group 2 were 7 (2–53 days old. All of them were followed up for 21 (4–49 months (group 1 and 40 (7–79 months (group 2 after arterial switch operation. Results. There was no operative mortality at both stages in group 1. The duration of ventilation, length of intensive care unit and hospital stay after surgery were considerably lower in group 1. Actuarial sur-vival and freedom from reoperation at 4 years in group 1 accounted for 100%, while in the con-trol group those indicators at 6 years ran to 98.5% and 94%, respectively. The only difference detected by echocardiography was the aortic valve hinge points Z-score (3.9±1.44 vs 3.1±1.27; p=0.025 and sinuses of Valsalva (3.8±1.41 vs 2.8±1.19; p=0.03, which were higher in the 1st group. There was no aortic regurgitation >1 grade in both groups. Conclusion. Two-stage repair of “simple” transposition of great arteries, when it’s necessary to delay arterial switch operation on the clinical grounds, can be performed with excellent clinical outcomes. The tendency of group 1 patients to have a larger neo-aortic root does not appear to bear any clinical significance in mid-term follow-up.Received 21 December 2016. Accepted 8 May 2017.Funding: The study had no sponsorship.Conflict of interest: The authors declare no conflict of interest. Author contributions Study concept and design: Kornoukhov O.Yu., Ilyin V.N.Data collection and

  2. Somatic transposition in the brain has the potential to influence the biosynthesis of metabolites involved in Parkinson’s disease and schizophrenia

    Directory of Open Access Journals (Sweden)

    Abrusán György

    2012-11-01

    Full Text Available Abstract It has been recently discovered that transposable elements show high activity in the brain of mammals, however, the magnitude of their influence on its functioning is unclear so far. In this paper, I use flux balance analysis to examine the influence of somatic retrotransposition on brain metabolism, and the biosynthesis of its key metabolites, including neurotransmitters. The analysis shows that somatic transposition in the human brain can influence the biosynthesis of more than 250 metabolites, including dopamine, serotonin and glutamate, shows large inter-individual variability in metabolic effects, and may contribute to the development of Parkinson’s disease and schizophrenia. Reviewers This article was reviewed by Dr Kenji Kojima (nominated by Dr Jerzy Jurka and Dr Eugene Koonin.

  3. [Gene doping: gene transfer and possible molecular detection].

    Science.gov (United States)

    Argüelles, Carlos Francisco; Hernández-Zamora, Edgar

    2007-01-01

    The use of illegal substances in sports to enhance athletic performance during competition has caused international sports organizations such as the COI and WADA to take anti doping measures. A new doping method know as gene doping is defined as "the non-therapeutic use of genes, genetic elements and/or cells that have the capacity to enhance athletic performance". However, gene doping in sports is not easily identified and can cause serious consequences. Molecular biology techniques are needed in order to distinguish the difference between a "normal" and an "altered" genome. Further, we need to develop new analytic methods and biological molecular techniques in anti-doping laboratories, and design programs that avoid the non therapeutic use of genes.

  4. Spontaneous germline excision of Tol1, a DNA-based transposable element naturally occurring in the medaka fish genome.

    Science.gov (United States)

    Watanabe, Kohei; Koga, Hajime; Nakamura, Kodai; Fujita, Akiko; Hattori, Akimasa; Matsuda, Masaru; Koga, Akihiko

    2014-04-01

    DNA-based transposable elements are ubiquitous constituents of eukaryotic genomes. Vertebrates are, however, exceptional in that most of their DNA-based elements appear to be inactivated. The Tol1 element of the medaka fish, Oryzias latipes, is one of the few elements for which copies containing an undamaged gene have been found. Spontaneous transposition of this element in somatic cells has previously been demonstrated, but there is only indirect evidence for its germline transposition. Here, we show direct evidence of spontaneous excision in the germline. Tyrosinase is the key enzyme in melanin biosynthesis. In an albino laboratory strain of medaka fish, which is homozygous for a mutant tyrosinase gene in which a Tol1 copy is inserted, we identified de novo reversion mutations related to melanin pigmentation. The gamete-based reversion rate was as high as 0.4%. The revertant fish carried the tyrosinase gene from which the Tol1 copy had been excised. We previously reported the germline transposition of Tol2, another DNA-based element that is thought to be a recent invader of the medaka fish genome. Tol1 is an ancient resident of the genome. Our results indicate that even an old element can contribute to genetic variation in the host genome as a natural mutator.

  5. Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype

    Science.gov (United States)

    Martinelli, Simone; De Luca, Alessandro; Stellacci, Emilia; Rossi, Cesare; Checquolo, Saula; Lepri, Francesca; Caputo, Viviana; Silvano, Marianna; Buscherini, Francesco; Consoli, Federica; Ferrara, Grazia; Digilio, Maria C.; Cavaliere, Maria L.; van Hagen, Johanna M.; Zampino, Giuseppe; van der Burgt, Ineke; Ferrero, Giovanni B.; Mazzanti, Laura; Screpanti, Isabella; Yntema, Helger G.; Nillesen, Willy M.; Savarirayan, Ravi; Zenker, Martin; Dallapiccola, Bruno; Gelb, Bruce D.; Tartaglia, Marco

    2010-01-01

    RAS signaling plays a key role in controlling appropriate cell responses to extracellular stimuli and participates in early and late developmental processes. Although enhanced flow through this pathway has been established as a major contributor to oncogenesis, recent discoveries have revealed that aberrant RAS activation causes a group of clinically related developmental disorders characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, ectodermal and musculoskeletal anomalies, and increased risk for certain malignancies. Here, we report that heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family. Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes. Phenotypic heterogeneity and variable expressivity were documented. Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies. Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS. These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies. PMID:20619386

  6. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism.

    Science.gov (United States)

    Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet; Kelsh, Robert N; Hansen, Lars; Levesque, Mitchell P; Vilhelmsen, Kaj; Møllgård, Kjeld; Stemple, Derek L; Rosenberg, Thomas

    2013-03-07

    Autosomal-recessive albinism is a hypopigmentation disorder with a broad phenotypic range. A substantial fraction of individuals with albinism remain genetically unresolved, and it has been hypothesized that more genes are to be identified. By using homozygosity mapping of an inbred Faroese family, we identified a 3.5 Mb homozygous region (10q22.2-q22.3) on chromosome 10. The region contains five protein-coding genes, and sequencing of one of these, C10orf11, revealed a nonsense mutation that segregated with the disease and showed a recessive inheritance pattern. Investigation of additional albinism-affected individuals from the Faroe Islands revealed that five out of eight unrelated affected persons had the nonsense mutation in C10orf11. Screening of a cohort of autosomal-recessive-albinism-affected individuals residing in Denmark showed a homozygous 1 bp duplication in C10orf11 in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted in substantially decreased pigmentation and a reduction of the apparent number of pigmented melanocytes. The morphant phenotype was rescued by wild-type C10orf11, but not by mutant C10orf11. In conclusion, we have identified a melanocyte-differentiation gene, C10orf11, which when mutated causes autosomal-recessive albinism in humans. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  7. Barbara McClintock and the Discovery of Jumping Genes

    Indian Academy of Sciences (India)

    milind1

    the Nobel Prize in 1983 for her work on genetic instability. (transposition). .... Getting accepted in the male world of science was not easy either. The awe and respect ... instead in the annual reports of the Carnegie Institution or in. Conference ...

  8. TDP-43 Loss-of-Function Causes Neuronal Loss Due to Defective Steroid Receptor-Mediated Gene Program Switching in Drosophila

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    Lies Vanden Broeck

    2013-01-01

    Full Text Available TDP-43 proteinopathy is strongly implicated in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative disorders. Whether TDP-43 neurotoxicity is caused by a novel toxic gain-of-function mechanism of the aggregates or by a loss of its normal function is unknown. We increased and decreased expression of TDP-43 (dTDP-43 in Drosophila. Although upregulation of dTDP-43 induced neuronal ubiquitin and dTDP-43-positive inclusions, both up- and downregulated dTDP-43 resulted in selective apoptosis of bursicon neurons and highly similar transcriptome alterations at the pupal-adult transition. Gene network analysis and genetic validation showed that both up- and downregulated dTDP-43 directly and dramatically increased the expression of the neuronal microtubule-associated protein Map205, resulting in cytoplasmic accumulations of the ecdysteroid receptor (EcR and a failure to switch EcR-dependent gene programs from a pupal to adult pattern. We propose that dTDP-43 neurotoxicity is caused by a loss of its normal function.

  9. A novel point mutation within the EDA gene causes an exon dropping in mature RNA in Holstein Friesian cattle breed affected by X-linked anhidrotic ectodermal dysplasia

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    Pariset Lorraine

    2011-07-01

    Full Text Available Abstract Background X-linked anhidrotic ectodermal dysplasia is a disorder characterized by abnormal development of tissues and organs of ectodermal origin caused by mutations in the EDA gene. The bovine EDA gene encodes the ectodysplasin A, a membrane protein expressed in keratinocytes, hair follicles and sweat glands, which is involved in the interactions between cell and cell and/or cell and matrix. Four mutations causing ectodermal dysplasia in cattle have been described so far. Results We identified a new single nucleotide polymorphism (SNP at the 9th base of exon 8 in the EDA gene in two calves of Holstein Friesian cattle breed affected by ectodermal dysplasia. This SNP is located in the exonic splicing enhancer (ESEs recognized by SRp40 protein. As a consequence, the spliceosome machinery is no longer able to recognize the sequence as exonic and causes exon skipping. The mutation determines the deletion of the entire exon (131 bp in the RNA processing, causing a severe alteration of the protein structure and thus the disease. Conclusion We identified a mutation, never described before, that changes the regulation of alternative splicing in the EDA gene and causes ectodermal dysplasia in cattle. The analysis of the SNP allows the identification of carriers that can transmit the disease to the offspring. This mutation can thus be exploited for a rational and efficient selection of unequivocally healthy cows for breeding.

  10. Partial Gene Deletions of PMP22 Causing Hereditary Neuropathy with Liability to Pressure Palsies

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    Sun-Mi Cho

    2014-01-01

    Full Text Available Hereditary neuropathy with liability to pressure palsies (HNPP is an autosomal neuropathy that is commonly caused by a reciprocal 1.5 Mb deletion on chromosome 17p11.2, at the site of the peripheral myelin protein 22 (PMP22 gene. Other patients with similar phenotypes have been shown to harbor point mutations or small deletions, although there is some clinical variation across these patients. In this report, we describe a case of HNPP with copy number changes in exon or promoter regions of PMP22. Multiplex ligation-dependent probe analysis revealed an exon 1b deletion in the patient, who had been diagnosed with HNPP in the first decade of life using molecular analysis.

  11. Mutations in OTOF, CLDN14 & SLC26A4 genes as major causes of hearing impairment in Dhadkai village, Jammu & Kashmir, India

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    Nishtha Pandey

    2017-01-01

    Interpretation & conclusions: This study suggested considerable genetic heterogeneity in the causation of hearing loss in Dhadkai. Recessive mutations were observed in at least three genes causing hearing loss: OTOF (p.R708X, SLC26A4 (p.Y556X and CLDN14 (p.V85D. Mutation p.R708X appeared to be the major cause of hearing impairment in Dhadkai.

  12. Toxin Gene Analysis of a Variant Strain of Clostridium difficile That Causes Human Clinical Disease

    Science.gov (United States)

    Sambol, Susan P.; Merrigan, Michelle M.; Lyerly, David; Gerding, Dale N.; Johnson, Stuart

    2000-01-01

    A toxin variant strain of Clostridium difficile was isolated from two patients with C. difficile-associated disease (CDAD), one of whom died from extensive pseudomembranous colitis. This strain, identified by restriction endonuclease analysis (REA) as type CF2, was not detected by an immunoassay for C. difficile toxin A. Culture supernatants of CF2 failed to elicit significant enterotoxic activity in the rabbit ileal loop assay but did produce atypical cytopathic effects in cell culture assay. Southern hybridization, PCR amplification, and DNA sequence analyses were performed on the toxin A (tcdA) and toxin B (tcdB) genes of type CF2 isolate 5340. Type CF2 5340 tcdA exhibited a 1,821-bp truncation, due to three deletions in the 3′ end of the gene, and a point mutation in the 5′ end of the gene, resulting in a premature stop codon at tcdA position 139. Type CF2 5340 tcdB exhibited multiple nucleotide base substitutions in the 5′ end of the gene compared to tcdB of the standard toxigenic strain VPI 10463. Type CF2 5340 toxin gene nucleotide sequences and deduced amino acid sequences showed a strong resemblance to those of the previously described variant C. difficile strain 1470, a strain reported to have reduced pathogenicity and no association with clinical illness in humans. REA of strain 1470 identified this strain as a distinct type (CF1) within the same REA group as the closely related type CF2. A review of our clinical-isolate collection identified five additional patients infected with type CF2, three of whom had documented CDAD. PCR amplification of the 3′ end of tcdA demonstrated identical 1.8-kb deletions in all seven type CF2 isolates. REA type CF2 is a toxin variant strain of C. difficile that retains the ability to cause disease in humans but is not detected in clinical immunoassays for toxin A. PMID:10992443

  13. Multiple Genes Cause Postmating Prezygotic Reproductive Isolation in the Drosophila virilis Group.

    Science.gov (United States)

    Ahmed-Braimah, Yasir H

    2016-12-07

    Understanding the genetic basis of speciation is a central problem in evolutionary biology. Studies of reproductive isolation have provided several insights into the genetic causes of speciation, especially in taxa that lend themselves to detailed genetic scrutiny. Reproductive barriers have usually been divided into those that occur before zygote formation (prezygotic) and after (postzygotic), with the latter receiving a great deal of attention over several decades. Reproductive barriers that occur after mating but before zygote formation [postmating prezygotic (PMPZ)] are especially understudied at the genetic level. Here, I present a phenotypic and genetic analysis of a PMPZ reproductive barrier between two species of the Drosophila virilis group: D. americana and D. virilis This species pair shows strong PMPZ isolation, especially when D. americana males mate with D. virilis females: ∼99% of eggs laid after these heterospecific copulations are not fertilized. Previous work has shown that the paternal loci contributing to this incompatibility reside on two chromosomes, one of which (chromosome 5) likely carries multiple factors. The other (chromosome 2) is fixed for a paracentric inversion that encompasses nearly half the chromosome. Here, I present two results. First, I show that PMPZ in this species cross is largely due to defective sperm storage in heterospecific copulations. Second, using advanced intercross and backcross mapping approaches, I identify genomic regions that carry genes capable of rescuing heterospecific fertilization. I conclude that paternal incompatibility between D. americana males and D. virilis females is underlain by four or more genes on chromosomes 2 and 5. Copyright © 2016 Ahmed-Braimah.

  14. UMD-USHbases: a comprehensive set of databases to record and analyse pathogenic mutations and unclassified variants in seven Usher syndrome causing genes.

    Science.gov (United States)

    Baux, David; Faugère, Valérie; Larrieu, Lise; Le Guédard-Méreuze, Sandie; Hamroun, Dalil; Béroud, Christophe; Malcolm, Sue; Claustres, Mireille; Roux, Anne-Françoise

    2008-08-01

    Using the Universal Mutation Database (UMD) software, we have constructed "UMD-USHbases", a set of relational databases of nucleotide variations for seven genes involved in Usher syndrome (MYO7A, CDH23, PCDH15, USH1C, USH1G, USH3A and USH2A). Mutations in the Usher syndrome type I causing genes are also recorded in non-syndromic hearing loss cases and mutations in USH2A in non-syndromic retinitis pigmentosa. Usher syndrome provides a particular challenge for molecular diagnostics because of the clinical and molecular heterogeneity. As many mutations are missense changes, and all the genes also contain apparently non-pathogenic polymorphisms, well-curated databases are crucial for accurate interpretation of pathogenicity. Tools are provided to assess the pathogenicity of mutations, including conservation of amino acids and analysis of splice-sites. Reference amino acid alignments are provided. Apparently non-pathogenic variants in patients with Usher syndrome, at both the nucleotide and amino acid level, are included. The UMD-USHbases currently contain more than 2,830 entries including disease causing mutations, unclassified variants or non-pathogenic polymorphisms identified in over 938 patients. In addition to data collected from 89 publications, 15 novel mutations identified in our laboratory are recorded in MYO7A (6), CDH23 (8), or PCDH15 (1) genes. Information is given on the relative involvement of the seven genes, the number and distribution of variants in each gene. UMD-USHbases give access to a software package that provides specific routines and optimized multicriteria research and sorting tools. These databases should assist clinicians and geneticists seeking information about mutations responsible for Usher syndrome.

  15. Two α1-Globin Gene Point Mutations Causing Severe Hb H Disease.

    Science.gov (United States)

    Jiang, Hua; Huang, Lv-Yin; Zhen, Li; Jiang, Fan; Li, Dong-Zhi

    Hb H disease is generally a moderate form of α-thalassemia (α-thal) that rarely requires regular blood transfusions. In this study, two Chinese families with members carrying transfusion-dependent Hb H disease were investigated for rare mutations on the α-globin genes (HBA1, HBA2). In one family, Hb Zürich-Albisrieden [α59(E8)Gly→Arg; HBA1: c.178G>C] in combination with the Southeast Asian (- - SEA ) deletion was the defect responsible for the severe phenotype. In another family, a novel hemoglobin (Hb) variant named Hb Sichuan (HBA1: c.393_394insT), causes α-thal and a severe phenotype when associated with the - - SEA deletion. As these two HBA1 mutations can present as continuous blood transfusion-dependent α-thal, it is important to take this point into account for detecting the carriers, especially in couples in which one partner is already a known α 0 -thal carrier.

  16. Genetic interactions between planar cell polarity genes cause diverse neural tube defects in mice

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    Jennifer N. Murdoch

    2014-10-01

    Full Text Available Neural tube defects (NTDs are among the commonest and most severe forms of developmental defect, characterized by disruption of the early embryonic events of central nervous system formation. NTDs have long been known to exhibit a strong genetic dependence, yet the identity of the genetic determinants remains largely undiscovered. Initiation of neural tube closure is disrupted in mice homozygous for mutations in planar cell polarity (PCP pathway genes, providing a strong link between NTDs and PCP signaling. Recently, missense gene variants have been identified in PCP genes in humans with NTDs, although the range of phenotypes is greater than in the mouse mutants. In addition, the sequence variants detected in affected humans are heterozygous, and can often be detected in unaffected individuals. It has been suggested that interactions between multiple heterozygous gene mutations cause the NTDs in humans. To determine the phenotypes produced in double heterozygotes, we bred mice with all three pairwise combinations of Vangl2Lp, ScribCrc and Celsr1Crsh mutations, the most intensively studied PCP mutants. The majority of double-mutant embryos had open NTDs, with the range of phenotypes including anencephaly and spina bifida, therefore reflecting the defects observed in humans. Strikingly, even on a uniform genetic background, variability in the penetrance and severity of the mutant phenotypes was observed between the different double-heterozygote combinations. Phenotypically, Celsr1Crsh;Vangl2Lp;ScribCrc triply heterozygous mutants were no more severe than doubly heterozygous or singly homozygous mutants. We propose that some of the variation between double-mutant phenotypes could be attributed to the nature of the protein disruption in each allele: whereas ScribCrc is a null mutant and produces no Scrib protein, Celsr1Crsh and Vangl2Lp homozygotes both express mutant proteins, consistent with dominant effects. The variable outcomes of these genetic

  17. Overexpression of mouse TTF-2 gene causes cleft palate

    Science.gov (United States)

    Meng, Tian; Shi, Jia-Yu; Wu, Min; Wang, Yan; Li, Ling; Liu, Yan; Zheng, Qian; Huang, Lei; Shi, Bing

    2012-01-01

    In humans, mutations of the gene encoding for thyroid transcription factor-2 (TTF-2 or FOXE1) result in Bamforth syndrome. Bamforth syndrome is characterized by agenesis, cleft palate, spiky hair and choanal atresia. TTF-2 null mice (TTF-2−/−) also exhibit cleft palate, suggesting its involvement in the palatogenesis. However, the molecular pathology and genetic regulation by TTF2 remain largely unknown. In the present study, the recombinant expression vector pBROAD3-TTF-2 containing the promoter of the mouse ROSA26 gene was created to form the structural gene of mouse TTF-2 and was microinjected into the male pronuclei of fertilized ova. Sequence analysis confirmed that the TTF-2 transgenic mouse model was established successfully. The transgenic mice displayed a phenotype of cleft palate. In addition, we found that TTF-2 was highly expressed in the medial edge epithelium (MEE) from the embryonic day 12.5 (E12.5) to E14.5 in TTF-2 transgenic mice. These observations suggest that overexpression of TTF-2 during palatogenesis may contribute to formation of cleft palate. PMID:22304410

  18. Somatic mutations in mismatch repair genes in sporadic gastric carcinomas are not a cause but a consequence of the mutator phenotype

    NARCIS (Netherlands)

    Pinto, Mafalda; Wub, Ying; Mensink, Rob G. J.; Cirnes, Luis; Seruca, Raquel; Hofstra, Robert M. W.

    2008-01-01

    In hereditary nonpolyposis colorectal cancer (HNPCC), patients' mismatch repair (MMR) gene mutations cause MMR deficiency, leading to microsatellite instability (MSI-H). MSI-H is also found in a substantial fraction of sporadic gastric carcinomas (SGC), mainly due to MLH1 promoter hypermethylation,

  19. Late Causes of Death After Pediatric Cardiac Surgery: A 60-Year Population-Based Study.

    Science.gov (United States)

    Raissadati, Alireza; Nieminen, Heta; Haukka, Jari; Sairanen, Heikki; Jokinen, Eero

    2016-08-02

    Comprehensive information regarding causes of late post-operative death following pediatric congenital cardiac surgery is lacking. The study sought to analyze late causes of death after congenital cardiac surgery by era and defect severity. We obtained data from a nationwide pediatric cardiac surgery database and Finnish population registry regarding patients who underwent cardiac surgery at Causes of death were determined using International Classification of Diseases diagnostic codes. Deaths among the study population were compared to a matched control population. Overall, 10,964 patients underwent 14,079 operations, with 98% follow-up. Early mortality (death rates correlated with defect severity. Heart failure was the most common mode of CHD-related death, but decreased after surgeries performed between 1990 and 2009. Sudden death after surgery for atrial septal defect, ventricular septal defect, tetralogy of Fallot, and transposition of the great arteries decreased to zero following operations from 1990 to 2009. Deaths from neoplasms, respiratory, neurological, and infectious disease were significantly more common among study patients than controls. Pneumonia caused the majority of non-CHD-related deaths among the study population. CHD-related deaths have decreased markedly but remain a challenge after surgery for severe cardiac defects. Premature deaths are generally more common among patients than the control population, warranting long-term follow-up after congenital cardiac surgery. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  20. EPILEPSY CAUSED BY PCDH19 GENE MUTATION: A REVIEW OF LITERATURE AND THE AUTHORS’ OBSERVATIONS

    Directory of Open Access Journals (Sweden)

    K. Yu. Mukhin

    2016-01-01

    Full Text Available Mutation in the PCDH19 gene was first described by L.M. Dibbens et al. in 2008. Mutations in this gene are associated with epilepsy and mental retardation limited to females. The clinical manifestations that are observed in some patients with PCDH19 mutation and Dravet syndrome that is caused by mutation in the SCN1A gene include the onset of febrile and afebrile seizures in infancy, serial seizures during fever, and regression in development after the onset of seizures. Due to the fact that the two diseases have common clinical signs, it is best to test for PCDH19 mutation in patients with the clinical picture of Dravet syndrome and a negative test for SCN1A. In general, the number of scientific papers devoted to analysis and recommendations for the choice of therapy in patients with rare genetic pathology is small now. We analyzed the specific features of clinical signs and therapy in our two observed female patients aged 4 and 11 years with verified PCDH19 mutation. Both patients were noted to have severe epilepsy with febrile convulsions with the development of status epilepticus and to be unresponsive to antiepileptic therapy. The use of different antiepileptic drugs (valproate, oxcarbazepine, phenobarbital, topiramate, levetiracetam at different combinations failed to control the course of epilepsy in the 4-year-old patient whereas the 11-year-old patient who took a combination of valproic acid and benzodiazepines achieved a positive effect.

  1. Long-term tinnitus suppression with linear octave frequency transposition hearing AIDS.

    Directory of Open Access Journals (Sweden)

    Elisabeth Peltier

    Full Text Available Over the last three years of hearing aid dispensing, it was observed that among 74 subjects fitted with a linear octave frequency transposition (LOFT hearing aid, 60 reported partial or complete tinnitus suppression during day and night, an effect still lasting after several months or years of daily use. We report in more details on 38 subjects from whom we obtained quantified measures of tinnitus suppression through visual analog scaling and several additional psychoacoustic and audiometric measures. The long-term suppression seems independent of subject age, and of duration and subjective localization of tinnitus. A small but significant correlation was found with audiogram losses but not with high frequency loss slope. Long-term tinnitus suppression was observed for different etiologies, but with a low success rate for sudden deafness. It should be noted that a majority of subjects (23 had a history of noise exposure. Tinnitus suppression started after a few days of LOFT hearing aid use and reached a maximum after a few weeks of daily use. For nine subjects different amounts of frequency shifting were tried and found more or less successful for long-term tinnitus suppression, no correlation was found with tinnitus pitch. When the use of the LOFT hearing aid was stopped tinnitus reappeared within a day, and after re-using the LOFT aid it disappeared again within a day. For about one third of the 38 subjects a classical amplification or a non linear frequency compression aid was also tried, and no such tinnitus suppression was observed. Besides improvements in audiometric sensitivity to high frequencies and in speech discrimination scores, LOFT can be considered as a remarkable opportunity to suppress tinnitus over a long time scale. From a pathophysiological viewpoint these observations seem to fit with a possible re-attribution of activity to previously deprived cerebral areas corresponding to high frequency coding.

  2. Correction of congenital ptosis of the eyelid by frontal muscle transposition

    Directory of Open Access Journals (Sweden)

    Jevtović Dobrica

    2002-01-01

    Full Text Available Congenital ptosis (CP represents a significant reconstructive problem Numerous studies have not yet provided full and satisfactory results. In this study, we have presented our experience in the surgical treatment of 108 patients by the use of Son Ye Guang's modified method - frontal muscle transposition. A total of 108 patients with CP were surgically treated at the Clinic for Plastic Surgery and Burns of the Military Medical Academy in the period 1991-2000. Unilateral ptosis was operated in 85 patients, and bilateral in 23 patients. CP was more frequently found in males (58.34% than in females (41.66%. The youngest patient was only 5.5 years old, and the oldest was 42, the average age was 21.3 years. All patients were operated on by the same surgeon, and were monitored monthly during the first six months and then twice a year for the next 3 years. Postoperative results were evaluated after 6 months: the action of raising the eyelids was compared to the full amplitude of movement of the eye on the healthy side. The closure of the eyelids and the symmetry of the palpebral fissure in a steady horizontal view was also assessed. The action of the opening as well as closure of the eyelids in full amplitude was obtained in all operated patients. Asymmetry of the palpebral fissure in a steady horizontal view up to 1 mm did not require additional correction. In 9 cases, asymmetry of the palpebral fissure greater than 1 mm was subsequently corrected. The advantages of this surgical method compared to the other, previously described techniques, were emphasized in the conclusion. The main advantage was the elimination of postoperative lagophthalmos, which represented the problem in all previously used methods.

  3. Two novel mutations in the sixth transmembrane segment of the thyrotropin receptor gene causing hyperfunctioning thyroid nodules.

    Science.gov (United States)

    Gozu, Hulya; Avsar, Melike; Bircan, Rifat; Claus, Maren; Sahin, Serap; Sezgin, Ozlem; Deyneli, Oguzhan; Paschke, Ralf; Cirakoglu, Beyazit; Akalin, Sema

    2005-04-01

    Autonomously functioning thyroid nodules (AFTNs) can present as hyperfunctioning adenomas or toxic multinodular goiters. In the last decade, a large number of activating mutations have been identified in the thyrotropin receptor (TSHR) gene in autonomously functioning thyroid nodules. Most have been situated close to, or within the sixth transmembrane segment and third intracellular loop of the TSHR where the receptor interacts with the Gs protein. In this study we describe two novel mutations in the sixth transmembrane segment of the TSHR causing hyperfunctioning thyroid nodules. Genomic DNAs were isolated from four hyperfunctioning thyroid nodules, normal tissues and peripheral leukocytes of two patients with toxic multinodular goiter. After amplifying the related regions, TSHR and G(s)alpha genes were analyzed by single-strand conformation polymorphism (SSCP) analysis. The precise localization of the mutations was identified by automatic DNA sequence analysis. Functional studies were done by site-directed mutagenesis and transfection of a mutant construct into COS-7 cells. We identified two novel TSHR mutations in two hyperfunctioning thyroid nodules: Phe631Val in the first patient and Iso630Met in the second patient. Both mutant receptors display an increase in constitutive stimulation of basal cyclic adenosine monophosphate (cAMP) levels compared to the wild-type receptor. This confirms that these mutant receptors cause hyperfunctioning thyroid nodules.

  4. Inflammatory peeling skin syndrome caused by homozygous genomic deletion in the PSORS1 region encompassing the CDSN gene.

    Science.gov (United States)

    Ishida-Yamamoto, Akemi; Furio, Laetitia; Igawa, Satomi; Honma, Masaru; Tron, Elodie; Malan, Valerie; Murakami, Masamoto; Hovnanian, Alain

    2014-01-01

    Peeling skin syndrome (PSS) type B is a rare recessive genodermatosis characterized by lifelong widespread, reddish peeling of the skin with pruritus. The disease is caused by small-scale mutations in the Corneodesmosin gene (CDSN) leading to premature termination codons. We report for the first time a Japanese case resulting from complete deletion of CDSN. Corneodesmosin was undetectable in the epidermis, and CDSN was unamplifiable by PCR. QMPSF analysis demonstrated deletion of CDSN exons inherited from each parent. Deletion mapping using microsatellite haplotyping, CGH array and PCR analysis established that the genomic deletion spanned 49-72 kb between HCG22 and TCF19, removing CDSN as well as five other genes within the psoriasis susceptibility region 1 (PSORS1) on 6p21.33. This observation widens the spectrum of molecular defects underlying PSS type B and shows that loss of these five genes from the PSORS1 region does not result in an additional cutaneous phenotype. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Altered Pre-mRNA Splicing Caused by a Novel Intronic Mutation c.1443+5G>A in the Dihydropyrimidinase (DPYS) Gene

    NARCIS (Netherlands)

    Nakajima, Yoko; Meijer, Judith; Zhang, Chunhua; Wang, Xu; Kondo, Tomomi; Ito, Tetsuya; Dobritzsch, Doreen; van Kuilenburg, André B. P.

    2016-01-01

    Dihydropyrimidinase (DHP) deficiency is an autosomal recessive disease caused by mutations in the DPYS gene. Patients present with highly elevated levels of dihydrouracil and dihydrothymine in their urine, blood and cerebrospinal fluid. The analysis of the effect of mutations in DPYS on pre-mRNA

  6. A novel mutation in the EDAR gene causes severe autosomal recessive hypohidrotic ectodermal dysplasia.

    Science.gov (United States)

    Henningsen, Emil; Svendsen, Mathias Tiedemann; Lildballe, Dorte Launholt; Jensen, Peter Kjestrup Axel

    2014-08-01

    We report on a 2-year-old girl presenting with a severe form of hypohidrotic ectodermal dysplasia (HED). The patient presented with hypotrichosis, anodontia, hypohidrosis, frontal bossing, prominent lips and ears, dry, pale skin, and dermatitis. The patient had chronic rhinitis with malodorous nasal discharge. The girl was the second born child of first-cousin immigrants from Northern Iraq. A novel homozygous mutation (c.84delC) in the EDAR gene was identified. This mutation most likely causes a frameshift in the protein product (p.S29fs*74). This results in abolition of all ectodysplasin-mediated NF-kB signalling. This complete loss-of-function mutation likely accounts for the severe clinical abnormalities in ectodermal structures in the described patient. © 2014 Wiley Periodicals, Inc.

  7. Unusual conservation of mitochondrial gene order in Crassostrea oysters: evidence for recent speciation in Asia

    Science.gov (United States)

    2010-01-01

    Background Oysters are morphologically plastic and hence difficult subjects for taxonomic and evolutionary studies. It is long been suspected, based on the extraordinary species diversity observed, that Asia Pacific is the epicenter of oyster speciation. To understand the species diversity and its evolutionary history, we collected five Crassostrea species from Asia and sequenced their complete mitochondrial (mt) genomes in addition to two newly released Asian oysters (C. iredalei and Saccostrea mordax) for a comprehensive analysis. Results The six Asian Crassostrea mt genomes ranged from 18,226 to 22,446 bp in size, and all coded for 39 genes (12 proteins, 2 rRNAs and 25 tRNAs) on the same strand. Their genomes contained a split of the rrnL gene and duplication of trnM, trnK and trnQ genes. They shared the same gene order that differed from an Atlantic sister species by as many as nine tRNA changes (6 transpositions and 3 duplications) and even differed significantly from S. mordax in protein-coding genes. Phylogenetic analysis indicates that the six Asian Crassostrea species emerged between 3 and 43 Myr ago, while the Atlantic species evolved 83 Myr ago. Conclusions The complete conservation of gene order in the six Asian Crassostrea species over 43 Myr is highly unusual given the remarkable rate of rearrangements in their sister species and other bivalves. It provides strong evidence for the recent speciation of the six Crassostrea species in Asia. It further indicates that changes in mt gene order may not be strictly a function of time but subject to other constraints that are presently not well understood. PMID:21189147

  8. Loss-of-function of a ubiquitin-related modifier promotes the mobilization of the active MITE mPing.

    Science.gov (United States)

    Tsukiyama, Takuji; Teramoto, Shota; Yasuda, Kanako; Horibata, Akira; Mori, Nanako; Okumoto, Yutaka; Teraishi, Masayoshi; Saito, Hiroki; Onishi, Akiko; Tamura, Kanako; Tanisaka, Takatoshi

    2013-05-01

    Miniature inverted-repeat transposable elements (MITEs) are widespread in both prokaryotic and eukaryotic genomes, where their copy numbers can attain several thousands. Little is known, however, about the genetic factor(s) affecting their transpositions. Here, we show that disruption of a gene encoding ubiquitin-like protein markedly enhances the transposition activity of a MITE mPing in intact rice plants without any exogenous stresses. We found that the transposition activity of mPing is far higher in the lines harboring a non-functional allele at the Rurm1 (Rice ubiquitin-related modifier-1) locus than in the wild-type line. Although the alteration of cytosine methylation pattern triggers the activation of transposable elements under exogenous stress conditions, the methylation degrees in the whole genome, the mPing-body region, and the mPing-flanking regions of the non-functional Rurm1 line were unchanged. This study provides experimental evidence for one of the models of genome shock theory that genetic accidents within cells enhance the transposition activities of transposable elements.

  9. Survival and health in liveborn infants with transposition of great arteries--a population-based study.

    Science.gov (United States)

    Garne, Ester; Loane, Maria A; Nelen, Vera; Bakker, Marian K; Gener, Blanca; Abramsky, Lenore; Addor, Marie-Claude; Queisser-Luft, Annette

    2007-01-01

    To describe treatment, survival, and morbidity for liveborn infants with isolated transposition of great arteries (TGA). Population-based data from 7 European registries of congenital malformations (EUROCAT). Ninety-seven infants were diagnosed with isolated TGA and livebirth prevalence was 2.0 per 10,000 livebirths. The majority of infants were treated with prostaglandins (83%) and 57% had a catheter atrial septostomia performed. Arterial switch surgery was performed in 78 infants, other or unknown type of surgery was performed in 3 cases, and for 6 infants there was no information on surgery. At 1 year of age 69 infants were alive (71%) and 24 (25%) were dead (4 unknown). There were 10 deaths before surgery and 58% of all deaths took place during the first week. There was no statistically significant regional difference in mortality. Eight infants diagnosed prenatally all survived to 1 year and only 71% of infants diagnosed after birth survived (P = 0.08). Data on morbidity at 1 year of age was available for 57 infants. Fifty-one infants were reported with normal health and development. In this population-based study survival for liveborn infants with TGA is lower than in studies published from tertiary centers. Outcome for survivors at 1 year of age seems favorable.

  10. Generation of an isogenic, gene-corrected iPSC line from a symptomatic 59-year-old female patient with frontotemporal dementia caused by an R406W mutation in the microtubule associated protein tau (MAPT) gene

    DEFF Research Database (Denmark)

    Nimsanor, Natakarn; Poulsen, Ulla; Rasmussen, Mikkel A.

    2016-01-01

    pluripotent stem cells (iPSCs) hold great promise to model FTDP-17 as such cells can be differentiated in vitro to the required cell type. Furthermore, gene-editing approaches allow generating isogenic gene-corrected controls that can be used as a very specific control. Here, we report the generation......Frontotemporal dementia with parkinsonism linked to chromosome 17q21.2 (FTDP-17) is an autosomal-dominant neurodegenerative disorder. Mutations in the MAPT (microtubule-associated protein tau) gene can cause FTDP-17, but the underlying pathomechanisms of the disease are still unknown. Induced...... of genetically corrected iPSCs from a 59-year-old female FTD-17 patient carrying an R406W mutation in the MAPT-gene....

  11. Generation of an isogenic, gene-corrected iPSC line from a symptomatic 57-year-old female patient with frontotemporal dementia caused by a P301L mutation in the microtubule associated protein tau (MAPT) gene

    DEFF Research Database (Denmark)

    Nimsanor, Natakarn; Kitiyanant, Narisorn; Poulsen, Ulla

    2016-01-01

    pluripotent stem cells (iPSCs) hold great promise to model FTDP-17 as such cells can be differentiated in vitro to the required cell type. Furthermore, gene-editing approaches allow generating isogenic gene-corrected controls that can be used as a very specific control. Here, we report the generation......Frontotemporal dementia with parkinsonism linked to chromosome 17q21.2 (FTDP-17) is an autosomal-dominant neurodegenerative disorder. Mutations in the MAPT (microtubule-associated protein tau)-gene can cause FTDP-17, but the underlying pathomechanisms of the disease are still unknown. Induced...... of genetically corrected iPSCs from a 57-year-old female FTD-17 patient carrying an P301L mutation in the MAPT-gene....

  12. Two novel mutations in the PPIB gene cause a rare pedigree of osteogenesis imperfecta type IX.

    Science.gov (United States)

    Jiang, Yu; Pan, Jingxin; Guo, Dongwei; Zhang, Wei; Xie, Jie; Fang, Zishui; Guo, Chunmiao; Fang, Qun; Jiang, Weiying; Guo, Yibin

    2017-06-01

    Osteogenesis imperfecta (OI) is a rare genetic skeletal disorder characterized by increased bone fragility and vulnerability to fractures. PPIB is identified as a candidate gene for OI-IX, here we detect two pathogenic mutations in PPIB and analyze the genotype-phenotype correlation in a Chinese family with OI. Next-generation sequencing (NGS) was used to screen the whole exome of the parents of proband. Screening of variation frequency, evolutionary conservation comparisons, pathogenicity evaluation, and protein structure prediction were conducted to assess the pathogenicity of the novel mutations. Sanger sequencing was used to confirm the candidate variants. RTQ-PCR was used to analyze the PPIB gene expression. All mutant genes screened out by NGS were excluded except PPIB. Two novel heterozygous PPIB mutations (father, c.25A>G; mother, c.509G>A) were identified in relation to osteogenesis imperfecta type IX. Both mutations were predicted to be pathogenic by bioinformatics analysis and RTQ-PCR analysis revealed downregulated PPIB expression in the two carriers. We report a rare pedigree with an autosomal recessive osteogenesis imperfecta type IX (OI-IX) caused by two novel PPIB mutations identified for the first time in China. The current study expands our knowledge of PPIB mutations and their associated phenotypes, and provides new information on the genetic defects associated with this disease for clinical diagnosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations.

    Science.gov (United States)

    Nagel-Wolfrum, Kerstin; Möller, Fabian; Penner, Inessa; Wolfrum, Uwe

    2014-09-01

    The eye has become an excellent target for gene therapy, and gene augmentation therapy of inherited retinal disorders has made major progress in recent years. Nevertheless, a recent study indicated that gene augmentation intervention might not stop the progression of retinal degeneration in patients. In addition, for many genes, viral-mediated gene augmentation is currently not feasible due to gene size and limited packaging capacity of viral vectors as well as expression of various heterogeneous isoforms of the target gene. Thus, alternative gene-based strategies to stop or delay the retinal degeneration are necessary. This review focuses on an alternative pharmacologic treatment strategy based on the usage of translational read-through inducing drugs (TRIDs) such as PTC124, aminoglycoside antibiotics, and designer aminoglycosides for overreading in-frame nonsense mutations. This strategy has emerged as an option for up to 30-50% of all cases of recessive hereditary retinal dystrophies. In-frame nonsense mutations are single-nucleotide alterations within the gene coding sequence resulting in a premature stop codon. Consequently, translation of such mutated genes leads to the synthesis of truncated proteins, which are unable to fulfill their physiologic functions. In this context, application of TRIDs facilitates the recoding of the premature termination codon into a sense codon, thus restoring syntheses of full-length proteins. So far, clinical trials for non-ocular diseases have been initiated for diverse TRIDs. Although the clinical outcome is not analyzed in detail, an excellent safety profile, namely for PTC124, was clearly demonstrated. Moreover, recent data demonstrated sustained read-through efficacies of nonsense mutations causing retinal degeneration, as manifested in the human Usher syndrome. In addition, a strong retinal biocompatibility for PTC124 and designer aminoglycosides has been demonstrated. In conclusion, recent progress emphasizes the

  14. Surgical treatment of the concomitant pathology in corrected transposition of great arteries

    Directory of Open Access Journals (Sweden)

    O.Ye. Repin

    2016-03-01

    Full Text Available The aim – to analyze our experience in the treatment of patients with congenitally corrected transposition of great arteries (CCTGA. Materials and methods. Thirty-nine patients with CCTGA (0.7 %, age from 4 months to 48 years, were observed since 1995 to 2014. Insufficiency of the tricuspid valve was diagnosed in 7 patients, ventricular septal defect (VSD – in 12, III degree AV blockade – in 5 patients (in 4 cases – primary AV blockade and in one case – after VSD repair, insufficiency of mitral valve – in 3 cases (in one of them as a result of bacterial endocarditis after implantation of the endocardial electrode, pulmonary stenosis – in 5. Rezults. Totally 24 surgeries were performed: correction of systemic valve insufficiency – in 6 patients (plastics – in 4 of them and prosthesis in 2 patients, VSD plastics – 9, pacemaker implantation – 4, mitral valve plastics – 2, pulmonary artery banding – 2, bidirectional Glenn – 1. Surgeries were performed without lethal outcomes. Patients were observed from 8 months till 14 years. Adequate correction of all associated pathology was achieved in all patients. Concerning the progressing of tricuspid valve insufficiency, replacement of it was done in 3 cases. Medical treatment of the progressive heart failure was prescribed to 48 years-old patient. Conclusion. The submitted material confirms the data regarding high risk of the development of AV blockade, tricuspid valve insufficiency, as well as right ventricular failure during 4–5th decade of life. Early revealing and adequate correction of accompanying defects and developing complications allows to achieve satisfactory immediate and long-term results.

  15. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies

    DEFF Research Database (Denmark)

    2014-01-01

    in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p...... = 8.2 × 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have...... analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1...

  16. Ipsilateral vascularised ulnar transposition autograft for limb-sparing surgery of the distal radius in 2 dogs with osteosarcoma : clinical communication

    Directory of Open Access Journals (Sweden)

    G.S. Irvine-Smith

    2006-06-01

    Full Text Available Canine osteosarcoma is the most commonly diagnosed primary bone tumour in the dog, affecting mainly large and giant breed dogs with the predilection site being the metaphysis of long bones, specifically the distal radius, proximal humerus, distal femur and proximal tibia and fibula. Treatment options are either palliative or curative intent therapy, the latter limb amputation or limb-sparing surgery together with chemotherapy. This article describes the use of an ipsilateral vascularised ulnar transposition autograft as well as chemotherapy in 2 dogs with osteosarcoma of the distal radius. Both dogs showed minimal complications with the technique and both survived over 381 days following the surgery. Complications seen were loosening of the screws and osteomyelitis. The procedure was well tolerated with excellent limb use. This technique is indicated for use in cases with small tumour size that have not broken through the bone cortex.

  17. Mutations in the LHX2 gene are not a frequent cause of micro/anophthalmia.

    Science.gov (United States)

    Desmaison, Annaïck; Vigouroux, Adeline; Rieubland, Claudine; Peres, Christine; Calvas, Patrick; Chassaing, Nicolas

    2010-12-18

    Microphthalmia and anophthalmia are at the severe end of the spectrum of abnormalities in ocular development. A few genes (orthodenticle homeobox 2 [OTX2], retina and anterior neural fold homeobox [RAX], SRY-box 2 [SOX2], CEH10 homeodomain-containing homolog [CHX10], and growth differentiation factor 6 [GDF6]) have been implicated mainly in isolated micro/anophthalmia but causative mutations of these genes explain less than a quarter of these developmental defects. The essential role of the LIM homeobox 2 (LHX2) transcription factor in early eye development has recently been documented. We postulated that mutations in this gene could lead to micro/anophthalmia, and thus performed molecular screening of its sequence in patients having micro/anophthalmia. Seventy patients having non-syndromic forms of colobomatous microphthalmia (n=25), isolated microphthalmia (n=18), or anophthalmia (n=17), and syndromic forms of micro/anophthalmia (n=10) were included in this study after negative molecular screening for OTX2, RAX, SOX2, and CHX10 mutations. Mutation screening of LHX2 was performed by direct sequencing of the coding sequences and intron/exon boundaries. Two heterozygous variants of unknown significance (c.128C>G [p.Pro43Arg]; c.776C>A [p.Pro259Gln]) were identified in LHX2 among the 70 patients. These variations were not identified in a panel of 100 control patients of mixed origins. The variation c.776C>A (p.Pro259Gln) was considered as non pathogenic by in silico analysis, while the variation c.128C>G (p.Pro43Arg) considered as deleterious by in silico analysis and was inherited from the asymptomatic father. Mutations in LHX2 do not represent a frequent cause of micro/anophthalmia.

  18. Parallel approach on sorting of genes in search of optimal solution.

    Science.gov (United States)

    Kumar, Pranav; Sahoo, G

    2018-05-01

    An important tool for comparing genome analysis is the rearrangement event that can transform one given genome into other. For finding minimum sequence of fission and fusion, we have proposed here an algorithm and have shown a transformation example for converting the source genome into the target genome. The proposed algorithm comprises of circular sequence i.e. "cycle graph" in place of mapping. The main concept of algorithm is based on optimal result of permutation. These sorting processes are performed in constant running time by showing permutation in the form of cycle. In biological instances it has been observed that transposition occurs half of the frequency as that of reversal. In this paper we are not dealing with reversal instead commencing with the rearrangement of fission, fusion as well as transposition. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Severe manifestation of Bartter syndrome Type IV caused by a novel insertion mutation in the BSND gene.

    Science.gov (United States)

    de Pablos, Augusto Luque; García-Nieto, Victor; López-Menchero, Jesús C; Ramos-Trujillo, Elena; González-Acosta, Hilaria; Claverie-Martín, Félix

    2014-05-01

    Bartter syndrome Type IV is a rare subtype of the Bartter syndromes that leads to both severe renal salt wasting and sensorineural deafness. This autosomal recessive disease is caused by mutations in the gene encoding barttin, BSND, an essential subunit of the ClC-K chloride channels expressed in renal and inner ear epithelia. Patients differ in the severity of renal symptoms, which appears to depend on the modification of channel function by the mutant barttin. To date, only a few BSND mutations have been reported, most of which are missense or nonsense mutations. In this study, we report the identification of the first insertion mutation, p.W102Vfs*7, in the BSND gene of a newborn girl with acute clinical symptoms including early-onset chronic renal failure. The results support previous data indicating that mutations that are predicted to abolish barttin expression are associated with a severe phenotype and early onset renal failure.

  20. Autosomal recessive posterior column ataxia with retinitis pigmentosa caused by novel mutations in the FLVCR1 gene.

    Science.gov (United States)

    Shaibani, Aziz; Wong, Lee-Jun; Wei Zhang, Victor; Lewis, Richard Alan; Shinawi, Marwan

    2015-01-01

    Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive disorder characterized by severe sensory ataxia, muscle weakness and atrophy, and progressive pigmentary retinopathy. Recently, mutations in the FLVCR1 gene were described in four families with this condition. We investigated the molecular basis and studied the phenotype of PCARP in a new family. The proband is a 33-year-old woman presented with sensory polyneuropathy and retinitis pigmentosa (RP). The constellation of clinical findings with normal metabolic and genetic evaluation, including mitochondrial DNA (mtDNA) analysis and normal levels of phytanic acid and vitamin E, prompted us to seek other causes of our patient's condition. Sequencing of FLVCR1 in the proband and targeted mutation testing in her two affected siblings revealed two novel variants, c.1547G > A (p.R516Q) and c.1593+5_+8delGTAA predicted, respectively, to be highly conserved throughout evolution and affecting the normal splicing, therefore, deleterious. This study supports the pathogenic role of FLVCR1 in PCARP and expands the molecular and clinical spectra of PCARP. We show for the first time that nontransmembrane domain (TMD) mutations in the FLVCR1 can cause PCARP, suggesting different mechanisms for pathogenicity. Our clinical data reveal that impaired sensation can be part of the phenotypic spectrum of PCARP. This study along with previously reported cases suggests that targeted sequencing of the FLVCR1 gene should be considered in patients with severe sensory ataxia, RP, and peripheral sensory neuropathy.

  1. Congenital analbuminemia caused by a novel aberrant splicing in the albumin gene.

    Science.gov (United States)

    Caridi, Gianluca; Dagnino, Monica; Erdeve, Omer; Di Duca, Marco; Yildiz, Duran; Alan, Serdar; Atasay, Begum; Arsan, Saadet; Campagnoli, Monica; Galliano, Monica; Minchiotti, Lorenzo

    2014-01-01

    Congenital analbuminemia is a rare autosomal recessive disorder manifested by the presence of a very low amount of circulating serum albumin. It is an allelic heterogeneous defect, caused by variety of mutations within the albumin gene in homozygous or compound heterozygous state. Herein we report the clinical and molecular characterization of a new case of congenital analbuminemia diagnosed in a female newborn of consanguineous (first degree cousins) parents from Ankara, Turkey, who presented with a low albumin concentration (A transition at position c.1652+1, the first base of intron 12, which inactivates the strongly conserved GT dinucleotide at the 5' splice site consensus sequence of this intron. The splicing defect results in the complete skipping of the preceding exon (exon 12) and in a frame-shift within exon 13 with a premature stop codon after the translation of three mutant amino acid residues. Our results confirm the clinical diagnosis of congenital analbuminemia in the proband and the inheritance of the trait and contribute to shed light on the molecular genetics of analbuminemia.

  2. A case report of novel mutation in PRF1 gene, which causes familial autosomal recessive hemophagocytic lymphohistiocytosis.

    Science.gov (United States)

    Bordbar, Mohammad Reza; Modarresi, Farzaneh; Farazi Fard, Mohammad Ali; Dastsooz, Hassan; Shakib Azad, Nader; Faghihi, Mohammad Ali

    2017-05-03

    Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening immunodeficiency and multi-organ disease that affects people of all ages and ethnic groups. Common symptoms and signs of this disease are high fever, hepatosplenomegaly, and cytopenias. Familial form of HLH disease, which is an autosomal recessive hematological disorder is due to disease-causing mutations in several genes essential for NK and T-cell granule-mediated cytotoxic function. For an effective cytotoxic response from cytotoxic T lymphocyte or NK cell encountering an infected cell or tumor cell, different processes are required, including trafficking, docking, priming, membrane fusion, and entry of cytotoxic granules into the target cell leading to apoptosis. Therefore, genes involved in these steps play important roles in the pathogenesis of HLH disease which include PRF1, UNC13D (MUNC13-4), STX11, and STXBP2 (MUNC18-2). Here, we report a novel missense mutation in an 8-year-old boy suffered from hepatosplenomegaly, hepatitis, epilepsy and pancytopenia. The patient was born to a first-cousin parents with no previous documented disease in his parents. To identify mutated gene in the proband, Whole Exome Sequencing (WES) utilizing next generation sequencing was used on an Illumina HiSeq 2000 platform on DNA sample from the patient. Results showed a novel deleterious homozygous missense mutation in PRF1 gene (NM_001083116: exon3: c. 1120 T > G, p.W374G) in the patient and then using Sanger sequencing it was confirmed in the proband and his parents. Since his parents were heterozygous for the identified mutation, autosomal recessive pattern of inheritance was confirmed in the family. Our study identified a rare new pathogenic missense mutation in PRF1 gene in patient with HLH disease and it is the first report of mutation in PRF1 in Iranian patients with this disease.

  3. Recurring dominant-negative mutations in the AVP-NPII gene cause neurohypophyseal diabetes insipidus

    Energy Technology Data Exchange (ETDEWEB)

    Repaske, D.R. [Children`s Hospital Medical Center, Cincinnati, OH (United States); Phillips, J.A.; Krishnamani, M.R.S. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States)] [and others

    1994-09-01

    Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a familial form of arginine vasopressin (or antidiuretic hormone) deficiency that is usually manifest in early childhood with polyuria, polydipsia and an antidiuretic response to exogenous vasopressin or its analogs. The phenotype is postulated to arise from gliosis and depletion of the magnocellular neurons that produce vasopressin in the supraoptic and paraventricular nuclei of the hypothalamus. ADNDI is caused by heterozygosity for a variety of mutations in the AVP-NPII gene which encodes vasopressin, its carrier protein (NPII) and a glycoprotein (copeptin) of unknown function. These mutations include: (1) Ala 19{r_arrow}Thr (G279A) in AVP`s signal peptide, (2) Gly 17{r_arrow}Val (G1740T), (3) Pro 24{r_arrow}Leu (C1761T), (4) Gly 57{r_arrow}Ser (G1859A) and (5) del Glu 47({delta}AGG 1824-26), all of which occur in NPII. In characterizing the AVP-NPII mutations in five non-related ADNDI kindreds, we have detected two kindreds having mutation 1 (G279A), two having mutation 3 (C1761T) and one having mutation 4 (G1859A) without any other allelic changes being detected. Two of these recurring mutations (G279A and G1859A) are transitions that occur at CpG dinucleotides while the third (C1761T) does not. Interestingly, families with the same mutations differed in their ethnicity or in their affected AVP-NPII allele`s associated haplotype of closely linked DNA polymorphisms. Our data indicated that at least three of five known AVP-NPII mutations causing ADNDI tend to recur but the mechanisms by which these dominant-negative mutations cause variable or progressive expression of the ADNDI phenotype remain unclear.

  4. «On the Origin of Species»: Didactic transposition to the curriculum and Portuguese science textbooks (1859-1959

    Directory of Open Access Journals (Sweden)

    Bento Cavadas

    2017-07-01

    Full Text Available This research aimed to contribute to the history of the teaching of Darwinism in the Portuguese curriculum from 1859 to 1959. To this end, it was analysed the didactic transposition of the book On the Origin of Species for the standards and textbooks of Natural Sciences of secondary education. This study showed that some standards did not address Darwinism (Standards of 1856, 1872, 1880, 1886, 1926 and 1929, while others only prescribed the study of some subjects of Darwinism (Standards of 1889 and 1905. The standards of 1895 were the ones that addressed more Darwinists ideas in the 19th century. In the 20th century, the overall approach to Darwinism was related to the study of transformist ideas (Standards of 1919 or evolution (Standards of 1936 and 1954. However, even when the respective standards did not make that prescription, the major part of textbooks addressed the mechanisms of Darwinian evolution: adaptation, variability, growth correlations, heredity, natural selection, vital competition, geographic isolation and sexual selection.

  5. A Gene Implicated in Activation of Retinoic Acid Receptor Targets Is a Novel Renal Agenesis Gene in Humans

    DEFF Research Database (Denmark)

    Brophy, Patrick D.; Rasmussen, Maria; Parida, Mrutyunjaya

    2017-01-01

    investigations have identified several gene variants that cause RA, including EYA1, LHX1, and WT1 However, whereas compound null mutations of genes encoding α and γ retinoic acid receptors (RARs) cause RA in mice, to date there have been no reports of variants in RAR genes causing RA in humans. In this study, we...... in humans....

  6. LOW MOLECULAR MASS POLYPEPTIDE AND TRANSPORTER ANTIGEN PEPTIDE GENES POLYMORPHISM AS THE RISK FACTORS OF CERVICAL CANCER WHICH CAUSED BY HUMAN PAPILLOMAVIRUS TYPE-16 INFECTION IN BALI

    Directory of Open Access Journals (Sweden)

    I N. B. Mahendra

    2015-12-01

    Full Text Available Background: Until recently, cervical cancer is one of the major problem in women’s health issue related to its high incidence and mortality rate. The etiology of cervical cancer is the high risk oncogenic group of Human Papillomavirus (HPV, especially HPV-16 and 18 and its phylogenies. Meanwhile in Bali, more than 50% of infection are caused by HPV-16 infection. The main objective of this study was to investigate the role of LMP-2, LMP-7, TAP-1 and TAP-2 gene polymorphism as the risk factor in the cervical cancer carcinogenesis that is caused by HPV-16 infection. Method: A nested non-paired case-control study was conducted at Obstetric and Gynecologic Department Sanglah General Hospital, Bali-Indonesia from March 1 until August 31, 2013. Laboratory testing was carried out at Laboratory of Histopathology Leiden University Medical Centre, Netherlands,. Results: A total of 40 samples were collected, consist of 20epithelial cervical cancer patients with positive HPV-16 infection as the case group and 20 non-cervical cancer patients with positive HPV-16 infection as the control group. Women infected by HPV-16 with LMP-7 gene polymorphism had a higher risk (OR=7.36, CI 95%=1.38-40.55, p=0.013 to be diagnosed with cervical cancer. Balinese women who were infected by HPV-16 with TAP-2 gene polymorphism had a higher risk (OR= 9.33, CI 95%=2.18-39.96, p=0.001 to be diagnosed with cervical cancer. Meanwhile, Balinese women who were infected by HPV-16 with LMP-7 and TAP-2 genes polymorphism had a higher risk (OR=12.67, CI 95%=1.40-114.42, p=0.020 to be diagnosed with cervical cancer. As the result, it was shown that both of this gene polymorphism was working synergistically. Conclusion: TAP-2 and LMP-7 genes polymorphism play a role in the carcinogenesis mechanism of cervical cancer that is caused by HPV-16 infection in Bali. Meanwhile, LMP-2 and TAP-1 genes polymorphism were not found to play a role in the immunology pathway of cervical cancer that is

  7. Novel Hypomorphic Alleles of the Mouse Tyrosinase Gene Induced by CRISPR-Cas9 Nucleases Cause Non-Albino Pigmentation Phenotypes.

    Science.gov (United States)

    Challa, Anil K; Boitet, Evan R; Turner, Ashley N; Johnson, Larry W; Kennedy, Daniel; Downs, Ethan R; Hymel, Katherine M; Gross, Alecia K; Kesterson, Robert A

    2016-01-01

    Tyrosinase is a key enzyme in melanin biosynthesis. Mutations in the gene encoding tyrosinase (Tyr) cause oculocutaneous albinism (OCA1) in humans. Alleles of the Tyr gene have been useful in studying pigment biology and coat color formation. Over 100 different Tyr alleles have been reported in mice, of which ≈24% are spontaneous mutations, ≈60% are radiation-induced, and the remaining alleles were obtained by chemical mutagenesis and gene targeting. Therefore, most mutations were random and could not be predicted a priori. Using the CRISPR-Cas9 system, we targeted two distinct regions of exon 1 to induce pigmentation changes and used an in vivo visual phenotype along with heteroduplex mobility assays (HMA) as readouts of CRISPR-Cas9 activity. Most of the mutant alleles result in complete loss of tyrosinase activity leading to an albino phenotype. In this study, we describe two novel in-frame deletion alleles of Tyr, dhoosara (Sanskrit for gray) and chandana (Sanskrit for sandalwood). These alleles are hypomorphic and show lighter pigmentation phenotypes of the body and eyes. This study demonstrates the utility of CRISPR-Cas9 system in generating domain-specific in-frame deletions and helps gain further insights into structure-function of Tyr gene.

  8. Novel Hypomorphic Alleles of the Mouse Tyrosinase Gene Induced by CRISPR-Cas9 Nucleases Cause Non-Albino Pigmentation Phenotypes.

    Directory of Open Access Journals (Sweden)

    Anil K Challa

    Full Text Available Tyrosinase is a key enzyme in melanin biosynthesis. Mutations in the gene encoding tyrosinase (Tyr cause oculocutaneous albinism (OCA1 in humans. Alleles of the Tyr gene have been useful in studying pigment biology and coat color formation. Over 100 different Tyr alleles have been reported in mice, of which ≈24% are spontaneous mutations, ≈60% are radiation-induced, and the remaining alleles were obtained by chemical mutagenesis and gene targeting. Therefore, most mutations were random and could not be predicted a priori. Using the CRISPR-Cas9 system, we targeted two distinct regions of exon 1 to induce pigmentation changes and used an in vivo visual phenotype along with heteroduplex mobility assays (HMA as readouts of CRISPR-Cas9 activity. Most of the mutant alleles result in complete loss of tyrosinase activity leading to an albino phenotype. In this study, we describe two novel in-frame deletion alleles of Tyr, dhoosara (Sanskrit for gray and chandana (Sanskrit for sandalwood. These alleles are hypomorphic and show lighter pigmentation phenotypes of the body and eyes. This study demonstrates the utility of CRISPR-Cas9 system in generating domain-specific in-frame deletions and helps gain further insights into structure-function of Tyr gene.

  9. Mutations in the evolutionarily highly conserved KEOPS complex genes cause nephrotic syndrome with microcephaly

    Science.gov (United States)

    Braun, Daniela A.; Rao, Jia; Mollet, Geraldine; Schapiro, David; Daugeron, Marie-Claire; Tan, Weizhen; Gribouval, Olivier; Boyer, Olivia; Revy, Patrick; Jobst-Schwan, Tilman; Schmidt, Johanna Magdalena; Lawson, Jennifer A.; Schanze, Denny; Ashraf, Shazia; Boddaert, Nathalie; Collinet, Bruno; Martin, Gaëlle; Liger, Dominique; Lovric, Svjetlana; Furlano, Monica; Guerrera, I. Chiara; Sanchez-Ferras, Oraly; Menten, Björn; Vergult, Sarah; De Rocker, Nina; Airik, Merlin; Hermle, Tobias; Shril, Shirlee; Widmeier, Eugen; Gee, Heon Yung; Choi, Won-Il; Sadowski, Carolin E.; Pabst, Werner L.; Warejko, Jillian; Daga, Ankana; LeBerre, Tamara Basta; Matejas, Verena; Behnam, Babak; Beeson, Brendan; Begtrup, Amber; Bruce, Malcolm; Ch'ng, Gaik-Siew; Lin, Shuan-Pei; Chang, Jui-Hsing; Chen, Chao-Huei; Cho, Megan T.; Gipson, Patrick E.; Hsu, Chyong-Hsin; Kari, Jameela A.; Ke, Yu-Yuan; Kiraly-Borri, Cathy; Lai, Wai-ming; Lemyre, Emmanuelle; Littlejohn, Rebecca Okasha; Masri, Amira; Moghtaderi, Mastaneh; Nakamura, Kazuyuki; Praet, Marleen; Prasad, Chitra; Prytula, Agnieszka; Roeder, Elizabeth; Rump, Patrick; Schnur, Rhonda E.; Shiihara, Takashi; Sinha, Manish; Soliman, Neveen A; Soulami, Kenza; Sweetser, David A.; Tsai, Wen-Hui; Tsai, Jeng-Daw; Vester, Udo; Viskochil, David H.; Vatanavicharn, Nithiwat; Waxler, Jessica L.; Wolf, Matthias T.F.; Wong, Sik-Nin; Poduri, Annapurna; Truglio, Gessica; Mane, Shrikant; Lifton, Richard P.; Bouchard, Maxime; Kannu, Peter; Chitayat, David; Magen, Daniella; Calleweart, Bert; van Tilbeurgh, Herman; Zenker, Martin; Antignac, Corinne; Hildebrandt, Friedhelm

    2018-01-01

    Galloway-Mowat syndrome (GAMOS) is a severe autosomal-recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies. To date, mutations of WDR73 are the only known monogenic cause of GAMOS and in most affected individuals the molecular diagnosis remains elusive. We here identify recessive mutations of OSGEP, TP53RK, TPRKB, or LAGE3, encoding the 4 subunits of the KEOPS complex in 33 individuals of 30 families with GAMOS. CRISPR/Cas9 knockout in zebrafish and mice recapitulates the human phenotype of microcephaly and results in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibits cell proliferation, which human mutations fail to rescue, and knockdown of either gene activates DNA damage response signaling and induces apoptosis. OSGEP and TP53RK molecularly interact and co-localize with the actin-regulating ARP2/3 complex. Furthermore, knockdown of OSGEP and TP53RK induces defects of the actin cytoskeleton and reduces migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identify 4 novel monogenic causes of GAMOS, describe the first link between KEOPS function and human disease, and delineate potential pathogenic mechanisms. PMID:28805828

  10. Another explanation for the cause of heterosis phenomenon

    Indian Academy of Sciences (India)

    of depression and the increase in individual genetic diversity is the cause of heterosis. ... Keywords. nonsense gene; vital gene; gene products; individual genetic diversity; number ..... These values of a variety created by hybrid method as well.

  11. Orthodontic treatment of a complete transposed impacted maxillary canine

    Directory of Open Access Journals (Sweden)

    Pi-Huei Liu

    2015-03-01

    Full Text Available Tooth transposition is a positional interchange of two adjacent teeth. Transposition most often occurs at maxillary canine. Moving transposed teeth to their normal positions is challenging because this requires bodily movement and translation of one tooth to pass another. This procedure may cause damage to the teeth or supporting structures. We report a case of complete transposition of maxillary canine and lateral incisor. Transposed teeth were successfully moved orthodontically to their normal positions. Multiple mechanics were meticulously applied to achieve complete correction of the tooth positions and to minimize root resorption and/or periodontal defects of canine and lateral incisors. Factors concerning treatment planning for transposed teeth are discussed.

  12. Anestesia en la transposición de los grandes vasos ANESTHESIA IN THE TRANSPOSITION OF THE GREAT VESSELS

    Directory of Open Access Journals (Sweden)

    Lincoln de la Parte Pérez

    2005-03-01

    Full Text Available La transposición de los grandes vasos es una cardiopatía compleja que se acompaña de una elevada mortalidad. Se conoce que el 45 % de los pacientes fallece durante el primer mes de vida y alrededor del 90 % antes del año. Las principales causas de la muerte son la hipoxia y la insuficiencia cardíaca. El desarrollo de las especialidades que trabajan en cirugía cardiovascular pediátrica ha permitido aumentar la supervivencia de estos niños, especialmente con el uso de prostaglandinas para mantener el ductus permeable, la técnica de Raskind-Miller ( septostomía de balón y una tendencia cada vez mayor a la corrección anatómica temprana (operación de Jatene en lugar de los clásicos procedimientos paliativos y las técnicas de corrección fisiológica de Senning y Mustard . Se presenta una revisión bibliográfica sobre los factores a tener en cuenta en el manejo anestésico de estos pacientes.The transposition of the great vessels is a complex heart disease accompanied of a high mortality. It is known that 45 % of the patients die during the first month of life and at about 90 % do it before being one year old. The main causes of death are hypoxia and heart failure. The development of the specialties working in pediatric cardiovascular surgery has allowed to increase the survival of these children, specially with the use of prostaglandins to maintain the ductus permeable, the Raskind-Miller's technique (balloon septostomy, and an increasing trend towards an early anatomical correction (Jatene's operation to replace the classical palliative procedures and Senning and Mustartd's techniques of physiological correction. A bibliographic review of the factors to be taken into account in the anesthetic management of these patients is presented.

  13. Lyme disease caused by Borrelia burgdorferi with two homeologous 16S rRNA genes: a case report

    Directory of Open Access Journals (Sweden)

    Lee SH

    2016-04-01

    Full Text Available Sin Hang Lee,1,21Pathology Department, Milford Hospital, Milford, CT, USA; 2Milford Molecular Diagnostics, Milford, CT, USA Abstract: Lyme disease (LD, the most common tick-borne disease in North America, is believed to be caused exclusively by Borrelia burgdorferi sensu stricto and is usually diagnosed by clinical evaluation and serologic assays. As reported previously in a peer-reviewed article, a 13-year-old boy living in the Northeast of the USA was initially diagnosed with LD based on evaluation of his clinical presentations and on serologic test results. The patient was treated with a course of oral doxycycline for 28 days, and the symptoms resolved. A year later, the boy developed a series of unusual symptoms and did not attend school for 1 year. A LD specialist reviewed the case and found the serologic test band patterns nondiagnostic of LD. The boy was admitted to a psychiatric hospital. After discharge from the psychiatric hospital, a polymerase chain reaction test performed in a winter month when the boy was 16 years old showed a low density of B. burgdorferi sensu lato in the blood of the patient, confirmed by partial 16S rRNA (ribosomal RNA gene sequencing. Subsequent DNA sequencing analysis presented in this report demonstrated that the spirochete isolate was a novel strain of B. burgdorferi with two homeologous 16S rRNA genes, which has never been reported in the world literature. This case report shows that direct DNA sequencing is a valuable tool for reliable molecular diagnosis of Lyme and related borrelioses, as well as for studies of the diversity of the causative agents of LD because LD patients infected by a rare or novel borrelial variant may produce an antibody pattern that can be different from the pattern characteristic of an infection caused by a typical B. burgdorferi sensu stricto strain. Keywords: Lyme disease, Borrelia burgdorferi, homeologous 16S rRNA genes, DNA sequencing

  14. Polymorphisms in metabolism and repair genes affects DNA damage caused by open-cast coal mining exposure.

    Science.gov (United States)

    Espitia-Pérez, Lyda; Sosa, Milton Quintana; Salcedo-Arteaga, Shirley; León-Mejía, Grethel; Hoyos-Giraldo, Luz Stella; Brango, Hugo; Kvitko, Katia; da Silva, Juliana; Henriques, João A P

    2016-09-15

    Increasing evidence suggest that occupational exposure to open-cast coal mining residues like dust particles, heavy metals and Polycyclic Aromatic Hydrocarbons (PAHs) may cause a wide range of DNA damage and genomic instability that could be associated to initial steps in cancer development and other work-related diseases. The aim of our study was to evaluate if key polymorphisms in metabolism genes CYP1A1Msp1, GSTM1Null, GSTT1Null and DNA repair genes XRCC1Arg194Trp and hOGG1Ser326Cys could modify individual susceptibility to adverse coal exposure effects, considering the DNA damage (Comet assay) and micronucleus formation in lymphocytes (CBMN) and buccal mucosa cells (BMNCyt) as endpoints for genotoxicity. The study population is comprised of 200 healthy male subjects, 100 open-cast coal-mining workers from "El Cerrejón" (world's largest open-cast coal mine located in Guajira - Colombia) and 100 non-exposed referents from general population. The data revealed a significant increase of CBMN frequency in peripheral lymphocytes of occupationally exposed workers carrying the wild-type variant of GSTT1 (+) gene. Exposed subjects carrying GSTT1null polymorphism showed a lower micronucleus frequency compared with their positive counterparts (FR: 0.83; P=0.04), while BMNCyt, frequency and Comet assay parameters in lymphocytes: Damage Index (DI) and percentage of DNA in the tail (Tail % DNA) were significantly higher in exposed workers with the GSTM1Null polymorphism. Other exfoliated buccal mucosa abnormalities related to cell death (Karyorrhexis and Karyolysis) were increased in GSTT/M1Null carriers. Nuclear buds were significantly higher in workers carrying the CYP1A1Msp1 (m1/m2, m2/m2) allele. Moreover, BMNCyt frequency and Comet assay parameters were significantly lower in exposed carriers of XRCC1Arg194Trp (Arg/Trp, Trp/Trp) and hOGG1Ser326Cys (Ser/Cys, Cys/Cys), thereby providing new data to the increasing evidence about the protective role of these polymorphisms

  15. Chronic granulomatous disease caused by mutations other than the common GT deletion in NCF1, the gene encoding the p47phox component of the phagocyte NADPH oxidase

    NARCIS (Netherlands)

    Roos, Dirk; de Boer, Martin; Köker, M. Yavuz; Dekker, Jan; Singh-Gupta, Vinita; Ahlin, Anders; Palmblad, Jan; Sanal, Ozden; Kurenko-Deptuch, Magdalena; Jolles, Stephen; Wolach, Baruch

    2006-01-01

    Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by defects in any of four genes encoding components of the leukocyte nicotinamide dinucleotide phosphate, reduced (NADPH) oxidase. One of these is the autosomal neutrophil cytosolic factor 1 (NCF1) gene encoding the p47phox

  16. The biology and potential for genetic research of transposable elements in filamentous fungi

    Directory of Open Access Journals (Sweden)

    Léia Cecilia de Lima Fávaro

    2005-12-01

    Full Text Available Recently many transposable elements have been identified and characterized in filamentous fungi, especially in species of agricultural, biotechnological and medical interest. Similar to the elements found in other eukaryotes, fungal transposons can be classified as class I elements (retrotransposons that use RNA and reverse transcriptase and class II elements (DNA transposons that use DNA. The changes (transposition and recombination caused by transposons can supply wide-ranging genetic variation, especially for species that do not have a sexual phase. The application of transposable elements to gene isolation and population analysis is an important tool for molecular biology and studies of fungal evolution.

  17. Graded versus ungraded inferior oblique anterior transposition in patients with asymmetric dissociated vertical deviation.

    Science.gov (United States)

    Rajavi, Zhale; Feizi, Mohadeseh; Naderi, Ali; Sabbaghi, Hamideh; Behradfar, Narges; Yaseri, Mehdi; Faghihi, Mohammad

    2017-12-01

    To report the surgical outcomes of graded versus ungraded inferior oblique anterior transposition (IOAT) in treatment of patients with asymmetric dissociated vertical deviation (DVD) and bilateral inferior oblique overaction (IOOA). A total of 74 eyes of 37 patients with asymmetric DVD (interocular difference of ≥5 Δ ) and bilateral IOOA of > +1 were included in this randomized clinical trial. In the ungraded group (n = 18), both inferior oblique muscles were sutured at the inferior rectus level; in the graded group (n = 19), the inferior oblique muscles of eyes with more DVD were sutured at the level of the inferior rectus and inferior oblique muscles of eyes with less DVD were sutured 2 mm posterior to the level of the inferior rectus muscle. DVD was significantly reduced in each group (P < 0.001 for both). Although the postoperative mean difference of asymmetry of DVD was less in the ungraded group compared to the graded group (1.2 ± 1.9 vs 3.2 ± 1.2 [P = 0.001]), the absolute amounts of reduction of DVD asymmetry were similar (4.3 ± 2.3 vs 4.4 ± 3.1 [P = 0.78]). IOOA and V patterns were also reduced postoperatively. Each method of IOAT was effective in reducing DVD, asymmetry, IOOA, and V patterns. Copyright © 2017 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

  18. Gene therapy: An overview

    Directory of Open Access Journals (Sweden)

    Sudip Indu

    2013-01-01

    Full Text Available Gene therapy "the use of genes as medicine" involves the transfer of a therapeutic or working copy of a gene into specific cells of an individual in order to repair a faulty gene copy. The technique may be used to replace a faulty gene, or to introduce a new gene whose function is to cure or to favorably modify the clinical course of a condition. The objective of gene therapy is to introduce new genetic material into target cells while causing no damage to the surrounding healthy cells and tissues, hence the treatment related morbidity is decreased. The delivery system includes a vector that delivers a therapeutic gene into the patient′s target cell. Functional proteins are created from the therapeutic gene causing the cell to return to a normal stage. The vectors used in gene therapy can be viral and non-viral. Gene therapy, an emerging field of biomedicine, is still at infancy and much research remains to be done before this approach to the treatment of condition will realize its full potential.

  19. Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene.

    Science.gov (United States)

    Gonçalves, Ana; Oliveira, Jorge; Coelho, Teresa; Taipa, Ricardo; Melo-Pires, Manuel; Sousa, Mário; Santos, Rosário

    2017-10-03

    A broad mutational spectrum in the dystrophin ( DMD ) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD , adding to the diversity of mutational events that give rise to D/BMD.

  20. Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene

    Science.gov (United States)

    Gonçalves, Ana; Coelho, Teresa; Melo-Pires, Manuel; Sousa, Mário

    2017-01-01

    A broad mutational spectrum in the dystrophin (DMD) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD, adding to the diversity of mutational events that give rise to D/BMD. PMID:28972564

  1. Intra-articular Entrapment of Medial Epicondyle Fracture Fragment in Elbow Joint Dislocation Causing Ulnar Neuropraxia: A Case Report

    Directory of Open Access Journals (Sweden)

    Syed J

    2017-03-01

    Full Text Available Traumatic elbow dislocations in children are rare but most of them are complex dislocations, and in such dislocations, medial humerus epicondyle fractureis the most common associated injury. Fracture incarceration in the elbow joint occurs in 5-18% of medial humerus epicondyle fractures but ulnar neuropraxia is very rare. Open reduction internal fixation is indicated in medial humerus epicondyle fracture with fracture incarceration, ulnar neuropraxia, marked instability or open fracture. Operative treatment options include fragment excision and sutures, closed or open reduction and Kirschner wire fixation, open reduction and suture fixation, open reduction and smooth pin fixation, and open reduction and screw fixation. However, ulnar nerve transposition is debatable as good outcome had been reported with and without nerve transposition. We report a case of a 13-year old boy, who presented with right elbow dislocation and intra-articular entrapment of medial humerus epicondyle fracture fragment, complicated with sensory ulnar neuropraxia, following a fall onto his right outstretched hand in a motor vehicle accident. The elbow joint was reduced using close manipulative reduction but the fracture fragment remained entrapped post-reduction. The patient then underwent open reduction and screw fixation of the medial humerus epicondyle fracture without ulnar nerve transposition. He had good functional outcome six weeks after surgical intervention, with complete recovery of ulnar neuropraxia six months later. Currently, he is doing well at school and is active with his sporting activity.

  2. Conferring of contracts by utilities in the Single European Market. Transposition of the sectoral directive where it concerns construction and delivery orders into German law

    International Nuclear Information System (INIS)

    Pick, H.; Wetzel, U.

    1994-01-01

    After the enactment of the Second Law Amending the Law on Budgetary Principles, the Ordinance on the Confering of Contracts, and the Ordinance on Verification; and the amendment of the ordinances on the placing of construction and delivery orders (VOB and VOL) the European Directives on so-called ''public'' tendering can be said to be transposed into German law as far as they concern construction and delivery orders. This means that as of 1 March 1994 besides the ''classical'' public contractors utilities, too, must invite bids Europe-wide. According to European law this also applies to service orders as of 1 July 1994, but this provision still awaits transposition into German law. (orig.) [de

  3. Natural selection in a population of Drosophila melanogaster explained by changes in gene expression caused by sequence variation in core promoter regions.

    Science.gov (United States)

    Sato, Mitsuhiko P; Makino, Takashi; Kawata, Masakado

    2016-02-09

    Understanding the evolutionary forces that influence variation in gene regulatory regions in natural populations is an important challenge for evolutionary biology because natural selection for such variations could promote adaptive phenotypic evolution. Recently, whole-genome sequence analyses have identified regulatory regions subject to natural selection. However, these studies could not identify the relationship between sequence variation in the detected regions and change in gene expression levels. We analyzed sequence variations in core promoter regions, which are critical regions for gene regulation in higher eukaryotes, in a natural population of Drosophila melanogaster, and identified core promoter sequence variations associated with differences in gene expression levels subjected to natural selection. Among the core promoter regions whose sequence variation could change transcription factor binding sites and explain differences in expression levels, three core promoter regions were detected as candidates associated with purifying selection or selective sweep and seven as candidates associated with balancing selection, excluding the possibility of linkage between these regions and core promoter regions. CHKov1, which confers resistance to the sigma virus and related insecticides, was identified as core promoter regions that has been subject to selective sweep, although it could not be denied that selection for variation in core promoter regions was due to linked single nucleotide polymorphisms in the regulatory region outside core promoter regions. Nucleotide changes in core promoter regions of CHKov1 caused the loss of two basal transcription factor binding sites and acquisition of one transcription factor binding site, resulting in decreased gene expression levels. Of nine core promoter regions regions associated with balancing selection, brat, and CG9044 are associated with neuromuscular junction development, and Nmda1 are associated with learning

  4. Cerebral oximetry monitoring in the management of severe hypoxaemia associated with transposition of the great arteries with balloon atrial septostomy.

    Science.gov (United States)

    Pérez Moreno, J C; Nájera Losada, D C; Sanabria Carretero, P; Paredes Lacave, Á; Benito Bartolomé, F

    2018-05-01

    Transposition of the great arteries (D-TGA) is one of the most common congenital heart diseases requiring neonatal surgical intervention. In the desperately ill neonate with TGA and the resultant hypoxaemia, acidemia, and congestive heart failure, improvement is often obtained with balloon atrial septostomy (BAS). Current methods employed to evaluate oxygen delivery and tissue consumption are frequently nonspecific. Near infrared spectroscopy (NIRS) allows a continuous non-invasive measurement of tissue oxygenation which reflects perfusion status in real time. Because little is known about the direct effect of BAS on the neonatal brain and on cerebral oxygenation, we measured the effectiveness of BAS in two patients with D-TGA using NIRS before and after BAS. We concluded BAS improves cerebral oxygen saturation in neonates with D-TGA. Copyright © 2017 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. A lack of immune system genes causes loss in high frequency hearing but does not disrupt cochlear synapse maturation in mice.

    Science.gov (United States)

    Calton, Melissa A; Lee, Dasom; Sundaresan, Srividya; Mendus, Diana; Leu, Rose; Wangsawihardja, Felix; Johnson, Kenneth R; Mustapha, Mirna

    2014-01-01

    Early cochlear development is marked by an exuberant outgrowth of neurites that innervate multiple targets. The establishment of mature cochlear neural circuits is, however, dependent on the pruning of inappropriate axons and synaptic connections. Such refinement also occurs in the central nervous system (CNS), and recently, genes ordinarily associated with immune and inflammatory processes have been shown to play roles in synaptic pruning in the brain. These molecules include the major histocompatibility complex class I (MHCI) genes, H2-K(b) and H2-D(b), and the complement cascade gene, C1qa. Since the mechanisms involved in synaptic refinement in the cochlea are not well understood, we investigated whether these immune system genes may be involved in this process and whether they are required for normal hearing function. Here we report that these genes are not necessary for normal synapse formation and refinement in the mouse cochlea. We further demonstrate that C1qa expression is not necessary for normal hearing in mice but the lack of expression of H2-K(b) and H2-D(b) causes hearing impairment. These data underscore the importance of the highly polymorphic family of MHCI genes in hearing in mice and also suggest that factors and mechanisms regulating synaptic refinement in the cochlea may be distinct from those in the CNS.

  6. Upregulation of proinflammatory genes in skin lesions may be the cause of keloid formation (Review)

    Science.gov (United States)

    DONG, XIANGLIN; MAO, SHAOLIN; WEN, HAO

    2013-01-01

    It was previously demonstrated that the main cause behind keloid formation may be keloid fibroblast abnormalities, which are closely associated with the microenvironment of the keloid lesion. The post-traumatic and chronic inflammation of the keloid lesion area suggest that inflammatory mediators play an important role in the keloid microenvironment and are crucial for keloid fibroblast abnormalities. In this study, we hypothesized that the mechanism underlying keloid formation may involve the continuous upregulation of proinflammatory gene expression in keloid lesions. This hypothesis may explain the inflammatory response, invasive growth and recurrence following resection of keloids, as well as the selective localization of keloids in specific parts of a patient’s body and the differences in localization among different patients. PMID:24649037

  7. Transposition of the SQUG methodology to the Belgian NPP(nuclear power station)

    International Nuclear Information System (INIS)

    Detroux, P.; Aelbrecht, D.; Naisse, J.C.; Greer, J.L.

    1991-01-01

    The units of a Belgian Nuclear PowerStation had to be seismically reassessed after ten years of operation because the seismic requirements were upgraded from 0.1g to 0.17g free field ground acceleration. Seismic requalification of the active equipment was a critical problem as the current classical methods were too conservative and their application would have lead to unacceptable replacement or reinforcement of a lot of equipment. The approach based on the use of past experience of seismic behavior of non nuclear equipment was chosen; this methodology was developed by the Seismic Qualification Utility Group (SQUG); a group of U.S. utilities and had to be transposed to the Belgian N.P.P. This transposition is described in this paper. It affects different aspects of the methodology. First, the impact of specific requests of the Safety Authorities on the elaboration of the Safe Shutdown Equipment List (SSEL) shall be examined. Then it is explained why the tedious work of specific relay screening was avoided by taking advantage of initial design features for both Instrumentation and Control (I and C) and Electrical power distribution system; the impact on the Electrical SSEL is also described. Afterwards, it is presented how it was possible to conduct a specific existing seismic qualification at 0.1 g free field ground acceleration. Finally, the resolution of specific important problems that arose from the application of the SQUG methodology, is presented such as the definition of the grade level and the conservatism of the classical Amplified Floor Spectra (criterion 1), the calculation of the nozzle loads on mechanical equipment connected to long unbraced piping and the transfer of these loads to the anchorage. (author)

  8. A case report: a heterozygous deletion (2791_2805 del) in exon 18 of the filamin C gene causing filamin C-related myofibrillar myopathies in a Chinese family.

    Science.gov (United States)

    Miao, Jing; Su, Fei-Fei; Liu, Xue-Mei; Wei, Xiao-Jing; Yuan, Yun; Yu, Xue-Fan

    2018-06-04

    Filamin C-related myofibrillar myopathies (MFM) are progressive skeletal myopathies with an autosomal dominant inheritance pattern. The conditions are caused by mutations of the filamin C gene (FLNC) located in the chromosome 7q32-q35 region. Genetic variations in the FLNC gene result in various clinical phenotypes. We describe a 43-year-old woman who suffered filamin C-related MFM, with symptoms first presenting in the proximal muscles of the lower limbs and eventually spreading to the upper limbs and distal muscles. The patient's serum level of creatine kinase was mildly increased. Mildy myopathic changes in the electromyographic exam and moderate lipomatous alterations in lower limb MRI were found. Histopathological examination revealed increased muscle fiber size variability, disturbances in oxidative enzyme activity, and the presence of abnormal protein aggregates and vacuoles in some muscle fibers. Ultrastructural analysis showed inclusions composed of thin filaments and interspersed granular densities. DNA sequencing analysis detected a novel 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the FLNC gene. The patient's father, sister, brother, three paternal aunts, one paternal uncle, and the uncle's son also had slowly progressive muscle weakness, and thus, we detected an autosomal dominant inheritance pattern of the disorder. A novel heterogeneous 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the Ig-like domain 7 of the FLNC gene was found to cause filamin C-related MFM. This deletion in the FLNC gene causes protein aggregation, abnormalities in muscle structure, and impairment in muscle fiber function, which leads to muscle weakness.

  9. Mobile genetic elements in protozoan parasites

    Indian Academy of Sciences (India)

    Unknown

    thought to aid the transposition of their nonautonomous counterparts .... experiments with gene fusion constructs) and vary in number in ... T. brucei. Since RIME insertion is thought to activate ..... actions to form an aggregate or core particle.

  10. Application of biclustering of gene expression data and gene set enrichment analysis methods to identify potentially disease causing nanomaterials

    Directory of Open Access Journals (Sweden)

    Andrew Williams

    2015-12-01

    Full Text Available Background: The presence of diverse types of nanomaterials (NMs in commerce is growing at an exponential pace. As a result, human exposure to these materials in the environment is inevitable, necessitating the need for rapid and reliable toxicity testing methods to accurately assess the potential hazards associated with NMs. In this study, we applied biclustering and gene set enrichment analysis methods to derive essential features of altered lung transcriptome following exposure to NMs that are associated with lung-specific diseases. Several datasets from public microarray repositories describing pulmonary diseases in mouse models following exposure to a variety of substances were examined and functionally related biclusters of genes showing similar expression profiles were identified. The identified biclusters were then used to conduct a gene set enrichment analysis on pulmonary gene expression profiles derived from mice exposed to nano-titanium dioxide (nano-TiO2, carbon black (CB or carbon nanotubes (CNTs to determine the disease significance of these data-driven gene sets.Results: Biclusters representing inflammation (chemokine activity, DNA binding, cell cycle, apoptosis, reactive oxygen species (ROS and fibrosis processes were identified. All of the NM studies were significant with respect to the bicluster related to chemokine activity (DAVID; FDR p-value = 0.032. The bicluster related to pulmonary fibrosis was enriched in studies where toxicity induced by CNT and CB studies was investigated, suggesting the potential for these materials to induce lung fibrosis. The pro-fibrogenic potential of CNTs is well established. Although CB has not been shown to induce fibrosis, it induces stronger inflammatory, oxidative stress and DNA damage responses than nano-TiO2 particles.Conclusion: The results of the analysis correctly identified all NMs to be inflammogenic and only CB and CNTs as potentially fibrogenic. In addition to identifying several

  11. A Mild Version of Danon Disease Caused by a Newly Recognized Mutation in the Lysosome-associated Membrane Protein-2 Gene.

    Science.gov (United States)

    Kyaw, Htoo; Shaik, Fatima; Lin, Aung Naing; Shinnar, Meir

    2018-02-04

    We present the case of a patient with dilated cardiomyopathy caused by a novel mutation in the lysosome-associated membrane protein-2 (LAMP-2) gene. Patients with pathogenic mutations of this gene typically suffer from Danon disease - a condition that leads to cognitive decline, severe skeletal myopathy, and severe hypertrophic cardiomyopathy. Our patient's presentation and clinical course, however, is different and much less severe than other patients with this disease. He did not suffer from neurologic and musculoskeletal complications. He is also possibly the longest-known survivor of this disease without a heart transplant. This disease is unfamiliar to many physicians, and our case highlights the importance of an awareness of this disorder, particularly because of its implications for both the patient and his family.

  12. A functional alternative splicing mutation in AIRE gene causes autoimmune polyendocrine syndrome type 1.

    Directory of Open Access Journals (Sweden)

    Junyu Zhang

    Full Text Available Autoimmune polyendocrine syndrome type 1 (APS-1 is a rare autosomal recessive disease defined by the presence of two of the three conditions: mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Loss-of-function mutations of the autoimmune regulator (AIRE gene have been linked to APS-1. Here we report mutational analysis and functional characterization of an AIRE mutation in a consanguineous Chinese family with APS-1. All exons of the AIRE gene and adjacent exon-intron sequences were amplified by PCR and subsequently sequenced. We identified a homozygous missense AIRE mutation c.463G>A (p.Gly155Ser in two siblings with different clinical features of APS-1. In silico splice-site prediction and minigene analysis were carried out to study the potential pathological consequence. Minigene splicing analysis and subsequent cDNA sequencing revealed that the AIRE mutation potentially compromised the recognition of the splice donor of intron 3, causing alternative pre-mRNA splicing by intron 3 retention. Furthermore, the aberrant AIRE transcript was identified in a heterozygous carrier of the c.463G>A mutation. The aberrant intron 3-retaining transcript generated a truncated protein (p.G155fsX203 containing the first 154 AIRE amino acids and followed by 48 aberrant amino acids. Therefore, our study represents the first functional characterization of the alternatively spliced AIRE mutation that may explain the pathogenetic role in APS-1.

  13. Dancing together and separate again: gymnosperms exhibit frequent changes of fundamental 5S and 35S rRNA gene (rDNA) organisation.

    Science.gov (United States)

    Garcia, S; Kovařík, A

    2013-07-01

    In higher eukaryotes, the 5S rRNA genes occur in tandem units and are arranged either separately (S-type arrangement) or linked to other repeated genes, in most cases to rDNA locus encoding 18S-5.8S-26S genes (L-type arrangement). Here we used Southern blot hybridisation, PCR and sequencing approaches to analyse genomic organisation of rRNA genes in all large gymnosperm groups, including Coniferales, Ginkgoales, Gnetales and Cycadales. The data are provided for 27 species (21 genera). The 5S units linked to the 35S rDNA units occur in some but not all Gnetales, Coniferales and in Ginkgo (∼30% of the species analysed), while the remaining exhibit separate organisation. The linked 5S rRNA genes may occur as single-copy insertions or as short tandems embedded in the 26S-18S rDNA intergenic spacer (IGS). The 5S transcript may be encoded by the same (Ginkgo, Ephedra) or opposite (Podocarpus) DNA strand as the 18S-5.8S-26S genes. In addition, pseudogenised 5S copies were also found in some IGS types. Both L- and S-type units have been largely homogenised across the genomes. Phylogenetic relationships based on the comparison of 5S coding sequences suggest that the 5S genes independently inserted IGS at least three times in the course of gymnosperm evolution. Frequent transpositions and rearrangements of basic units indicate relatively relaxed selection pressures imposed on genomic organisation of 5S genes in plants.

  14. Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but also isolated asymmetry or an SRS-like phenotype.

    NARCIS (Netherlands)

    Bliek, J.; Terhal, P.; Bogaard, M.J. van den; Maas, S.M.; Hamel, B.C.J.; Salieb-Beugelaar, G.; Simon, M.; Letteboer, T.; Smagt, J. van der; Kroes, H.Y.; Mannens, M.

    2006-01-01

    The H19 differentially methylated region (DMR) controls the allele-specific expression of both the imprinted H19 tumor-suppressor gene and the IGF2 growth factor. Hypermethylation of this DMR--and subsequently of the H19 promoter region--is a major cause of the clinical features of gigantism and/or

  15. Generation of comprehensive transposon insertion mutant library for the model archaeon, Haloferax volcanii, and its use for gene discovery.

    Science.gov (United States)

    Kiljunen, Saija; Pajunen, Maria I; Dilks, Kieran; Storf, Stefanie; Pohlschroder, Mechthild; Savilahti, Harri

    2014-12-09

    Archaea share fundamental properties with bacteria and eukaryotes. Yet, they also possess unique attributes, which largely remain poorly characterized. Haloferax volcanii is an aerobic, moderately halophilic archaeon that can be grown in defined media. It serves as an excellent archaeal model organism to study the molecular mechanisms of biological processes and cellular responses to changes in the environment. Studies on haloarchaea have been impeded by the lack of efficient genetic screens that would facilitate the identification of protein functions and respective metabolic pathways. Here, we devised an insertion mutagenesis strategy that combined Mu in vitro DNA transposition and homologous-recombination-based gene targeting in H. volcanii. We generated an insertion mutant library, in which the clones contained a single genomic insertion. From the library, we isolated pigmentation-defective and auxotrophic mutants, and the respective insertions pinpointed a number of genes previously known to be involved in carotenoid and amino acid biosynthesis pathways, thus validating the performance of the methodologies used. We also identified mutants that had a transposon insertion in a gene encoding a protein of unknown or putative function, demonstrating that novel roles for non-annotated genes could be assigned. We have generated, for the first time, a random genomic insertion mutant library for a halophilic archaeon and used it for efficient gene discovery. The library will facilitate the identification of non-essential genes behind any specific biochemical pathway. It represents a significant step towards achieving a more complete understanding of the unique characteristics of halophilic archaea.

  16. Random mutagenesis in Corynebacterium glutamicum ATCC 13032 using an IS6100-based transposon vector identified the last unknown gene in the histidine biosynthesis pathway

    Directory of Open Access Journals (Sweden)

    Gaigalat Lars

    2006-08-01

    Full Text Available Abstract Background Corynebacterium glutamicum, a Gram-positive bacterium of the class Actinobacteria, is an industrially relevant producer of amino acids. Several methods for the targeted genetic manipulation of this organism and rational strain improvement have been developed. An efficient transposon mutagenesis system for the completely sequenced type strain ATCC 13032 would significantly advance functional genome analysis in this bacterium. Results A comprehensive transposon mutant library comprising 10,080 independent clones was constructed by electrotransformation of the restriction-deficient derivative of strain ATCC 13032, C. glutamicum RES167, with an IS6100-containing non-replicative plasmid. Transposon mutants had stable cointegrates between the transposon vector and the chromosome. Altogether 172 transposon integration sites have been determined by sequencing of the chromosomal inserts, revealing that each integration occurred at a different locus. Statistical target site analyses revealed an apparent absence of a target site preference. From the library, auxotrophic mutants were obtained with a frequency of 2.9%. By auxanography analyses nearly two thirds of the auxotrophs were further characterized, including mutants with single, double and alternative nutritional requirements. In most cases the nutritional requirement observed could be correlated to the annotation of the mutated gene involved in the biosynthesis of an amino acid, a nucleotide or a vitamin. One notable exception was a clone mutagenized by transposition into the gene cg0910, which exhibited an auxotrophy for histidine. The protein sequence deduced from cg0910 showed high sequence similarities to inositol-1(or 4-monophosphatases (EC 3.1.3.25. Subsequent genetic deletion of cg0910 delivered the same histidine-auxotrophic phenotype. Genetic complementation of the mutants as well as supplementation by histidinol suggests that cg0910 encodes the hitherto unknown

  17. Comparison of lentiviral and sleeping beauty mediated αβ T cell receptor gene transfer.

    Directory of Open Access Journals (Sweden)

    Anne-Christine Field

    Full Text Available Transfer of tumour antigen-specific receptors to T cells requires efficient delivery and integration of transgenes, and currently most clinical studies are using gamma retroviral or lentiviral systems. Whilst important proof-of-principle data has been generated for both chimeric antigen receptors and αβ T cell receptors, the current platforms are costly, time-consuming and relatively inflexible. Alternative, more cost-effective, Sleeping Beauty transposon-based plasmid systems could offer a pathway to accelerated clinical testing of a more diverse repertoire of recombinant high affinity T cell receptors. Nucleofection of hyperactive SB100X transposase-mediated stable transposition of an optimised murine-human chimeric T cell receptor specific for Wilm's tumour antigen from a Sleeping Beauty transposon plasmid. Whilst transfer efficiency was lower than that mediated by lentiviral transduction, cells could be readily enriched and expanded, and mediated effective target cells lysis in vitro and in vivo. Integration sites of transposed TCR genes in primary T cells were almost randomly distributed, contrasting the predilection of lentiviral vectors for transcriptionally active sites. The results support exploitation of the Sleeping Beauty plasmid based system as a flexible and adaptable platform for accelerated, early-phase assessment of T cell receptor gene therapies.

  18. Duplication and Loss of Function of Genes Encoding RNA Polymerase III Subunit C4 Causes Hybrid Incompatibility in Rice

    Directory of Open Access Journals (Sweden)

    Giao Ngoc Nguyen

    2017-08-01

    Full Text Available Reproductive barriers are commonly observed in both animals and plants, in which they maintain species integrity and contribute to speciation. This report shows that a combination of loss-of-function alleles at two duplicated loci, DUPLICATED GAMETOPHYTIC STERILITY 1 (DGS1 on chromosome 4 and DGS2 on chromosome 7, causes pollen sterility in hybrid progeny derived from an interspecific cross between cultivated rice, Oryza sativa, and an Asian annual wild rice, O. nivara. Male gametes carrying the DGS1 allele from O. nivara (DGS1-nivaras and the DGS2 allele from O. sativa (DGS2-T65s were sterile, but female gametes carrying the same genotype were fertile. We isolated the causal gene, which encodes a protein homologous to DNA-dependent RNA polymerase (RNAP III subunit C4 (RPC4. RPC4 facilitates the transcription of 5S rRNAs and tRNAs. The loss-of-function alleles at DGS1-nivaras and DGS2-T65s were caused by weak or nonexpression of RPC4 and an absence of RPC4, respectively. Phylogenetic analysis demonstrated that gene duplication of RPC4 at DGS1 and DGS2 was a recent event that occurred after divergence of the ancestral population of Oryza from other Poaceae or during diversification of AA-genome species.

  19. Genetic recombination as a major cause of mutagenesis in the human globin gene clusters.

    Science.gov (United States)

    Borg, Joseph; Georgitsi, Marianthi; Aleporou-Marinou, Vassiliki; Kollia, Panagoula; Patrinos, George P

    2009-12-01

    Homologous recombination is a frequent phenomenon in multigene families and as such it occurs several times in both the alpha- and beta-like globin gene families. In numerous occasions, genetic recombination has been previously implicated as a major mechanism that drives mutagenesis in the human globin gene clusters, either in the form of unequal crossover or gene conversion. Unequal crossover results in the increase or decrease of the human globin gene copies, accompanied in the majority of cases with minor phenotypic consequences, while gene conversion contributes either to maintaining sequence homogeneity or generating sequence diversity. The role of genetic recombination, particularly gene conversion in the evolution of the human globin gene families has been discussed elsewhere. Here, we summarize our current knowledge and review existing experimental evidence outlining the role of genetic recombination in the mutagenic process in the human globin gene families.

  20. Heterozygous ABCC8 mutations are a cause of MODY.

    Science.gov (United States)

    Bowman, P; Flanagan, S E; Edghill, E L; Damhuis, A; Shepherd, M H; Paisey, R; Hattersley, A T; Ellard, S

    2012-01-01

    The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic beta cell ATP-sensitive potassium (K(ATP)) channel. Inactivating mutations cause congenital hyperinsulinism (CHI) and activating mutations cause transient neonatal diabetes (TNDM) or permanent neonatal diabetes (PNDM) that can usually be treated with sulfonylureas. Sulfonylurea sensitivity is also a feature of HNF1A and HNF4A MODY, but patients referred for genetic testing with clinical features of these types of diabetes do not always have mutations in the HNF1A/4A genes. Our aim was to establish whether mutations in the ABCC8 gene cause MODY that is responsive to sulfonylurea therapy. We sequenced the ABCC8 gene in 85 patients with a BMI MODY criteria, with two diagnosed after 25 years and one patient, who had no family history of diabetes, as a result of a proven de novo mutation. ABCC8 mutations can cause MODY in patients whose clinical features are similar to those with HNF1A/4A MODY. Therefore, sequencing of ABCC8 in addition to the known MODY genes should be considered if such features are present, to facilitate optimal clinical management of these patients.

  1. Exposure to nickel, chromium, or cadmium causes distinct changes in the gene expression patterns of a rat liver derived cell line.

    Directory of Open Access Journals (Sweden)

    Matthew G Permenter

    Full Text Available Many heavy metals, including nickel (Ni, cadmium (Cd, and chromium (Cr are toxic industrial chemicals with an exposure risk in both occupational and environmental settings that may cause harmful outcomes. While these substances are known to produce adverse health effects leading to disease or health problems, the detailed mechanisms remain unclear. To elucidate the processes involved in the toxicity of nickel, cadmium, and chromium at the molecular level and to perform a comparative analysis, H4-II-E-C3 rat liver-derived cell lines were treated with soluble salts of each metal using concentrations derived from viability assays, and gene expression patterns were determined with DNA microarrays. We identified both common and unique biological responses to exposure to the three metals. Nickel, cadmium, chromium all induced oxidative stress with both similar and unique genes and pathways responding to this stress. Although all three metals are known to be genotoxic, evidence for DNA damage in our study only exists in response to chromium. Nickel induced a hypoxic response as well as inducing genes involved in chromatin structure, perhaps by replacing iron in key proteins. Cadmium distinctly perturbed genes related to endoplasmic reticulum stress and invoked the unfolded protein response leading to apoptosis. With these studies, we have completed the first gene expression comparative analysis of nickel, cadmium, and chromium in H4-II-E-C3 cells.

  2. Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene.

    Science.gov (United States)

    Saugier-Veber, Pascale; Marguet, Florent; Lecoquierre, François; Adle-Biassette, Homa; Guimiot, Fabien; Cipriani, Sara; Patrier, Sophie; Brasseur-Daudruy, Marie; Goldenberg, Alice; Layet, Valérie; Capri, Yline; Gérard, Marion; Frébourg, Thierry; Laquerrière, Annie

    2017-05-01

    Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla.

  3. Generation of a human iPSC line from a patient with congenital glaucoma caused by mutation in CYP1B1 gene

    Directory of Open Access Journals (Sweden)

    Arantxa Bolinches-Amorós

    2018-04-01

    Full Text Available The human iPSC cell line, GLC-FiPS4F1 (ESi047-A, derived from dermal fibroblast from the patient with congenital glaucoma caused by the mutation of the gene CYP1B1, was generated by non-integrative reprogramming technology using OCT3/4, SOX2, CMYC and KLF4 reprogramming factors.

  4. Miniature transposable sequences are frequently mobilized in the bacterial plant pathogen Pseudomonas syringae pv. phaseolicola.

    Directory of Open Access Journals (Sweden)

    Leire Bardaji

    Full Text Available Mobile genetic elements are widespread in Pseudomonas syringae, and often associate with virulence genes. Genome reannotation of the model bean pathogen P. syringae pv. phaseolicola 1448A identified seventeen types of insertion sequences and two miniature inverted-repeat transposable elements (MITEs with a biased distribution, representing 2.8% of the chromosome, 25.8% of the 132-kb virulence plasmid and 2.7% of the 52-kb plasmid. Employing an entrapment vector containing sacB, we estimated that transposition frequency oscillated between 2.6×10(-5 and 1.1×10(-6, depending on the clone, although it was stable for each clone after consecutive transfers in culture media. Transposition frequency was similar for bacteria grown in rich or minimal media, and from cells recovered from compatible and incompatible plant hosts, indicating that growth conditions do not influence transposition in strain 1448A. Most of the entrapped insertions contained a full-length IS801 element, with the remaining insertions corresponding to sequences smaller than any transposable element identified in strain 1448A, and collectively identified as miniature sequences. From these, fragments of 229, 360 and 679-nt of the right end of IS801 ended in a consensus tetranucleotide and likely resulted from one-ended transposition of IS801. An average 0.7% of the insertions analyzed consisted of IS801 carrying a fragment of variable size from gene PSPPH_0008/PSPPH_0017, showing that IS801 can mobilize DNA in vivo. Retrospective analysis of complete plasmids and genomes of P. syringae suggests, however, that most fragments of IS801 are likely the result of reorganizations rather than one-ended transpositions, and that this element might preferentially contribute to genome flexibility by generating homologous regions of recombination. A further miniature sequence previously found to affect host range specificity and virulence, designated MITEPsy1 (100-nt, represented an average 2

  5. Miniature transposable sequences are frequently mobilized in the bacterial plant pathogen Pseudomonas syringae pv. phaseolicola.

    Science.gov (United States)

    Bardaji, Leire; Añorga, Maite; Jackson, Robert W; Martínez-Bilbao, Alejandro; Yanguas-Casás, Natalia; Murillo, Jesús

    2011-01-01

    Mobile genetic elements are widespread in Pseudomonas syringae, and often associate with virulence genes. Genome reannotation of the model bean pathogen P. syringae pv. phaseolicola 1448A identified seventeen types of insertion sequences and two miniature inverted-repeat transposable elements (MITEs) with a biased distribution, representing 2.8% of the chromosome, 25.8% of the 132-kb virulence plasmid and 2.7% of the 52-kb plasmid. Employing an entrapment vector containing sacB, we estimated that transposition frequency oscillated between 2.6×10(-5) and 1.1×10(-6), depending on the clone, although it was stable for each clone after consecutive transfers in culture media. Transposition frequency was similar for bacteria grown in rich or minimal media, and from cells recovered from compatible and incompatible plant hosts, indicating that growth conditions do not influence transposition in strain 1448A. Most of the entrapped insertions contained a full-length IS801 element, with the remaining insertions corresponding to sequences smaller than any transposable element identified in strain 1448A, and collectively identified as miniature sequences. From these, fragments of 229, 360 and 679-nt of the right end of IS801 ended in a consensus tetranucleotide and likely resulted from one-ended transposition of IS801. An average 0.7% of the insertions analyzed consisted of IS801 carrying a fragment of variable size from gene PSPPH_0008/PSPPH_0017, showing that IS801 can mobilize DNA in vivo. Retrospective analysis of complete plasmids and genomes of P. syringae suggests, however, that most fragments of IS801 are likely the result of reorganizations rather than one-ended transpositions, and that this element might preferentially contribute to genome flexibility by generating homologous regions of recombination. A further miniature sequence previously found to affect host range specificity and virulence, designated MITEPsy1 (100-nt), represented an average 2.4% of the total

  6. A four-element based transposon system for allele specific tagging ...

    Indian Academy of Sciences (India)

    The four-element based construct would include both Ds and dSpm along with relevant marker genes and .... subsequent generations after transposition has taken place so as to ..... Cardon G H, Frey M, Seadler H and Gierl A 1993 Definition.

  7. Insertion Sequence-Caused Large Scale-Rearrangements in the Genome of Escherichia coli

    Science.gov (United States)

    2016-07-18

    affordable ap- proach to genome-wide characterization of genetic varia - tion in bacterial and eukaryotic genomes (1–3). In addition to small-scale...Paired-End Reads), that uses a graph-based al- gorithm (27) capable of detecting most large-scale varia - tion involving repetitive regions, including novel...Avila,P., Grinsted,J. and De La Cruz,F. (1988) Analysis of the variable endpoints generated by one-ended transposition of Tn21.. J. Bacteriol., 170

  8. Altered Gene Expression in Three Plant Species in Response to Treatment with Nep1, a Fungal Protein That Causes Necrosis

    Science.gov (United States)

    Keates, Sarah E.; Kostman, Todd A.; Anderson, James D.; Bailey, Bryan A.

    2003-01-01

    Nep1 is an extracellular fungal protein that causes necrosis when applied to many dicotyledonous plants, including invasive weed species. Using transmission electron microscopy, it was determined that application of Nep1 (1.0 μg mL–1, 0.1% [v/v] Silwet-L77) to Arabidopsis and two invasive weed species, spotted knapweed (Centaurea maculosa) and dandelion (Taraxacum officinale), caused a reduction in the thickness of the cuticle and a breakdown of chloroplasts 1 to 4 h after treatment. Membrane breakdown was most severe in cells closest to the surface of application. Differential display was used to isolate cDNA clones from the three species showing differential expression in response to Nep1 treatment. Differential gene expression was observed for a putative serpin (CmSER-1) and a calmodulin-like (CmCAL-1) protein from spotted knapweed, and a putative protein phosphatase 2C (ToPP2C-1) and cytochrome P-450 (ToCYP-1) protein from dandelion. In addition, differential expression was observed for genes coding for a putative protein kinase (AtPK-1), a homolog (AtWI-12) of wound-induced WI12, a homolog (AtLEA-1) of late embryogenesis abundant LEA-5, a WRKY-18 DNA-binding protein (AtWRKY-18), and a phospholipase D (AtPLD-1) from Arabidopsis. Genes showing elevated mRNA levels in Nep1-treated (5 μg mL–1, 0.1% [v/v] Silwet-L77) leaves 15 min after Nep1 treatment included CmSER-1 and CmCAL-1 for spotted knapweed, ToCYP-1 and CmCAL-1 for dandelion, and AtPK-1, AtWRKY-18, AtWI-12, and AtLEA-1 for Arabidopsis. Levels of mRNA for AtPLD-1 (Arabidopsis) and ToPP2C-1 (dandelion) decreased rapidly in Silwet-l77-treated plants between 15 min and 4 h of treatment, but were maintained or decreased more slowly over time in Nep1-treated (5 μg mL–1, 0.1% [v/v] Silwet-L77) leaves. In general, increases in mRNA band intensities were in the range of two to five times, with only ToCYP-1 in dandelion exceeding an increase of 10 times. The identified genes have been shown to be involved

  9. MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.

    Directory of Open Access Journals (Sweden)

    Patricia Blanchet

    2017-08-01

    Full Text Available Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense. The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.

  10. Role of zebrafish cytochrome P450 CYP1C genes in the reduced mesencephalic vein blood flow caused by activation of AHR2

    International Nuclear Information System (INIS)

    Kubota, Akira; Stegeman, John J.; Woodin, Bruce R.; Iwanaga, Toshihiko; Harano, Ryo; Peterson, Richard E.; Hiraga, Takeo; Teraoka, Hiroki

    2011-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes various signs of toxicity in early life stages of vertebrates through activation of the aryl hydrocarbon receptor (AHR). We previously reported a sensitive and useful endpoint of TCDD developmental toxicity in zebrafish, namely a decrease in blood flow in the dorsal midbrain, but downstream genes involved in the effect are not known. The present study addressed the role of zebrafish cytochrome P450 1C (CYP1C) genes in association with a decrease in mesencephalic vein (MsV) blood flow. The CYP1C subfamily was recently discovered in fish and includes the paralogues CYP1C1 and CYP1C2, both of which are induced via AHR2 in zebrafish embryos. We used morpholino antisense oligonucleotides (MO or morpholino) to block initiation of translation of the target genes. TCDD-induced mRNA expression of CYP1Cs and a decrease in MsV blood flow were both blocked by gene knockdown of AHR2. Gene knockdown of CYP1C1 by two different morpholinos and CYP1C2 by two different morpholinos, but not by their 5 nucleotide-mismatch controls, was effective in blocking reduced MsV blood flow caused by TCDD. The same CYP1C-MOs prevented reduction of blood flow in the MsV caused by β-naphthoflavone (BNF), representing another class of AHR agonists. Whole-mount in situ hybridization revealed that mRNA expression of CYP1C1 and CYP1C2 was induced by TCDD most strongly in branchiogenic primordia and pectoral fin buds. In situ hybridization using head transverse sections showed that TCDD increased the expression of both CYP1Cs in endothelial cells of blood vessels, including the MsV. These results indicate a potential role of CYP1C1 and CYP1C2 in the local circulation failure induced by AHR2 activation in the dorsal midbrain of the zebrafish embryo. - Research Highlights: → We examine the roles of zebrafish CYP1C1 and CYP1C2 in TCDD developmental toxicity. → TCDD induces mRNA expression of both CYP1Cs in the mesencephalic vein. → Knockdown of each

  11. Derepression of the plant Chromovirus LORE1 induces germline transposition in regenerated plants.

    Directory of Open Access Journals (Sweden)

    Eigo Fukai

    2010-03-01

    Full Text Available Transposable elements represent a large proportion of the eukaryotic genomes. Long Terminal Repeat (LTR retrotransposons are very abundant and constitute the predominant family of transposable elements in plants. Recent studies have identified chromoviruses to be a widely distributed lineage of Gypsy elements. These elements contain chromodomains in their integrases, which suggests a preference for insertion into heterochromatin. In turn, this preference might have contributed to the patterning of heterochromatin observed in host genomes. Despite their potential importance for our understanding of plant genome dynamics and evolution, the regulatory mechanisms governing the behavior of chromoviruses and their activities remain largely uncharacterized. Here, we report a detailed analysis of the spatio-temporal activity of a plant chromovirus in the endogenous host. We examined LORE1a, a member of the endogenous chromovirus LORE1 family from the model legume Lotus japonicus. We found that this chromovirus is stochastically de-repressed in plant populations regenerated from de-differentiated cells and that LORE1a transposes in the male germline. Bisulfite sequencing of the 5' LTR and its surrounding region suggests that tissue culture induces a loss of epigenetic silencing of LORE1a. Since LTR promoter activity is pollen specific, as shown by the analysis of transgenic plants containing an LTR::GUS fusion, we conclude that male germline-specific LORE1a transposition in pollen grains is controlled transcriptionally by its own cis-elements. New insertion sites of LORE1a copies were frequently found in genic regions and show no strong insertional preferences. These distinctive novel features of LORE1 indicate that this chromovirus has considerable potential for generating genetic and epigenetic diversity in the host plant population. Our results also define conditions for the use of LORE1a as a genetic tool.

  12. Stem loop sequences specific to transposable element IS605 are found linked to lipoprotein genes in Borrelia plasmids.

    Directory of Open Access Journals (Sweden)

    Nicholas Delihas

    Full Text Available BACKGROUND: Plasmids of Borrelia species are dynamic structures that contain a large number of repetitive genes, gene fragments, and gene fusions. In addition, the transposable element IS605/200 family, as well as degenerate forms of this IS element, are prevalent. In Helicobacter pylori, flanking regions of the IS605 transposase gene contain sequences that fold into identical small stem loops. These function in transposition at the single-stranded DNA level. METHODOLOGY/PRINCIPAL FINDINGS: In work reported here, bioinformatics techniques were used to scan Borrelia plasmid genomes for IS605 transposable element specific stem loop sequences. Two variant stem loop motifs are found in the left and right flanking regions of the transposase gene. Both motifs appear to have dispersed in plasmid genomes and are found "free-standing" and phylogenetically conserved without the associated IS605 transposase gene or the adjacent flanking sequence. Importantly, IS605 specific stem loop sequences are also found at the 3' ends of lipoprotein genes (PFam12 and PFam60, however the left and right sequences appear to develop their own evolutionary patterns. The lipoprotein gene-linked left stem loop sequences maintain the IS605 stem loop motif in orthologs but only at the RNA level. These show mutations whereby variants fold into phylogenetically conserved RNA-type stem loops that contain the wobble non-Watson-Crick G-U base-pairing. The right flanking sequence is associated with the family lipoprotein-1 genes. A comparison of homologs shows that the IS605 stem loop motif rapidly dissipates, but a more elaborate secondary structure appears to develop in its place. CONCLUSIONS/SIGNIFICANCE: Stem loop sequences specific to the transposable element IS605 are present in plasmid regions devoid of a transposase gene and significantly, are found linked to lipoprotein genes in Borrelia plasmids. These sequences are evolutionarily conserved and/or structurally developed in

  13. Fanconi anemia: causes and consequences of genetic instability.

    Science.gov (United States)

    Kalb, R; Neveling, K; Nanda, I; Schindler, D; Hoehn, H

    2006-01-01

    Fanconi anemia (FA) is a rare recessive disease that reflects the cellular and phenotypic consequences of genetic instability: growth retardation, congenital malformations, bone marrow failure, high risk of neoplasia, and premature aging. At the cellular level, manifestations of genetic instability include chromosomal breakage, cell cycle disturbance, and increased somatic mutation rates. FA cells are exquisitely sensitive towards oxygen and alkylating drugs such as mitomycin C or diepoxybutane, pointing to a function of FA genes in the defense against reactive oxygen species and other DNA damaging agents. FA is caused by biallelic mutations in at least 12 different genes which appear to function in the maintenance of genomic stability. Eight of the FA proteins form a nuclear core complex with a catalytic function involving ubiquitination of the central FANCD2 protein. The posttranslational modification of FANCD2 promotes its accumulation in nuclear foci, together with known DNA maintenance proteins such as BRCA1, BRCA2, and the RAD51 recombinase. Biallelic mutations in BRCA2 cause a severe FA-like phenotype, as do biallelic mutations in FANCD2. In fact, only leaky or hypomorphic mutations in this central group of FA genes appear to be compatible with life birth and survival. The newly discovered FANCJ (= BRIP1) and FANCM (= Hef ) genes correspond to known DNA-maintenance genes (helicase resp. helicase-associated endonuclease for fork-structured DNA). These genes provide the most convincing evidence to date of a direct involvement of FA genes in DNA repair functions associated with the resolution of DNA crosslinks and stalled replication forks. Even though genetic instability caused by mutational inactivation of the FANC genes has detrimental effects for the majority of FA patients, around 20% of patients appear to benefit from genetic instability since genetic instability also increases the chance of somatic reversion of their constitutional mutations. Intragenic

  14. Intronic PAH gene mutations cause a splicing defect by a novel mechanism involving U1snRNP binding downstream of the 5' splice site

    DEFF Research Database (Denmark)

    Martínez-Pizarro, Ainhoa; Dembic, Maja; Pérez, Belén

    2018-01-01

    Phenylketonuria (PKU), one of the most common inherited diseases of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene. Recently, PAH exon 11 was identified as a vulnerable exon due to a weak 3' splice site, with different exonic mutations affecting exon 11 ...

  15. Novel Compound Heterozygous CLCNKB Gene Mutations (c.1755A>G/ c.848_850delTCT) Cause Classic Bartter Syndrome.

    Science.gov (United States)

    Wang, Chunli; Chen, Ying; Zheng, Bixia; Zhu, Mengshu; Fan, Jia; Wang, Juejin; Jia, Zhanjun; Huang, Songming; Zhang, Aihua

    2018-02-14

    Inactivated variants in CLCNKB gene encoding the basolateral chloride channel ClC-Kb cause classic Bartter syndrome characterized by hypokalemic metabolic alkalosis and hyperreninemic hyperaldosteronism. Here we identified two cBS siblings presenting hypokalemia in a Chinese family due to novel compound heterozygous CLCNKB mutations (c.848_850delTCT/c.1755A>G). Compound heterozygosity was confirmed by amplifying and sequencing the patient's genomic DNA. The synonymous mutation c.1755A>G (Thr585Thr) was located at +2bp from the 5' splice donor site in exon 15, further transcript analysis demonstrated that this single nucleotide mutation causes exclusion of exon 15 in the cDNA from the proband and his mother. Furthermore, we investigated the expression and protein trafficking change of c.848_850delTCT (TCT) and exon 15 deletion(E15)mutation in vitro. The E15 mutation markedly decreased the expression of ClC-Kb and resulted in a low-molecular-weight band (~55kD) trapping in the endoplasmic reticulum, while the TCT mutant only decreased the total and plasma membrane ClC-Kb protein expression but did not affect the subcellular localization. Finally, we studied the physiological functions of mutations by using whole-cell patch clamp and found that E15 or TCT mutation decreased the current of ClC-Kb/barttin channel. These results suggested that the compound defective mutations of CLCNKB gene are the molecular mechanism of the two cBS siblings.

  16. Café-au-lait macules and pediatric malignancy caused by biallelic mutations in the DNA mismatch repair (MMR) gene PMS2.

    Science.gov (United States)

    Jackson, Carl-Christian; Holter, Spring; Pollett, Aaron; Clendenning, Mark; Chou, Shirley; Senter, Leigha; Ramphal, Raveena; Gallinger, Steven; Boycott, Kym

    2008-06-01

    A 14-year-old male presented with a T4 sigmoid adenocarcinoma, PMS2 protein and high frequency microsatellite instability. Germline analysis identified biallelic PMS2 missense mutations. A new cancer syndrome caused by biallelic mutations in the mismatch repair genes, including PMS2, is now emerging and is characterized by café-au-lait macules, colonic polyps and a distinctive tumor spectrum. (c) 2007 Wiley-Liss, Inc.

  17. Mutations in the Caenorhabditis elegans orthologs of human genes required for mitochondrial tRNA modification cause similar electron transport chain defects but different nuclear responses.

    Science.gov (United States)

    Navarro-González, Carmen; Moukadiri, Ismaïl; Villarroya, Magda; López-Pascual, Ernesto; Tuck, Simon; Armengod, M-Eugenia

    2017-07-01

    Several oxidative phosphorylation (OXPHOS) diseases are caused by defects in the post-transcriptional modification of mitochondrial tRNAs (mt-tRNAs). Mutations in MTO1 or GTPBP3 impair the modification of the wobble uridine at position 5 of the pyrimidine ring and cause heart failure. Mutations in TRMU affect modification at position 2 and cause liver disease. Presently, the molecular basis of the diseases and why mutations in the different genes lead to such different clinical symptoms is poorly understood. Here we use Caenorhabditis elegans as a model organism to investigate how defects in the TRMU, GTPBP3 and MTO1 orthologues (designated as mttu-1, mtcu-1, and mtcu-2, respectively) exert their effects. We found that whereas the inactivation of each C. elegans gene is associated with a mild OXPHOS dysfunction, mutations in mtcu-1 or mtcu-2 cause changes in the expression of metabolic and mitochondrial stress response genes that are quite different from those caused by mttu-1 mutations. Our data suggest that retrograde signaling promotes defect-specific metabolic reprogramming, which is able to rescue the OXPHOS dysfunction in the single mutants by stimulating the oxidative tricarboxylic acid cycle flux through complex II. This adaptive response, however, appears to be associated with a biological cost since the single mutant worms exhibit thermosensitivity and decreased fertility and, in the case of mttu-1, longer reproductive cycle. Notably, mttu-1 worms also exhibit increased lifespan. We further show that mtcu-1; mttu-1 and mtcu-2; mttu-1 double mutants display severe growth defects and sterility. The animal models presented here support the idea that the pathological states in humans may initially develop not as a direct consequence of a bioenergetic defect, but from the cell's maladaptive response to the hypomodification status of mt-tRNAs. Our work highlights the important association of the defect-specific metabolic rewiring with the pathological phenotype

  18. Inactivation of promoter 1B of APC causes partial gene silencing: evidence for a significant role of the promoter in regulation and causative of familial adenomatous polyposis

    DEFF Research Database (Denmark)

    Rohlin, A; Engwall, Y; Fritzell, K

    2011-01-01

    inactivation of promoter 1B is disease causing in FAP; (ii) expression of transcripts from promoter 1B is generated at considerable higher levels compared with 1A, demonstrating a hitherto unknown importance of 1B; (iii) adenoma formation in FAP, caused by impaired function of promoter 1B, does not require......Familial adenomatous polyposis (FAP) is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Two promoters, 1A and 1B, have been recognized in APC, and 1B is thought to have a minor role in the regulation of the gene. We have identified a novel deletion encompassing half...... of this promoter in the largest family (Family 1) of the Swedish Polyposis Registry. The mutation leads to an imbalance in allele-specific expression of APC, and transcription from promoter 1B was highly impaired in both normal colorectal mucosa and blood from mutation carriers. To establish the significance...

  19. Restless 5S: the re-arrangement(s) and evolution of the nuclear ribosomal DNA in land plants.

    Science.gov (United States)

    Wicke, Susann; Costa, Andrea; Muñoz, Jesùs; Quandt, Dietmar

    2011-11-01

    Among eukaryotes two types of nuclear ribosomal DNA (nrDNA) organization have been observed. Either all components, i.e. the small ribosomal subunit, 5.8S, large ribosomal subunit, and 5S occur tandemly arranged or the 5S rDNA forms a separate cluster of its own. Generalizations based on data derived from just a few model organisms have led to a superimposition of structural and evolutionary traits to the entire plant kingdom asserting that plants generally possess separate arrays. This study reveals that plant nrDNA organization into separate arrays is not a distinctive feature, but rather assignable almost solely to seed plants. We show that early diverging land plants and presumably streptophyte algae share a co-localization of all rRNA genes within one repeat unit. This raises the possibility that the state of rDNA gene co-localization had occurred in their common ancestor. Separate rDNA arrays were identified for all basal seed plants and water ferns, implying at least two independent 5S rDNA transposition events during land plant evolution. Screening for 5S derived Cassandra transposable elements which might have played a role during the transposition events, indicated that this retrotransposon is absent in early diverging vascular plants including early fern lineages. Thus, Cassandra can be rejected as a primary mechanism for 5S rDNA transposition in water ferns. However, the evolution of Cassandra and other eukaryotic 5S derived elements might have been a side effect of the 5S rDNA cluster formation. Structural analysis of the intergenic spacers of the ribosomal clusters revealed that transposition events partially affect spacer regions and suggests a slightly different transcription regulation of 5S rDNA in early land plants. 5S rDNA upstream regulatory elements are highly divergent or absent from the LSU-5S spacers of most early divergent land plant lineages. Several putative scenarios and mechanisms involved in the concerted relocation of hundreds of 5S

  20. Towards controlled mutagenesis with transposons Ac and Tam3

    Energy Technology Data Exchange (ETDEWEB)

    Haring, M; Veken, J; Windrich, R; Kneppers, T; Rommens, C; Nijkamp, H J.J.; Hille, J [Department of Genetics, Free University, Amsterdam (Netherlands)

    1990-01-01

    Full text: The discovery of mobile genetic elements in plants has permitted the use of these transposons for insertional mutagenesis. This applies so far only to Zea mays and Antirrhinum majus, because other plant transposable elements have not been characterised so thoroughly at the genetic and the molecular level. To establish whether transposons (Ac from maize and Tam3 from Antirrhinum) remain mobile in heterologous hosts, either in somatic tissue or after meiosis, a phenotypic assay system for transposition was developed. The separation of the two transposition functions will allow controlled mutagenesis of plant genes. Our results indicate that both transposable elements remain active in heterologous hosts. (author)

  1. Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I).

    OpenAIRE

    Hoth, C F; Milunsky, A; Lipsky, N; Sheffer, R; Clarren, S K; Baldwin, C T

    1993-01-01

    Waardenburg syndrome type I (WS-I) is an autosomal dominant disorder characterized by sensorineural hearing loss, dystopia canthorum, pigmentary disturbances, and other developmental defects. Klein-Waardenburg syndrome (WS-III) is a disorder with many of the same characteristics as WS-I and includes musculoskeletal abnormalities. We have recently reported the identification and characterization of one of the first gene defects, in the human PAX3 gene, which causes WS-I. PAX3 is a DNA-binding ...

  2. Leveraging gene-environment interactions and endotypes for asthma gene discovery

    DEFF Research Database (Denmark)

    Bønnelykke, Klaus; Ober, Carole

    2016-01-01

    , such as childhood asthma with severe exacerbations, and on relevant exposures that are involved in gene-environment interactions (GEIs), such as rhinovirus infections, will improve detection of asthma genes and our understanding of the underlying mechanisms. We will discuss the challenges of considering GEIs......Asthma is a heterogeneous clinical syndrome that includes subtypes of disease with different underlying causes and disease mechanisms. Asthma is caused by a complex interaction between genes and environmental exposures; early-life exposures in particular play an important role. Asthma is also...... heritable, and a number of susceptibility variants have been discovered in genome-wide association studies, although the known risk alleles explain only a small proportion of the heritability. In this review, we present evidence supporting the hypothesis that focusing on more specific asthma phenotypes...

  3. Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects.

    Science.gov (United States)

    Anand, Deepti; Agrawal, Smriti A; Slavotinek, Anne; Lachke, Salil A

    2018-04-01

    Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are documented. This effort reveals FOXE3, HSF4, MAF, and PITX3 to have 33, 16, 18, and 7 unique causal mutations, respectively. Loss-of-function mutant animals for these genes have served to model the pathobiology of the associated human defects, and we discuss the currently known molecular function of these genes, particularly with emphasis on their role in ocular development. Finally, we make the detailed FOXE3, HSF4, MAF, and PITX3 variant information available in the Leiden Online Variation Database (LOVD) platform at https://www.LOVD.nl/FOXE3, https://www.LOVD.nl/HSF4, https://www.LOVD.nl/MAF, and https://www.LOVD.nl/PITX3. Thus, this article informs on key variants in transcription factor genes linked to cataract, aphakia, corneal opacity, glaucoma, microcornea, microphthalmia, anterior segment mesenchymal dysgenesis, and Ayme-Gripp syndrome, and facilitates their access through Web-based databases. © 2018 Wiley Periodicals, Inc.

  4. ABCD syndrome is caused by a homozygous mutation in the EDNRB gene.

    Science.gov (United States)

    Verheij, Joke B G M; Kunze, Jürgen; Osinga, Jan; van Essen, Anthonie J; Hofstra, Robert M W

    2002-03-15

    ABCD syndrome is an autosomal recessive syndrome characterized by albinism, black lock, cell migration disorder of the neurocytes of the gut (Hirschsprung disease [HSCR]), and deafness. This phenotype clearly overlaps with the features of the Shah-Waardenburg syndrome, comprising sensorineural deafness; hypopigmentation of skin, hair, and irides; and HSCR. Therefore, we screened DNA of the index patient of the ABCD syndrome family for mutations in the endothelin B receptor (EDNRB) gene, a gene known to be involved in Shah-Waardenburg syndrome. A homozygous nonsense mutation in exon 3 (R201X) of the EDNRB gene was found. We therefore suggest that ABCD syndrome is not a separate entity, but an expression of Shah-Waardenburg syndrome.

  5. Clinical features and surgical outcomes of complete transposition of the great arteries

    Directory of Open Access Journals (Sweden)

    Suk Jin Hong

    2012-10-01

    Full Text Available &lt;B&gt;Purpose:&lt;/B&gt; This single-center study aimed to assess the clinical features and surgical approaches and outcomes of complete transposition of the great arteries (TGA. &lt;B&gt;Methods:&lt;/B&gt; TGA patients who had undergone surgical correction at the Kyungpook National University Hospital from January 2000 to December 2010, were retrospectively evaluated for patient characteristics, clinical manifestation, preoperative management, intraoperative findings, postoperative progress, and follow-up status. &lt;B&gt;Results:&lt;/B&gt; Twenty-eight patients (17 boys and 11 girls, mean age= 10.6±21.5 days were included and were categorized as follows: group I, TGA with intact ventricular septum (n=13; group II, TGA with ventricular septal defect (VSD, n=12; and group III, TGA/VSD with pulmonary stenosis (n=3. Group I underwent the most intensive preoperative management (balloon atrial septostomy and prostaglandin E1 medication. Group II showed the highest incidence of heart failure (P&lt;0.05. Usual and unusual coronary anatomy patterns were observed in 20 (71% and 8 patients, respectively. Arterial and half-turned truncal switch operations were performed in 25 and 3 patients (Group III, respectively. Postoperative complications included cardiac arrhythmias (8 patients, central nervous system complications (3 patients, acute renal failure (1 patient, infections (3 patients, and cardiac tamponade (1 patient, and no statistically significant difference was observed between the groups. Group II showed the mildest aortic regurgitation on follow-up echocardiograms (P&lt;0.05. One patient underwent reoperation, and 1 died. The overall mortality rate was 4%. &lt;B&gt;Conclusion:&lt;/B&gt; Our study showed favorable results in all the groups and no significant difference in postoperative complication, reoperation, and mortality among the groups. However, our results were

  6. A mutation in the LAMC2 gene causes the Herlitz junctional epidermolysis bullosa (H-JEB in two French draft horse breeds

    Directory of Open Access Journals (Sweden)

    Guérin Gérard

    2003-03-01

    Full Text Available Abstract Epidermolysis bullosa (EB is a heterogeneous group of inherited diseases characterised by skin blistering and fragility. In humans, one of the most severe forms of EB known as Herlitz-junctional EB (H-JEB, is caused by mutations in the laminin 5 genes. EB has been described in several species, like cattle, sheep, dogs, cats and horses where the mutation, a cytosine insertion in exon 10 of the LAMC2 gene, was very recently identified in Belgian horses as the mutation responsible for JEB. In this study, the same mutation was found to be totally associated with the JEB phenotype in two French draft horse breeds, Trait Breton and Trait Comtois. This result provides breeders a molecular test to better manage their breeding strategies by genetic counselling.

  7. PREVALENCE OF POLYMORPHISM OF THE TLR 9 TYPE GENE IN PATIENTS WITH INFECTIOUS MONONUCLEOSIS CAUSED BY EPSTEIN-BARR VIRUS

    Directory of Open Access Journals (Sweden)

    Popov M.M.

    2017-10-01

    Full Text Available Introduction. The prevalence of polymorphism -1486 T/C of TLR-9 gene in 52 patients with infectious mononucleosis (IM caused by the Epstein-Barr virus was studied. Based on the results obtained, three main genotypes -1486 T/C of the gene TLR-9-TT, TC, CC, were identified. The study of the frequency of occurrence of individual genotypes in patients with IV revealed dominance of CC and TT genotypes in comparison with the control group. The study of the frequency distribution of the -1486 T/C polymorphism of the TLR-9 gene for different genotypes showed the specificity of the changes for the CC genotype in patients with IM and the absence of such changes for the TT and TC genotypes. Aim of research. To establish the frequency of the polymorphism -1486 T/C of the TLR-9 gene in patients with IM caused by the Epstein-Barr virus. Materials and methods. A study to determine the polymorphism -1486 T/C of the TLR-9 gene was conducted in 52 patients with IM. Among them, women - 31 (59,6%, men - 21 (40,4% at the age of 18 to 34 years. The control group for studying the prevalence of the polymorphism -1486 T/C of the TLR-9 gene was 40 healthy donors. The mean age was 24,2±2,4 years, with a range from 18 to 44 years. To detect DNA VEB using the reverse transcription PCR method with hybridization-fluorescent detection of amplification products, Amplisens (Russia reagent kits were used. The polymorphic region -1486 T/ C, rs187084 of the TLR9 gene was studied by real-time PCR amplification by determining the length of the restriction fragments-PCR using Ncol restriction enzyme and oligonucleotide primers. Results. An analysis of the results of polymorphism -1486 T/C of the TLR-9 gene made it possible to identify three main genotypes - TT, TC, CC. The allotment frequency of the discovered -1486Т/С SNP genotypes of the gene TLR-9 in patients with ІМ was the following: ТТ genotype – 17 % (9 patients, ТС – 46 % (24 patients and СС – 37 % (19

  8. Lactobacillus zeae protects Caenorhabditis elegans from enterotoxigenic Escherichia coli-caused death by inhibiting enterotoxin gene expression of the pathogen.

    Directory of Open Access Journals (Sweden)

    Mengzhou Zhou

    Full Text Available BACKGROUND: The nematode Caenorhabditis elegans has become increasingly used for screening antimicrobials and probiotics for pathogen control. It also provides a useful tool for studying microbe-host interactions. This study has established a C. elegans life-span assay to preselect probiotic bacteria for controlling K88(+ enterotoxigenic Escherichia coli (ETEC, a pathogen causing pig diarrhea, and has determined a potential mechanism underlying the protection provided by Lactobacillus. METHODOLOGY/PRINCIPAL FINDINGS: Life-span of C. elegans was used to measure the response of worms to ETEC infection and protection provided by lactic acid-producing bacteria (LAB. Among 13 LAB isolates that varied in their ability to protect C. elegans from death induced by ETEC strain JG280, Lactobacillus zeae LB1 offered the highest level of protection (86%. The treatment with Lactobacillus did not reduce ETEC JG280 colonization in the nematode intestine. Feeding E. coli strain JFF4 (K88(+ but lacking enterotoxin genes of estA, estB, and elt did not cause death of worms. There was a significant increase in gene expression of estA, estB, and elt during ETEC JG280 infection, which was remarkably inhibited by isolate LB1. The clone with either estA or estB expressed in E. coli DH5α was as effective as ETEC JG280 in killing the nematode. However, the elt clone killed only approximately 40% of worms. The killing by the clones could also be prevented by isolate LB1. The same isolate only partially inhibited the gene expression of enterotoxins in both ETEC JG280 and E. coli DH5α in-vitro. CONCLUSIONS/SIGNIFICANCE: The established life-span assay can be used for studies of probiotics to control ETEC (for effective selection and mechanistic studies. Heat-stable enterotoxins appeared to be the main factors responsible for the death of C. elegans. Inhibition of ETEC enterotoxin production, rather than interference of its intestinal colonization, appears to be the

  9. The identification of a gene (Cwp1), silenced during Solanum evolution, which causes cuticle microfissuring and dehydration when expressed in tomato fruit.

    Science.gov (United States)

    Hovav, Ran; Chehanovsky, Noam; Moy, Michal; Jetter, Reinhard; Schaffer, Arthur A

    2007-11-01

    One of the most intriguing phenomena of fleshy fruit is the ability to maintain high water content at maturity, even following harvest. This is accomplished by a fruit cuticle that is highly impermeable to water diffusion. In this paper, we report on a novel genotype of tomato, developed via introgression from the wild species Solanum habrochaites, which is characterized by microfissuring of the fruit cuticle and dehydration of the mature fruit. The microfissure/dehydration phenotype is inherited as a single gene, termed Cwp1 (cuticular water permeability). The gene was fine mapped, and its identity was determined by map-based cloning and differential expression analysis in near-isogenic lines. Causality of the Cwp1 gene was shown by the heterologous transgenic expression of the gene in the cultivated tomato, which caused a microfissured fruit cuticle leading to dehydrated fruit. Cwp1 encodes for a protein of unidentified function in the DUF833 domain family. The gene is expressed in the fruit epidermis of the dehydrating genotype harbouring the wild-species introgression, but not in the cultivated tomato. It is expressed only in the primitive green-fruited wild tomato species, but is not expressed in the cultivated Solanum lycopersicum and the closely related Solanum cheesmaniae and Solanum pimpinellifolium, indicating a pre-adaptive role for Cwp1 silencing in the evolution and domestication of the cultivated tomato.

  10. Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity?

    DEFF Research Database (Denmark)

    Zimmermann, E; Ängquist, L H; Mirza, S S

    2015-01-01

    Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has......-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P ... hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0...

  11. Short tandem repeats in CdLS-causing genes: distribution and ...

    Indian Academy of Sciences (India)

    and SMC3, as all STRs for these genes fall in noncoding region only. ... This indicates that more repeated STRs are at the risk of replication ... patients versus controls. ... ing from a balance between slippage events and point mutations. Proc.

  12. Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia

    DEFF Research Database (Denmark)

    Moore, Daniel J; Onoufriadis, Alexandros; Shoemark, Amelia

    2013-01-01

    Primary ciliary dyskinesia (PCD) is a ciliopathy characterized by airway disease, infertility, and laterality defects, often caused by dual loss of the inner dynein arms (IDAs) and outer dynein arms (ODAs), which power cilia and flagella beating. Using whole-exome and candidate-gene Sanger resequ...

  13. A matter of phylogenetic scale: Distinguishing incomplete lineage sorting from lateral gene transfer as the cause of gene tree discord in recent versus deep diversification histories.

    Science.gov (United States)

    Knowles, L Lacey; Huang, Huateng; Sukumaran, Jeet; Smith, Stephen A

    2018-03-01

    Discordant gene trees are commonly encountered when sequences from thousands of loci are applied to estimate phylogenetic relationships. Several processes contribute to this discord. Yet, we have no methods that jointly model different sources of conflict when estimating phylogenies. An alternative to analyzing entire genomes or all the sequenced loci is to identify a subset of loci for phylogenetic analysis. If we can identify data partitions that are most likely to reflect descent from a common ancestor (i.e., discordant loci that indeed reflect incomplete lineage sorting [ILS], as opposed to some other process, such as lateral gene transfer [LGT]), we can analyze this subset using powerful coalescent-based species-tree approaches. Test data sets were simulated where discord among loci could arise from ILS and LGT. Data sets where analyzed using the newly developed program CLASSIPHY (Huang et al., ) to assess whether our ability to distinguish the cause of discord among loci varied when ILS and LGT occurred in the recent versus deep past and whether the accuracy of these inferences were affected by the mutational process. We show that accuracy of probabilistic classification of individual loci by the cause of discord differed when ILS and LGT events occurred more recently compared with the distant past and that the signal-to-noise ratio arising from the mutational process contributes to difficulties in inferring LGT data partitions. We discuss our findings in terms of the promise and limitations of identifying subsets of loci for species-tree inference that will not violate the underlying coalescent model (i.e., data partitions in which ILS, and not LGT, contributes to discord). We also discuss the empirical implications of our work given the many recalcitrant nodes in the tree of life (e.g., origins of angiosperms, amniotes, or Neoaves), and recent arguments for concatenating loci. © 2018 Botanical Society of America.

  14. Epilepsy caused by an abnormal alternative splicing with dosage effect of the SV2A gene in a chicken model.

    Directory of Open Access Journals (Sweden)

    Marine Douaud

    Full Text Available Photosensitive reflex epilepsy is caused by the combination of an individual's enhanced sensitivity with relevant light stimuli, such as stroboscopic lights or video games. This is the most common reflex epilepsy in humans; it is characterized by the photoparoxysmal response, which is an abnormal electroencephalographic reaction, and seizures triggered by intermittent light stimulation. Here, by using genetic mapping, sequencing and functional analyses, we report that a mutation in the acceptor site of the second intron of SV2A (the gene encoding synaptic vesicle glycoprotein 2A is causing photosensitive reflex epilepsy in a unique vertebrate model, the Fepi chicken strain, a spontaneous model where the neurological disorder is inherited as an autosomal recessive mutation. This mutation causes an aberrant splicing event and significantly reduces the level of SV2A mRNA in homozygous carriers. Levetiracetam, a second generation antiepileptic drug, is known to bind SV2A, and SV2A knock-out mice develop seizures soon after birth and usually die within three weeks. The Fepi chicken survives to adulthood and responds to levetiracetam, suggesting that the low-level expression of SV2A in these animals is sufficient to allow survival, but does not protect against seizures. Thus, the Fepi chicken model shows that the role of the SV2A pathway in the brain is conserved between birds and mammals, in spite of a large phylogenetic distance. The Fepi model appears particularly useful for further studies of physiopathology of reflex epilepsy, in comparison with induced models of epilepsy in rodents. Consequently, SV2A is a very attractive candidate gene for analysis in the context of both mono- and polygenic generalized epilepsies in humans.

  15. Subgenomic Diversity Patterns Caused by Directional Selection in Bread Wheat Gene Pools

    Directory of Open Access Journals (Sweden)

    Kai Voss-Fels

    2015-07-01

    Full Text Available Genetic diversity represents the fundamental key to breeding success, providing the basis for breeders to select varieties with constantly improving yield performance. On the other hand, strong selection during domestication and breeding have eliminated considerable genetic diversity in the breeding pools of major crops, causing erosion of genetic potential for adaptation to emerging challenges like climate change. High-throughput genomic technologies can address this dilemma by providing detailed knowledge to characterize and replenish genetic diversity in breeding programs. In hexaploid bread wheat ( L., the staple food for 35% of the world’s population, bottlenecks during allopolyploidisation followed by strong artificial selection have considerably narrowed diversity to the extent that yields in many regions appear to be unexpectedly stagnating. In this study, we used a 90,000 single nucleotide polymorphism (SNP wheat genotyping array to assay high-frequency, polymorphic SNP markers in 460 accessions representing different phenological diversity groups from Asian, Australian, European, and North American bread wheat breeding materials. Detailed analysis of subgroup diversity at the chromosome and subgenome scale revealed highly distinct patterns of conserved linkage disequilibrium between different gene pools. The data enable identification of genome regions in most need of rejuvenation with novel diversity and provide a high-resolution molecular basis for genomic-assisted introgression of new variation into chromosome segments surrounding directionally selected metaloci conferring important adaptation and quality traits.

  16. Idiopathic neonatal necrotising fasciitis caused by community-acquired MSSA encoding Panton Valentine Leukocidin genes.

    LENUS (Irish Health Repository)

    Dunlop, Rebecca L E

    2012-02-01

    Neonatal necrotising fasciitis is very rare in comparison to the adult presentation of the disease and a Plastic Surgeon may only encounter one such case during his or her career. Often this is initially misdiagnosed and managed as simple cellulitis. It generally affects previously healthy babies, the site is often the lower back area and a history of minor skin trauma may be elicited. The causative organism is usually Streptococcus or polymicrobial, as is the case in the adult population. We present the case of a previously healthy 11-day-old infant with idiopathic, rapidly progressive necrotising fasciitis of the back, cause by Methicillin sensitive Staphylococcus aureus (MSSA) infection. The strain was isolated and found to encode the Panton-Valentine Leukocidin genes, which have been associated with particularly severe necrotising infections in other sites, with high mortality. These strains are the subject of specific treatment and eradication guidance in the UK but awareness of this and the importance of obtaining detailed culture typing is likely to be low amongst Plastic Surgeons.

  17. Integration profile and safety of an adenovirus hybrid-vector utilizing hyperactive sleeping beauty transposase for somatic integration.

    Directory of Open Access Journals (Sweden)

    Wenli Zhang

    Full Text Available We recently developed adenovirus/transposase hybrid-vectors utilizing the previously described hyperactive Sleeping Beauty (SB transposase HSB5 for somatic integration and we could show stabilized transgene expression in mice and a canine model for hemophilia B. However, the safety profile of these hybrid-vectors with respect to vector dose and genotoxicity remains to be investigated. Herein, we evaluated this hybrid-vector system in C57Bl/6 mice with escalating vector dose settings. We found that in all mice which received the hyperactive SB transposase, transgene expression levels were stabilized in a dose-dependent manner and that the highest vector dose was accompanied by fatalities in mice. To analyze potential genotoxic side-effects due to somatic integration into host chromosomes, we performed a genome-wide integration site analysis using linker-mediated PCR (LM-PCR and linear amplification-mediated PCR (LAM-PCR. Analysis of genomic DNA samples obtained from HSB5 treated female and male mice revealed a total of 1327 unique transposition events. Overall the chromosomal distribution pattern was close-to-random and we observed a random integration profile with respect to integration into gene and non-gene areas. Notably, when using the LM-PCR protocol, 27 extra-chromosomal integration events were identified, most likely caused by transposon excision and subsequent transposition into the delivered adenoviral vector genome. In total, this study provides a careful evaluation of the safety profile of adenovirus/Sleeping Beauty transposase hybrid-vectors. The obtained information will be useful when designing future preclinical studies utilizing hybrid-vectors in small and large animal models.

  18. Disruption of Ttll5/stamp gene (tubulin tyrosine ligase-like protein 5/SRC-1 and TIF2-associated modulatory protein gene) in male mice causes sperm malformation and infertility.

    Science.gov (United States)

    Lee, Geun-Shik; He, Yuanzheng; Dougherty, Edward J; Jimenez-Movilla, Maria; Avella, Matteo; Grullon, Sean; Sharlin, David S; Guo, Chunhua; Blackford, John A; Awasthi, Smita; Zhang, Zhenhuan; Armstrong, Stephen P; London, Edra C; Chen, Weiping; Dean, Jurrien; Simons, S Stoney

    2013-05-24

    TTLL5/STAMP (tubulin tyrosine ligase-like family member 5) has multiple activities in cells. TTLL5 is one of 13 TTLLs, has polyglutamylation activity, augments the activity of p160 coactivators (SRC-1 and TIF2) in glucocorticoid receptor-regulated gene induction and repression, and displays steroid-independent growth activity with several cell types. To examine TTLL5/STAMP functions in whole animals, mice were prepared with an internal deletion that eliminated several activities of the Stamp gene. This mutation causes both reduced levels of STAMP mRNA and C-terminal truncation of STAMP protein. Homozygous targeted mutant (Stamp(tm/tm)) mice appear normal except for marked decreases in male fertility associated with defects in progressive sperm motility. Abnormal axonemal structures with loss of tubulin doublets occur in most Stamp(tm/tm) sperm tails in conjunction with substantial reduction in α-tubulin polyglutamylation, which closely correlates with the reduction in mutant STAMP mRNA. The axonemes in other structures appear unaffected. There is no obvious change in the organs for sperm development of WT versus Stamp(tm/tm) males despite the levels of WT STAMP mRNA in testes being 20-fold higher than in any other organ examined. This defect in male fertility is unrelated to other Ttll genes or 24 genes previously identified as important for sperm function. Thus, STAMP appears to participate in a unique, tissue-selective TTLL-mediated pathway for α-tubulin polyglutamylation that is required for sperm maturation and motility and may be relevant for male fertility.

  19. Disruption of Ttll5/Stamp Gene (Tubulin Tyrosine Ligase-like Protein 5/SRC-1 and TIF2-associated Modulatory Protein Gene) in Male Mice Causes Sperm Malformation and Infertility*

    Science.gov (United States)

    Lee, Geun-Shik; He, Yuanzheng; Dougherty, Edward J.; Jimenez-Movilla, Maria; Avella, Matteo; Grullon, Sean; Sharlin, David S.; Guo, Chunhua; Blackford, John A.; Awasthi, Smita; Zhang, Zhenhuan; Armstrong, Stephen P.; London, Edra C.; Chen, Weiping; Dean, Jurrien; Simons, S. Stoney

    2013-01-01

    TTLL5/STAMP (tubulin tyrosine ligase-like family member 5) has multiple activities in cells. TTLL5 is one of 13 TTLLs, has polyglutamylation activity, augments the activity of p160 coactivators (SRC-1 and TIF2) in glucocorticoid receptor-regulated gene induction and repression, and displays steroid-independent growth activity with several cell types. To examine TTLL5/STAMP functions in whole animals, mice were prepared with an internal deletion that eliminated several activities of the Stamp gene. This mutation causes both reduced levels of STAMP mRNA and C-terminal truncation of STAMP protein. Homozygous targeted mutant (Stamptm/tm) mice appear normal except for marked decreases in male fertility associated with defects in progressive sperm motility. Abnormal axonemal structures with loss of tubulin doublets occur in most Stamptm/tm sperm tails in conjunction with substantial reduction in α-tubulin polyglutamylation, which closely correlates with the reduction in mutant STAMP mRNA. The axonemes in other structures appear unaffected. There is no obvious change in the organs for sperm development of WT versus Stamptm/tm males despite the levels of WT STAMP mRNA in testes being 20-fold higher than in any other organ examined. This defect in male fertility is unrelated to other Ttll genes or 24 genes previously identified as important for sperm function. Thus, STAMP appears to participate in a unique, tissue-selective TTLL-mediated pathway for α-tubulin polyglutamylation that is required for sperm maturation and motility and may be relevant for male fertility. PMID:23558686

  20. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex.

    Science.gov (United States)

    Zeng, Ling-Hui; Rensing, Nicholas R; Zhang, Bo; Gutmann, David H; Gambello, Michael J; Wong, Michael

    2011-02-01

    Tuberous Sclerosis Complex (TSC) is an autosomal dominant, multi-system disorder, typically involving severe neurological symptoms, such as epilepsy, cognitive deficits and autism. Two genes, TSC1 and TSC2, encoding the proteins hamartin and tuberin, respectively, have been identified as causing TSC. Although there is a substantial overlap in the clinical phenotype produced by TSC1 and TSC2 mutations, accumulating evidence indicates that TSC2 mutations cause more severe neurological manifestations than TSC1 mutations. In this study, the neurological phenotype of a novel mouse model involving conditional inactivation of the Tsc2 gene in glial-fibrillary acidic protein (GFAP)-positive cells (Tsc2(GFAP1)CKO mice) was characterized and compared with previously generated Tsc1(GFAP1)CKO mice. Similar to Tsc1(GFAP1)CKO mice, Tsc2(GFAP1)CKO mice exhibited epilepsy, premature death, progressive megencephaly, diffuse glial proliferation, dispersion of hippocampal pyramidal cells and decreased astrocyte glutamate transporter expression. However, Tsc2(GFAP1)CKO mice had an earlier onset and higher frequency of seizures, as well as significantly more severe histological abnormalities, compared with Tsc1(GFAP1)CKO mice. The differences between Tsc1(GFAP1)CKO and Tsc2(GFAP1)CKO mice were correlated with higher levels of mammalian target of rapamycin (mTOR) activation in Tsc2(GFAP1)CKO mice and were reversed by the mTOR inhibitor, rapamycin. These findings provide novel evidence in mouse models that Tsc2 mutations intrinsically cause a more severe neurological phenotype than Tsc1 mutations and suggest that the difference in phenotype may be related to the degree to which Tsc1 and Tsc2 inactivation causes abnormal mTOR activation.

  1. Chlorosis caused by two recessively interacting genes reveals a role of RNA helicase in hybrid breakdown in Arabidopsis thaliana.

    Science.gov (United States)

    Plötner, Björn; Nurmi, Markus; Fischer, Axel; Watanabe, Mutsumi; Schneeberger, Korbinian; Holm, Svante; Vaid, Neha; Schöttler, Mark Aurel; Walther, Dirk; Hoefgen, Rainer; Weigel, Detlef; Laitinen, Roosa A E

    2017-07-01

    Hybrids often differ in fitness from their parents. They may be superior, translating into hybrid vigour or heterosis, but they may also be markedly inferior, because of hybrid weakness or incompatibility. The underlying genetic causes for the latter can often be traced back to genes that evolve rapidly because of sexual or host-pathogen conflicts. Hybrid weakness may manifest itself only in later generations, in a phenomenon called hybrid breakdown. We have characterized a case of hybrid breakdown among two Arabidopsis thaliana accessions, Shahdara (Sha, Tajikistan) and Lövvik-5 (Lov-5, Northern Sweden). In addition to chlorosis, a fraction of the F 2 plants have defects in leaf and embryo development, and reduced photosynthetic efficiency. Hybrid chlorosis is due to two major-effect loci, of which one, originating from Lov-5, appears to encode an RNA helicase (AtRH18). To examine the role of the chlorosis allele in the Lövvik area, in addition to eight accessions collected in 2009, we collected another 240 accessions from 15 collections sites, including Lövvik, from Northern Sweden in 2015. Genotyping revealed that Lövvik collection site is separated from the rest. Crosses between 109 accessions from this area and Sha revealed 85 cases of hybrid chlorosis, indicating that the chlorosis-causing allele is common in this area. These results suggest that hybrid breakdown alleles not only occur at rapidly evolving loci, but also at genes that code for conserved processes. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  2. A novel mutation in the AGXT gene causing primary hyperoxaluria ...

    Indian Academy of Sciences (India)

    synthesis of an aberrant gene product (Williams et al. 2009). Wild-type AGXT .... The urinary oxalate excretion was assayed by a colorimet- ric enzymatic method in ... ure, with clearance = 70 mL/min per 1.73 m2, urea = 7 mmol/L, creatinine ...

  3. Mutations in the PFN1 gene are not a common cause in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration in France.

    Science.gov (United States)

    Lattante, Serena; Le Ber, Isabelle; Camuzat, Agnès; Brice, Alexis; Kabashi, Edor

    2013-06-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are 2 adult onset neurological disorders with overlapping symptoms and clinical characteristics. It is well established that they share a common pathologic and genetic background. Recently, mutations in profilin 1 gene (PFN1) have been identified in patients with familial ALS, suggesting a role for this gene in the pathogenesis of the disease. Based on this, we hypothesized that mutations in PFN1 might also contribute to FTLD disease. We studied a French cohort of 165 ALS/FTLD patients, without finding any variant. We conclude that mutations in PFN1 are not a common cause for ALS/FTLD in France. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Retinal Diseases Caused by Mutations in Genes Not Specifically Associated with the Clinical Diagnosis.

    Directory of Open Access Journals (Sweden)

    Xia Wang

    Full Text Available When seeking a confirmed molecular diagnosis in the research setting, patients with one descriptive diagnosis of retinal disease could carry pathogenic variants in genes not specifically associated with that description. However, this event has not been evaluated systematically in clinical diagnostic laboratories that validate fully all target genes to minimize false negatives/positives.We performed targeted next-generation sequencing analysis on 207 ocular disease-related genes for 42 patients whose DNA had been tested negative for disease-specific panels of genes known to be associated with retinitis pigmentosa, Leber congenital amaurosis, or exudative vitreoretinopathy.Pathogenic variants, including single nucleotide variations and copy number variations, were identified in 9 patients, including 6 with variants in syndromic retinal disease genes and 3 whose molecular diagnosis could not be distinguished easily from their submitted clinical diagnosis, accounting for 21% (9/42 of the unsolved cases.Our study underscores the clinical and genetic heterogeneity of retinal disorders and provides valuable reference to estimate the fraction of clinical samples whose retinal disorders could be explained by genes not specifically associated with the corresponding clinical diagnosis. Our data suggest that sequencing a larger set of retinal disorder related genes can increase the molecular diagnostic yield, especially for clinically hard-to-distinguish cases.

  5. Novel mutations in the SCNN1A gene causing Pseudohypoaldosteronism type 1.

    Directory of Open Access Journals (Sweden)

    Jian Wang

    Full Text Available Pseudohypoaldosteronism type 1 (PHA1 is a rare inherited disease characterized by resistance to the actions of aldosterone. Mutations in the subunit genes (SCNN1A, SCNN1B, SCNN1G of the epithelial sodium channel (ENaC and the NR3C2 gene encoding the mineralocorticoid receptor, result in systemic PHA1 and renal PHA1 respectively. Common clinical manifestations of PHA1 include salt wasting, hyperkalaemia, metabolic acidosis and elevated plasma aldosterone levels in the neonatal period. In this study, we describe the clinical and biochemical manifestations in two Chinese patients with systemic PHA1. Sequence analysis of the SCNN1A gene revealed a compound heterozygous mutation (c.1311delG and c.1439+1G>C in one patient and a homozygous mutation (c.814_815insG in another patient, all three variants are novel. Further analysis of the splicing pattern in a minigene construct showed that the c.1439+1G>C mutation can lead to the retainment of intron 9 as the 5'-donor splice site disappears during post-transcriptional processing of mRNA. In conclusion, our study identified three novel SCNN1A gene mutations in two Chinese patients with systemic PHA1.

  6. Ty1-copia elements reveal diverse insertion sites linked to polymorphisms among flax (Linum usitatissimum L.) accessions.

    Science.gov (United States)

    Galindo-González, Leonardo; Mhiri, Corinne; Grandbastien, Marie-Angèle; Deyholos, Michael K

    2016-12-07

    Initial characterization of the flax genome showed that Ty1-copia retrotransposons are abundant, with several members being recently inserted, and in close association with genes. Recent insertions indicate a potential for ongoing transpositional activity that can create genomic diversity among accessions, cultivars or varieties. The polymorphisms generated constitute a good source of molecular markers that may be associated with phenotype if the insertions alter gene activity. Flax, where accessions are bred mainly for seed nutritional properties or for fibers, constitutes a good model for studying the relationship of transpositional activity with diversification and breeding. In this study, we estimated copy number and used a type of transposon display known as Sequence-Specific Amplification Polymorphisms (SSAPs), to characterize six families of Ty1-copia elements across 14 flax accessions. Polymorphic insertion sites were sequenced to find insertions that could potentially alter gene expression, and a preliminary test was performed with selected genes bearing transposable element (TE) insertions. Quantification of six families of Ty1-copia elements indicated different abundances among TE families and between flax accessions, which suggested diverse transpositional histories. SSAPs showed a high level of polymorphism in most of the evaluated retrotransposon families, with a trend towards higher levels of polymorphism in low-copy number families. Ty1-copia insertion polymorphisms among cultivars allowed a general distinction between oil and fiber types, and between spring and winter types, demonstrating their utility in diversity studies. Characterization of polymorphic insertions revealed an overwhelming association with genes, with insertions disrupting exons, introns or within 1 kb of coding regions. A preliminary test on the potential transcriptional disruption by TEs of four selected genes evaluated in three different tissues, showed one case of significant

  7. Polycystic kidney disease in the medaka (Oryzias latipes pc mutant caused by a mutation in the Gli-Similar3 (glis3 gene.

    Directory of Open Access Journals (Sweden)

    Hisashi Hashimoto

    Full Text Available Polycystic kidney disease (PKD is a common hereditary disease in humans. Recent studies have shown an increasing number of ciliary genes that are involved in the pathogenesis of PKD. In this study, the Gli-similar3 (glis3 gene was identified as the causal gene of the medaka pc mutant, a model of PKD. In the pc mutant, a transposon was found to be inserted into the fourth intron of the pc/glis3 gene, causing aberrant splicing of the pc/glis3 mRNA and thus a putatively truncated protein with a defective zinc finger domain. pc/glis3 mRNA is expressed in the epithelial cells of the renal tubules and ducts of the pronephros and mesonephros, and also in the pancreas. Antisense oligonucleotide-mediated knockdown of pc/glis3 resulted in cyst formation in the pronephric tubules of medaka fry. Although three other glis family members, glis1a, glis1b and glis2, were found in the medaka genome, none were expressed in the embryonic or larval kidney. In the pc mutant, the urine flow rate in the pronephros was significantly reduced, which was considered to be a direct cause of renal cyst formation. The cilia on the surface of the renal tubular epithelium were significantly shorter in the pc mutant than in wild-type, suggesting that shortened cilia resulted in a decrease in driving force and, in turn, a reduction in urine flow rate. Most importantly, EGFP-tagged pc/glis3 protein localized in primary cilia as well as in the nucleus when expressed in mouse renal epithelial cells, indicating a strong connection between pc/glis3 and ciliary function. Unlike human patients with GLIS3 mutations, the medaka pc mutant shows none of the symptoms of a pancreatic phenotype, such as impaired insulin expression and/or diabetes, suggesting that the pc mutant may be suitable for use as a kidney-specific model for human GLIS3 patients.

  8. A mitochondrial tRNA(His) gene mutation causing pigmentary retinopathy and neurosensorial deafness.

    Science.gov (United States)

    Crimi, M; Galbiati, S; Perini, M P; Bordoni, A; Malferrari, G; Sciacco, M; Biunno, I; Strazzer, S; Moggio, M; Bresolin, N; Comi, G P

    2003-04-08

    We have identified a heteroplasmic G to A mutation at position 12,183 of the mitochondrial transfer RNA Histidine (tRNA(His)) gene in three related patients. These phenotypes varied according to mutation heteroplasmy: one had severe pigmentary retinopathy, neurosensorial deafness, testicular dysfunction, muscle hypotrophy, and ataxia; the other two had only retinal and inner ear involvement. The mutation is in a highly conserved region of the T(psi)C stem of the tRNA(His) gene and may alter secondary structure formation. This is the first described pathogenic, maternally inherited mutation of the mitochondrial tRNA(His) gene.

  9. A novel AMELX mutation causes hypoplastic amelogenesis imperfecta.

    Science.gov (United States)

    Kim, Young-Jae; Kim, Youn Jung; Kang, Jenny; Shin, Teo Jeon; Hyun, Hong-Keun; Lee, Sang-Hoon; Lee, Zang Hee; Kim, Jung-Wook

    2017-04-01

    Amelogenesis imperfecta (AI) is a hereditary genetic defect affecting tooth enamel. AI is heterogeneous in clinical phenotype as well as in genetic etiology. To date, more than 10 genes have been associated with the etiology of AI. Amelogenin is the most abundant enamel matrix protein, most of which is encoded by the amelogenin gene in the X-chromosome (AMELX). More than 16 alternative splicing transcripts have been identified in the murine Amelx gene. The purpose of this study was to identify the genetic cause of an AI family. We recruited a family with hypoplastic AI and performed mutational analysis on the candidate gene based on the clinical phenotype. Mutational analysis revealed a missense mutation in exon 6 (NM_182680.1; c.242C > T), which changes a sequence in a highly conserved amino acid (NP_872621.1; p.Pro81Leu). Furthermore, a splicing assay using a minigene displayed that the mutation changed the mRNA splicing repertory. In this study, we identified a novel AMELX missense mutation causing hypoplastic AI, and this mutation also resulted in altered mRNA splicing. These results will not only expand the mutation spectrum causing AI but also broaden our understanding of the biological mechanism of enamel formation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. American Society of Gene & Cell Therapy

    Science.gov (United States)

    ... Gene & Cell Therapy Defined Gene therapy and cell therapy are overlapping fields of biomedical research that aim to repair the direct cause of genetic diseases. Read More Gene & Cell Therapy FAQ's Read the most common questions raised by ...

  11. Impact of pacing on systemic ventricular function in L-transposition of the great arteries.

    Science.gov (United States)

    Hofferberth, Sophie C; Alexander, Mark E; Mah, Douglas Y; Bautista-Hernandez, Victor; del Nido, Pedro J; Fynn-Thompson, Francis

    2016-01-01

    To assess the impact of univentricular versus biventricular pacing (BiVP) on systemic ventricular function in patients with congenitally corrected transposition of the great arteries (ccTGA). We performed a retrospective review of all patients with a diagnosis of ccTGA who underwent pacemaker insertion. From 1993 to 2014, 53 patients were identified from the cardiology database and surgical records. Overall mortality was 7.5% (n = 4). One patient required transplantation and 3 late deaths occurred secondary to end-stage heart failure. Median follow-up was 3.7 years (range, 4 days to 22.5 years). Twenty-five (47%) underwent univentricular pacing only, of these, 8 (32%) developed significant systemic ventricular dysfunction. Twenty-eight (53%) received BiVP, 17 (26%) were upgraded from a dual-chamber system, 11 (21%) received primary BiVP. Fourteen (82%) of the 17 undergoing secondary BiVP demonstrated systemic ventricular dysfunction at the time of pacer upgrade, with 7 (50%) demonstrating improved systemic ventricular function after pacemaker upgrade. Overall, 42 (79%) patients underwent univentricular pacing, with 22 (52%) developing significant systemic ventricular dysfunction. In contrast, the 11 (21%) who received primary BiVP had preserved systemic ventricular function at latest follow-up. Late-onset systemic ventricular dysfunction is a major complication associated with the use of univentricular pacing in patients with ccTGA. All patients with ccTGA who develop heart block should undergo primary biventricular pacing, as this prevents late systemic ventricular dysfunction. Preemptive placement of BiVP leads at the time of anatomical repair or other permanent palliative procedure will facilitate subsequent BiVP should heart block develop. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  12. Steroidogenic factor-1 (SF-1 gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration

    Directory of Open Access Journals (Sweden)

    Servant Nadège

    2010-03-01

    Full Text Available Abstract Background Primary amenorrhea due to 46,XY disorders of sex differentiation (DSD is a frequent reason for consultation in endocrine and gynecology clinics. Among the genetic causes of low-testosterone primary amenorrhea due to 46,XY DSD, SRY gene is reported to be frequently involved, but other genes, such as SF1 and WT1, have never been studied for their prevalence. Methods We directly sequenced SRY, SF1 and WT1 genes in 15 adolescent girls with primary amenorrhea, low testosterone concentration, and XY karyotype, to determine the prevalence of mutations. We also analyzed the LH receptor gene in patients with high LH and normal FSH concentrations. Results Among the 15 adolescents with primary amenorrhea and low testosterone concentration, we identified two new SRY mutations, five new SF1 mutations and one new LH receptor gene mutation. Our study confirms the 10-15% prevalence of SRY mutations and shows the high prevalence (33% of SF1 abnormalities in primary amenorrhea due to 46,XY DSD with low plasma testosterone concentration. Conclusions The genetic analysis of low-testosterone primary amenorrhea is complex as several factors may be involved. This work underlines the need to systematically analyze the SF1 sequence in girls with primary amenorrhea due to 46,XY DSD and low testosterone, as well as in newborns with 46,XY DSD.

  13. Two novel mutations in ILDR1 gene cause autosomal recessive ...

    Indian Academy of Sciences (India)

    In a recent screening programme on hearing loss (HL), we examined 17 common autosomal recessive nonsyndromic hearing loss (ARNSHL) genes in every consanguineous Ira- nian family with ARNSHL that was referred to our centre. We first screened GJB2 mutations and then utilized a panel of three to four short ...

  14. [Reconstruction of medial patellofemoral ligament with transposition of great adductor muscular tendon for the treatment of teenagers' recurrent patellar dislocation].

    Science.gov (United States)

    Shao, Chuan-Qiang; Chen, Chang-Chun; Zhao, Chun-Cheng; Yang, Hong-Mei; Kang, Yan-Zhong

    2017-06-25

    To investigate surgical method and clinical curative effects of medial patellofemoral ligament (MPFL) reconstruction with great adductor muscular tendon in treating teenagers' recurrent patellar dislocation. From May 2012 to September 2014, 19 patients with recurrent dislocation of patellar, including 6 males and 13 females with an average of 16 years old (ranged from 13 to 17 years), the courses of disease ranged from 3 to 18 months(averaged 6 months). All patients were underwent great adductor muscular tendon transposition to reconstruct medial patellofemoral ligament. The curative effects were evaluated by preoperative and postoperative with Lysholm scores and Patellofemoral angle and Q angle. All patients were followed up from 12 to 18 months with an average of 16.5 months. Primary healing was achieved at stage I. No pain, swelling and patellar dislocation or subluxation occurred. Patellofemoral angle increased from preoperative (-3.8±4.9)° to (10.3±4.1)° postoperatively. Q angle decreased from preoperative(16.4±3.1)° to(10.5±1.2)° postoperatively; Lysholm scores were improved from preoperative (68.6±8.5) to (93.7±6.5) final follow-up ( P teenagers' recurrent patellar dislocation.

  15. Gene expression profiling and candidate gene resequencing identifies pathways and mutations important for malignant transformation caused by leukemogenic fusion genes.

    Science.gov (United States)

    Novak, Rachel L; Harper, David P; Caudell, David; Slape, Christopher; Beachy, Sarah H; Aplan, Peter D

    2012-12-01

    NUP98-HOXD13 (NHD13) and CALM-AF10 (CA10) are oncogenic fusion proteins produced by recurrent chromosomal translocations in patients with acute myeloid leukemia (AML). Transgenic mice that express these fusions develop AML with a long latency and incomplete penetrance, suggesting that collaborating genetic events are required for leukemic transformation. We employed genetic techniques to identify both preleukemic abnormalities in healthy transgenic mice as well as collaborating events leading to leukemic transformation. Candidate gene resequencing revealed that 6 of 27 (22%) CA10 AMLs spontaneously acquired a Ras pathway mutation and 8 of 27 (30%) acquired an Flt3 mutation. Two CA10 AMLs acquired an Flt3 internal-tandem duplication, demonstrating that these mutations can be acquired in murine as well as human AML. Gene expression profiles revealed a marked upregulation of Hox genes, particularly Hoxa5, Hoxa9, and Hoxa10 in both NHD13 and CA10 mice. Furthermore, mir196b, which is embedded within the Hoxa locus, was overexpressed in both CA10 and NHD13 samples. In contrast, the Hox cofactors Meis1 and Pbx3 were differentially expressed; Meis1 was increased in CA10 AMLs but not NHD13 AMLs, whereas Pbx3 was consistently increased in NHD13 but not CA10 AMLs. Silencing of Pbx3 in NHD13 cells led to decreased proliferation, increased apoptosis, and decreased colony formation in vitro, suggesting a previously unexpected role for Pbx3 in leukemic transformation. Published by Elsevier Inc.

  16. YBR/EiJ mice: a new model of glaucoma caused by genes on chromosomes 4 and 17

    Directory of Open Access Journals (Sweden)

    K. Saidas Nair

    2016-08-01

    Full Text Available A variety of inherited animal models with different genetic causes and distinct genetic backgrounds are needed to help dissect the complex genetic etiology of glaucoma. The scarcity of such animal models has hampered progress in glaucoma research. Here, we introduce a new inherited glaucoma model: the inbred mouse strain YBR/EiJ (YBR. YBR mice develop a form of pigmentary glaucoma. They exhibit a progressive age-related pigment-dispersing iris disease characterized by iris stromal atrophy. Subsequently, these mice develop elevated intraocular pressure (IOP and glaucoma. Genetic mapping studies utilizing YBR as a glaucoma-susceptible strain and C57BL/6J as a glaucoma-resistant strain were performed to identify genetic loci responsible for the iris disease and high IOP. A recessive locus linked to Tyrp1b on chromosome 4 contributes to iris stromal atrophy and high IOP. However, this is not the only important locus. A recessive locus on YBR chromosome 17 causes high IOP independent of the iris stromal atrophy. In specific eyes with high IOP caused by YBR chromosome 17, the drainage angle (through which ocular fluid leaves the eye is largely open. The YBR alleles of genes on chromosomes 4 and 17 underlie the development of high IOP and glaucoma but do so through independent mechanisms. Together, these two loci act in an additive manner to increase the susceptibility of YBR mice to the development of high IOP. The chromosome 17 locus is important not only because it causes IOP elevation in mice with largely open drainage angles but also because it exacerbates IOP elevation and glaucoma induced by pigment dispersion. Therefore, YBR mice are a valuable resource for studying the genetic etiology of IOP elevation and glaucoma, as well as for testing new treatments.

  17. Danon’s disease as a cause of hypertrophic cardiomyopathy

    Directory of Open Access Journals (Sweden)

    I. V. Leontyeva

    2015-01-01

    Full Text Available Hypertrophic cardiomyopathy is the most common inherited disease of the myocardium. The causes of the disease are heterogeneous; its primary form results from mutations in the genes encoding cardiac sarcomeric proteins; its secondary (metabolic and syndromic forms develop due to mutations in the genes encoding non-sarcomeric proteins. Glycogenosis is the most common cause of the metabolic ones of hypertrophic cardiomyopathy. Danon’s disease (lysosome-associated membrane protein 2 (LAMP2-cardiomyopathy is a form of glycogenosis and it is characterized by a typical triad: hypertrophic cardiomyopathy, mental retardation, and skeletal myopathy. The disease occurs with mutations in the LAMP2 gene; X-linked dominant inheritance. LAMP2-cardiomyopathy does not virtually differ in its clinical manifestations from the severe form of hypertrophic cardiomyopathy, which results from mutations in the sarcomeric protein genes. The disease is characterized by a poor progressive course with the high probability of causing sudden death or with the progression of severe heart failure. Implantation of a cardioverter defibrillator is a main method to prevent sudden cardiac death. 

  18. Insertional engineering of chromosomes with Sleeping Beauty transposition: an overview.

    Science.gov (United States)

    Grabundzija, Ivana; Izsvák, Zsuzsanna; Ivics, Zoltán

    2011-01-01

    Novel genetic tools and mutagenesis strategies based on the Sleeping Beauty (SB) transposable element are currently under development with a vision to link primary DNA sequence information to gene functions in vertebrate models. By virtue of its inherent capacity to insert into DNA, the SB transposon can be developed into powerful tools for chromosomal manipulations. Mutagenesis screens based on SB have numerous advantages including high throughput and easy identification of mutated alleles. Forward genetic approaches based on insertional mutagenesis by engineered SB transposons have the advantage of providing insight into genetic networks and pathways based on phenotype. Indeed, the SB transposon has become a highly instrumental tool to induce tumors in experimental animals in a tissue-specific -manner with the aim of uncovering the genetic basis of diverse cancers. Here, we describe a battery of mutagenic cassettes that can be applied in conjunction with SB transposon vectors to mutagenize genes, and highlight versatile experimental strategies for the generation of engineered chromosomes for loss-of-function as well as gain-of-function mutagenesis for functional gene annotation in vertebrate models.

  19. Diabetes-causing gene, kruppel-like factor 11, modulates the antinociceptive response of chronic ethanol intake.

    Science.gov (United States)

    Ou, Xiao-Ming; Udemgba, Chinelo; Wang, Niping; Dai, Xiaoli; Lomberk, Gwen; Seo, Seungmae; Urrutia, Raul; Wang, Junming; Duncan, Jeremy; Harris, Sharonda; Fairbanks, Carolyn A; Zhang, Xiao

    2014-02-01

    Alcohol (EtOH [ethanol]) is an antinociceptive agent, working in part, by reducing sensitivity to painful stimuli. The transcription factor Kruppel-like factor 11 (KLF11), a human diabetes-causing gene that also regulates the neurotransmitter metabolic enzymes monoamine oxidase (MAO), has recently been identified as an EtOH-inducible gene. However, its role in antinociception remains unknown. Consequently, we investigated the function of KLF11 in chronic EtOH-induced antinociception using a genetically engineered knockout mouse model. Wild-type (Klf11(+/+) ) and KLF11 knockout (Klf11(-/-) ) mice were fed a liquid diet containing EtOH for 28 days with increasing amounts of EtOH from 0% up to a final concentration of 6.4%, representing a final diet containing 36% of calories primarily from EtOH. Control mice from both genotypes were fed liquid diet without EtOH for 28 days. The EtOH-induced antinociceptive effect was determined using the tail-flick test before and after EtOH exposure (on day 29). In addition, the enzyme activity and mRNA levels of MAO A and MAO B were measured by real-time RT-PCR and enzyme assays, respectively. EtOH produced an antinociceptive response to thermal pain in Klf11(+/+) mice, as expected. In contrast, deletion of KLF11 in the Klf11(-/-) mice abolished the EtOH-induced antinociceptive effect. The mRNA and protein levels of KLF11 were significantly increased in the brain prefrontal cortex of Klf11(+/+) mice exposed to EtOH compared with control Klf11(+/+) mice. Furthermore, MAO enzyme activities were affected differently in Klf11 wild-type versus Klf11 knockout mice exposed to chronic EtOH. Chronic EtOH intake significantly increased MAO B activity in Klf11(+/+) mice. The data show KLF11 modulation of EtOH-induced antinociception. The KLF11-targeted MAO B enzyme may contribute more significantly to EtOH-induced antinociception. Thus, this study revealed a new role for the KLF11 gene in the mechanisms underlying the antinociceptive

  20. Targeting Herpetic Keratitis by Gene Therapy

    Directory of Open Access Journals (Sweden)

    Hossein Mostafa Elbadawy

    2012-01-01

    Full Text Available Ocular gene therapy is rapidly becoming a reality. By November 2012, approximately 28 clinical trials were approved to assess novel gene therapy agents. Viral infections such as herpetic keratitis caused by herpes simplex virus 1 (HSV-1 can cause serious complications that may lead to blindness. Recurrence of the disease is likely and cornea transplantation, therefore, might not be the ideal therapeutic solution. This paper will focus on the current situation of ocular gene therapy research against herpetic keratitis, including the use of viral and nonviral vectors, routes of delivery of therapeutic genes, new techniques, and key research strategies. Whereas the correction of inherited diseases was the initial goal of the field of gene therapy, here we discuss transgene expression, gene replacement, silencing, or clipping. Gene therapy of herpetic keratitis previously reported in the literature is screened emphasizing candidate gene therapy targets. Commonly adopted strategies are discussed to assess the relative advantages of the protective therapy using antiviral drugs and the common gene therapy against long-term HSV-1 ocular infections signs, inflammation and neovascularization. Successful gene therapy can provide innovative physiological and pharmaceutical solutions against herpetic keratitis.

  1. Meta-Analysis of Transcriptional Responses to Mastitis-Causing Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Sidra Younis

    Full Text Available Bovine mastitis is a widespread disease in dairy cows, and is often caused by bacterial mammary gland infection. Mastitis causes reduced milk production and leads to excessive use of antibiotics. We present meta-analysis of transcriptional profiles of bovine mastitis from 10 studies and 307 microarrays, allowing identification of much larger sets of affected genes than any individual study. Combining multiple studies provides insight into the molecular effects of Escherichia coli infection in vivo and uncovers differences between the consequences of E. coli vs. Staphylococcus aureus infection of primary mammary epithelial cells (PMECs. In udders, live E. coli elicits inflammatory and immune defenses through numerous cytokines and chemokines. Importantly, E. coli infection causes downregulation of genes encoding lipid biosynthesis enzymes that are involved in milk production. Additionally, host metabolism is generally suppressed. Finally, defensins and bacteria-recognition genes are upregulated, while the expression of the extracellular matrix protein transcripts is silenced. In PMECs, heat-inactivated E. coli elicits expression of ribosomal, cytoskeletal and angiogenic signaling genes, and causes suppression of the cell cycle and energy production genes. We hypothesize that heat-inactivated E. coli may have prophylactic effects against mastitis. Heat-inactivated S. aureus promotes stronger inflammatory and immune defenses than E. coli. Lipopolysaccharide by itself induces MHC antigen presentation components, an effect not seen in response to E. coli bacteria. These results provide the basis for strategies to prevent and treat mastitis and may lead to the reduction in the use of antibiotics.

  2. L1-mediated retrotransposition of murine B1 and B2 SINEs recapitulated in cultured cells.

    Science.gov (United States)

    Dewannieux, Marie; Heidmann, Thierry

    2005-06-03

    SINEs are short interspersed nucleotide elements with transpositional activity, present at a high copy number (up to a million) in mammalian genomes. They are 80-400 bp long, non-coding sequences which derive either from the 7SL RNA (e.g. human Alus, murine B1s) or tRNA (e.g. murine B2s) polymerase III-driven genes. We have previously demonstrated that Alus very efficiently divert the enzymatic machinery of the autonomous L1 LINE (long interspersed nucleotide element) retrotransposons to transpose at a high rate. Here we show, using an ex vivo assay for transposition, that both B1 and B2 SINEs can be mobilized by murine LINEs, with the hallmarks of a bona fide retrotransposition process, including target site duplications of varying lengths and integrations into A-rich sequences. Despite different phylogenetic origins, transposition of the tRNA-derived B2 sequences is as efficient as that of the human Alus, whereas that of B1s is 20-100-fold lower despite a similar high copy number of these elements in the mouse genome. We provide evidence, via an appropriate nucleotide substitution within the B1 sequence in a domain essential for its intracellular targeting, that the current B1 SINEs are not optimal for transposition, a feature most probably selected for the host sake in the course of evolution.

  3. New insights into the evolutionary origins of the recombination-activating gene proteins and V(D)J recombination.

    Science.gov (United States)

    Carmona, Lina Marcela; Schatz, David G

    2017-06-01

    The adaptive immune system of jawed vertebrates relies on V(D)J recombination as one of the main processes to generate the diverse array of receptors necessary for the recognition of a wide range of pathogens. The DNA cleavage reaction necessary for the assembly of the antigen receptor genes from an array of potential gene segments is mediated by the recombination-activating gene proteins RAG1 and RAG2. The RAG proteins have been proposed to originate from a transposable element (TE) as they share mechanistic and structural similarities with several families of transposases and are themselves capable of mediating transposition. A number of RAG-like proteins and TEs with sequence similarity to RAG1 and RAG2 have been identified, but only recently has their function begun to be characterized, revealing mechanistic links to the vertebrate RAGs. Of particular significance is the discovery of ProtoRAG, a transposon superfamily found in the genome of the basal chordate amphioxus. ProtoRAG has many of the sequence and mechanistic features predicted for the ancestral RAG transposon and is likely to be an evolutionary relative of RAG1 and RAG2. In addition, early observations suggesting that RAG1 is able to mediate V(D)J recombination in the absence of RAG2 have been confirmed, implying independent evolutionary origins for the two RAG genes. Here, recent progress in identifying and characterizing RAG-like proteins and the TEs that encode them is summarized and a refined model for the evolution of V(D)J recombination and the RAG proteins is presented. © 2016 Federation of European Biochemical Societies.

  4. A PiggyBac-mediated approach for muscle gene transfer or cell therapy

    Directory of Open Access Journals (Sweden)

    Déborah Ley

    2014-11-01

    Full Text Available An emerging therapeutic approach for Duchenne muscular dystrophy is the transplantation of autologous myogenic progenitor cells genetically modified to express dystrophin. The use of this approach is challenged by the difficulty in maintaining these cells ex vivo while keeping their myogenic potential, and ensuring sufficient transgene expression following their transplantation and myogenic differentiation in vivo. We investigated the use of the piggyBac transposon system to achieve stable gene expression when transferred to cultured mesoangioblasts and into murine muscles. Without selection, up to 8% of the mesoangioblasts expressed the transgene from 1 to 2 genomic copies of the piggyBac vector. Integration occurred mostly in intergenic genomic DNA and transgene expression was stable in vitro. Intramuscular transplantation of mouse Tibialis anterior muscles with mesoangioblasts containing the transposon led to sustained myofiber GFP expression in vivo. In contrast, the direct electroporation of the transposon-donor plasmids in the mouse Tibialis muscles in vivo did not lead to sustained transgene expression despite molecular evidence of piggyBac transposition in vivo. Together these findings provide a proof-of-principle that piggyBac transposon may be considered for mesoangioblast cell-based therapies of muscular dystrophies.

  5. Dialysis Arteriovenous Fistula Failure and Angioplasty: Intimal Hyperplasia and Other Causes of Access Failure

    Science.gov (United States)

    Duque, Juan C.; Tabbara, Marwan; Martinez, Laisel; Cardona, Jose; Vazquez-Padron, Roberto I; Salman, Loay H

    2016-01-01

    Arteriovenous fistula (AVF) is the preferred hemodialysis access type because it has better patency rates and fewer complications than other access types. However, primary failure remains a common problem impeding AVF maturation and adding to patients’ morbidity and mortality. Juxta-anastomotic (or inflow) stenosis is the most common reason leading to primary failure, and percutaneous transluminal angioplasty (PTA) continues to be the gold standard treatment with excellent success rates. Intimal hyperplasia (IH) has been traditionally blamed as the main pathophysiologic culprit, but new evidence raises doubts regarding the contribution of IH alone to primary failure. We report a 64-year-old man with a two-stage brachio-basilic AVF that was complicated by failure four months after creation. Angiogram showed multiple juxta-anastomotic and mid-fistula stenotic lesions. PTA was successful in assisting maturation and subsequently cannulating AVF for hemodialysis treatment. We failed to identify the underlying cause of stenosis as biopsy specimens from fistula tissue obtained at the time of transposition revealed no occlusive IH. This case emphasizes the need for additional research on factors contributing to AVF failure besides IH, and highlights the need for more therapeutic options to reduce AVF failure rate. PMID:28084215

  6. Homozygous mutation in the NPHP3 gene causing foetal nephronophthisis

    DEFF Research Database (Denmark)

    Abdullah, Uzma; Farooq, Muhammad; Fatima, Ambrin

    2017-01-01

    We present a case of a foetal sonographic finding of hyper-echogenic kidneys, which led to a strategic series of genetic tests and identified a homozygous mutation (c.424C > T, p. R142*) in the NPHP3 gene. Our study provides a rare presentation of NPHP3-related ciliopathy and adds to the mutation...

  7. In silico analysis of miRNA-mediated gene regulation in OCA and OA genes.

    Science.gov (United States)

    Kamaraj, Balu; Gopalakrishnan, Chandrasekhar; Purohit, Rituraj

    2014-12-01

    Albinism is an autosomal recessive genetic disorder due to low secretion of melanin. The oculocutaneous albinism (OCA) and ocular albinism (OA) genes are responsible for melanin production and also act as a potential targets for miRNAs. The role of miRNA is to inhibit the protein synthesis partially or completely by binding with the 3'UTR of the mRNA thus regulating gene expression. In this analysis, we predicted the genetic variation that occurred in 3'UTR of the transcript which can be a reason for low melanin production thus causing albinism. The single nucleotide polymorphisms (SNPs) in 3'UTR cause more new binding sites for miRNA which binds with mRNA which leads to inhibit the translation process either partially or completely. The SNPs in the mRNA of OCA and OA genes can create new binding sites for miRNA which may control the gene expression and lead to hypopigmentation. We have developed a computational procedure to determine the SNPs in the 3'UTR region of mRNA of OCA (TYR, OCA2, TYRP1 and SLC45A2) and OA (GPR143) genes which will be a potential cause for albinism. We identified 37 SNPs in five genes that are predicted to create 87 new binding sites on mRNA, which may lead to abrogation of the translation process. Expression analysis confirms that these genes are highly expressed in skin and eye regions. It is well supported by enrichment analysis that these genes are mainly involved in eye pigmentation and melanin biosynthesis process. The network analysis also shows how the genes are interacting and expressing in a complex network. This insight provides clue to wet-lab researches to understand the expression pattern of OCA and OA genes and binding phenomenon of mRNA and miRNA upon mutation, which is responsible for inhibition of translation process at genomic levels.

  8. Common Variable Immunodeficiency Caused by FANC Mutations.

    Science.gov (United States)

    Sekinaka, Yujin; Mitsuiki, Noriko; Imai, Kohsuke; Yabe, Miharu; Yabe, Hiromasa; Mitsui-Sekinaka, Kanako; Honma, Kenichi; Takagi, Masatoshi; Arai, Ayako; Yoshida, Kenichi; Okuno, Yusuke; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Muramatsu, Hideki; Kojima, Seiji; Hira, Asuka; Takata, Minoru; Ohara, Osamu; Ogawa, Seishi; Morio, Tomohiro; Nonoyama, Shigeaki

    2017-07-01

    Common variable immunodeficiency (CVID) is the most common adult-onset primary antibody deficiency disease due to various causative genes. Several genes, which are known to be the cause of different diseases, have recently been reported as the cause of CVID in patients by performing whole exome sequencing (WES) analysis. Here, we found FANC gene mutations as a cause of adult-onset CVID in two patients. B cells were absent and CD4 + T cells were skewed toward CD45RO + memory T cells. T-cell receptor excision circles (TRECs) and signal joint kappa-deleting recombination excision circles (sjKRECs) were undetectable in both patients. Both patients had no anemia, neutropenia, or thrombocytopenia. Using WES, we identified compound heterozygous mutations of FANCE in one patient and homozygous mutation of FANCA in another patient. The impaired function of FANC protein complex was confirmed by a monoubiquitination assay and by chromosome fragility test. We then performed several immunological evaluations including quantitative lymphocyte analysis and TRECs/sjKRECs analysis for 32 individuals with Fanconi anemia (FA). In total, 22 FA patients (68.8%) were found to have immunological abnormalities, suggesting that such immunological findings may be common in FA patients. These data indicate that FANC mutations are involved in impaired lymphogenesis probably by the accumulation of DNA replication stress, leading to CVID. It is important to diagnose FA because it drastically changes clinical management. We propose that FANC mutations can cause isolated immunodeficiency in addition to bone marrow failure and malignancy.

  9. Subinhibitory concentrations of antibiotics affect stress and virulence gene expression in Listeria monocytogenes and cause enhanced stress sensitivity but do not affect Caco‐2 cell invasion

    DEFF Research Database (Denmark)

    Knudsen, Gitte Maegaard; Holch, Anne; Gram, Lone

    2012-01-01

    with promoter fusions, 14 of 16 antibiotics induced or repressed expression of one or more stress and/or virulence genes. Despite ampicillin‐induced up‐regulation of PinlA‐lacZ expression, Caco‐2 cell invasion was not affected. Subinhibitory concentrations of ampicillin and tetracycline caused up‐ and down...

  10. The complete chloroplast genome sequences of Lychnis wilfordii and Silene capitata and comparative analyses with other Caryophyllaceae genomes.

    Science.gov (United States)

    Kang, Jong-Soo; Lee, Byoung Yoon; Kwak, Myounghai

    2017-01-01

    The complete chloroplast genomes of Lychnis wilfordii and Silene capitata were determined and compared with ten previously reported Caryophyllaceae chloroplast genomes. The chloroplast genome sequences of L. wilfordii and S. capitata contain 152,320 bp and 150,224 bp, respectively. The gene contents and orders among 12 Caryophyllaceae species are consistent, but several microstructural changes have occurred. Expansion of the inverted repeat (IR) regions at the large single copy (LSC)/IRb and small single copy (SSC)/IR boundaries led to partial or entire gene duplications. Additionally, rearrangements of the LSC region were caused by gene inversions and/or transpositions. The 18 kb inversions, which occurred three times in different lineages of tribe Sileneae, were thought to be facilitated by the intermolecular duplicated sequences. Sequence analyses of the L. wilfordii and S. capitata genomes revealed 39 and 43 repeats, respectively, including forward, palindromic, and reverse repeats. In addition, a total of 67 and 56 simple sequence repeats were discovered in the L. wilfordii and S. capitata chloroplast genomes, respectively. Finally, we constructed phylogenetic trees of the 12 Caryophyllaceae species and two Amaranthaceae species based on 73 protein-coding genes using both maximum parsimony and likelihood methods.

  11. Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility.

    Science.gov (United States)

    Nuttle, Xander; Giannuzzi, Giuliana; Duyzend, Michael H; Schraiber, Joshua G; Narvaiza, Iñigo; Sudmant, Peter H; Penn, Osnat; Chiatante, Giorgia; Malig, Maika; Huddleston, John; Benner, Chris; Camponeschi, Francesca; Ciofi-Baffoni, Simone; Stessman, Holly A F; Marchetto, Maria C N; Denman, Laura; Harshman, Lana; Baker, Carl; Raja, Archana; Penewit, Kelsi; Janke, Nicolette; Tang, W Joyce; Ventura, Mario; Banci, Lucia; Antonacci, Francesca; Akey, Joshua M; Amemiya, Chris T; Gage, Fred H; Reymond, Alexandre; Eichler, Evan E

    2016-08-11

    Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. Here we reconstruct the evolutionary history of the locus and identify bolA family member 2 (BOLA2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95-kilobase-pair segment containing BOLA2 duplicated across the critical region approximately 282 thousand years ago (ka), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carried one or more copies of the duplication, which nearly fixed early in the human lineage--a pattern unlikely to have arisen so rapidly in the absence of selection (P sapiens-specific duplication. In summary, the duplicative transposition of BOLA2 at the root of the H. sapiens lineage about 282 ka simultaneously increased copy number of a gene associated with iron homeostasis and predisposed our species to recurrent rearrangements associated with disease.

  12. A novel A792D mutation in the CSF1R gene causes hereditary diffuse leukoencephalopathy with axonal spheroids characterized by slow progression

    Directory of Open Access Journals (Sweden)

    Sakiho Ueda

    2015-03-01

    Full Text Available Hereditary diffuse leukoencephalopathy with spheroids (HDLS is an autosomal dominant white matter disease that causes adult-onset cognitive impairment. The clinical manifestations are a variable combination of personality and behavioral changes, cognitive decline, parkinsonism, spasticity, and epilepsy. In 2012, mutations in the gene encoding colony stimulating factor 1 receptor (CSF1R were identified as the cause of HDLS. As the numbers of reported mutations are limited, the understanding of whole pathogenesis needs accumulation of disease-causing mutations with detailed clinical descriptions. We describe a Japanese family with autosomal dominant adult-onset cognitive impairment and characteristic white matter lesions. Genetic testing revealed a novel p.A792D mutation in the tyrosine kinase domain of CSF1R in two affected family members. The symptom profile of the present cases mostly matched the previously reported cases, with the notable exceptions of late-onset and long disease duration.

  13. Emergence of a Staphylococcus aureus Clone Resistant to Mupirocin and Fusidic Acid Carrying Exotoxin Genes and Causing Mainly Skin Infections.

    Science.gov (United States)

    Doudoulakakis, Anastassios; Spiliopoulou, Iris; Spyridis, Nikolaos; Giormezis, Nikolaos; Kopsidas, John; Militsopoulou, Maria; Lebessi, Evangelia; Tsolia, Maria

    2017-08-01

    Skin and soft tissue infections (SSTIs) caused by mupirocin-resistant Staphylococcus aureus strains have recently increased in number in our settings. We sought to evaluate the characteristics of these cases over a 43-month period. Data for all community-acquired staphylococcal infections caused by mupirocin-resistant strains were retrospectively reviewed. Genes encoding products producing high-level resistance (HLR) to mupirocin ( mupA ), fusidic acid resistance ( fusB ), resistance to macrolides and lincosamides ( ermC and ermA ), Panton-Valentine leukocidin (PVL) ( lukS/lukF -PV), exfoliative toxins ( eta and etb ), and fibronectin binding protein A ( fnbA ) were investigated by PCRs in 102 selected preserved strains. Genotyping was performed by SCC mec and agr typing, whereas clonality was determined by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). A total of 437 cases among 2,137 staphylococcal infections were recorded in 2013 to 2016; they were all SSTIs with the exception of 1 case of primary bacteremia. Impetigo was the predominant clinical entity (371 cases [84.9%]), followed by staphylococcal scalded skin syndrome (21 cases [4.8%]), and there were no abscesses. The number of infections detected annually increased during the study years. All except 3 isolates were methicillin susceptible. The rates of HLR to mupirocin and constitutive resistance to clindamycin were 99% and 20.1%, respectively. Among the 102 tested strains, 100 (98%) were mupA positive and 97 (95%) were fusB positive, 26/27 clindamycin-resistant strains (96.3%) were ermA positive, 83 strains (81.4%) were lukS/lukF positive, 95 (93%) carried both eta and etb genes, and 99 (97%) were fnbA positive. Genotyping of methicillin-sensitive S. aureus (MSSA) strains revealed that 96/99 (96.7%) belonged to one main pulsotype, pulsotype 1, classified as sequence type 121 (ST121). The emergence of a single MSSA clone (ST121) causing impetigo was documented. Resistance to

  14. A mutation in the MATP gene causes the cream coat colour in the horse

    Directory of Open Access Journals (Sweden)

    Guérin Gérard

    2003-01-01

    Full Text Available Abstract In horses, basic colours such as bay or chestnut may be partially diluted to buckskin and palomino, or extremely diluted to cream, a nearly white colour with pink skin and blue eyes. This dilution is expected to be controlled by one gene and we used both candidate gene and positional cloning strategies to identify the "cream mutation". A horse panel including reference colours was established and typed for different markers within or in the neighbourhood of two candidate genes. Our data suggest that the causal mutation, a G to A transition, is localised in exon 2 of the MATP gene leading to an aspartic acid to asparagine substitution in the encoded protein. This conserved mutation was also described in mice and humans, but not in medaka.

  15. Genetic defect causing familial Alzheimer's disease maps on chromosome 21

    Energy Technology Data Exchange (ETDEWEB)

    St. George-Hyslop, P.H.; Tanzi, R.E.; Polinsky, R.J.; Haines, J.L.; Nee, L.; Watkins, P.C.; Myers, R.H.; Feldman, R.G.; Pollen, D.; Drachman, D.; Growdon, J.

    1987-02-20

    Alzheimer's disease is a leading cause of morbidity and mortality among the elderly. Several families have been described in which Alzheimer's disease is caused by an autosomal dominant gene defect. The chromosomal location of this defective gene has been discovered by using genetic linkage to DNA markers on chromosome 21. The localization on chromosome 21 provides an explanation for the occurrence of Alzheimer's disease-like pathology in Down syndrome. Isolation and characterization of the gene at this locus may yield new insights into the nature of the defect causing familial Alzheimer's disease and possibly, into the etiology of all forms of Alzheimer's disease.

  16. Indemnisation des dommages résultant de soins de santé. Phase V : impact budgétaire de la transposition du système français en Belgique

    OpenAIRE

    Yerna, Benoît-Laurent; Maréchal, Xavier; Denuit, Michel; Closon, Jean-Pierre; Vinck, Imgard

    2009-01-01

    L’objectif de la présente étude consiste, d’une part, à décrire le système français d’indemnisation des victimes de dommages médicaux et, d’autre part, à calculer l’impact budgétaire de la transposition d’un tel système en Belgique. Les spécificités du système qui sera introduit en Belgique n’étant pas connues au moment de l’étude, le coût a été calculé sur la base des modalités du système en vigueur en France. Les statistiques françaises de fréquences des différents types de dommages (infect...

  17. A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene.

    Science.gov (United States)

    Bitner-Glindzicz, M; Lindley, K J; Rutland, P; Blaydon, D; Smith, V V; Milla, P J; Hussain, K; Furth-Lavi, J; Cosgrove, K E; Shepherd, R M; Barnes, P D; O'Brien, R E; Farndon, P A; Sowden, J; Liu, X Z; Scanlan, M J; Malcolm, S; Dunne, M J; Aynsley-Green, A; Glaser, B

    2000-09-01

    Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, vestibular hypofunction and childhood onset retinitis pigmentosa. It is an autosomal recessive condition and is subdivided on the basis of linkage analysis into types 1A through 1E. Usher type 1C maps to the region containing the genes ABCC8 and KCNJ11 (encoding components of ATP-sensitive K + (KATP) channels), which may be mutated in patients with hyperinsulinism. We identified three individuals from two consanguineous families with severe hyperinsulinism, profound congenital sensorineural deafness, enteropathy and renal tubular dysfunction. The molecular basis of the disorder is a homozygous 122-kb deletion of 11p14-15, which includes part of ABCC8 and overlaps with the locus for Usher syndrome type 1C and DFNB18. The centromeric boundary of this deletion includes part of a gene shown to be mutated in families with type 1C Usher syndrome, and is hence assigned the name USH1C. The pattern of expression of the USH1C protein is consistent with the clinical features exhibited by individuals with the contiguous gene deletion and with isolated Usher type 1C.

  18. Validation of reference genes for quantifying changes in gene expression in virus-infected tobacco.

    Science.gov (United States)

    Baek, Eseul; Yoon, Ju-Yeon; Palukaitis, Peter

    2017-10-01

    To facilitate quantification of gene expression changes in virus-infected tobacco plants, eight housekeeping genes were evaluated for their stability of expression during infection by one of three systemically-infecting viruses (cucumber mosaic virus, potato virus X, potato virus Y) or a hypersensitive-response-inducing virus (tobacco mosaic virus; TMV) limited to the inoculated leaf. Five reference-gene validation programs were used to establish the order of the most stable genes for the systemically-infecting viruses as ribosomal protein L25 > β-Tubulin > Actin, and the least stable genes Ubiquitin-conjugating enzyme (UCE) genes were EF1α > Cysteine protease > Actin, and the least stable genes were GAPDH genes, three defense responsive genes were examined to compare their relative changes in gene expression caused by each virus. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Systemic right ventricular fibrosis detected by cardiovascular magnetic resonance is associated with clinical outcome, mainly new-onset atrial arrhythmia, in patients after atrial redirection surgery for transposition of the great arteries.

    Science.gov (United States)

    Rydman, Riikka; Gatzoulis, Michael A; Ho, Siew Yen; Ernst, Sabine; Swan, Lorna; Li, Wei; Wong, Tom; Sheppard, Mary; McCarthy, Karen P; Roughton, Michael; Kilner, Philip J; Pennell, Dudley J; Babu-Narayan, Sonya V

    2015-05-01

    We hypothesized that fibrosis detected by late gadolinium enhancement (LGE) cardiovascular magnetic resonance predicts outcomes in patients with transposition of the great arteries post atrial redirection surgery. These patients have a systemic right ventricle (RV) and are at risk of arrhythmia, premature RV failure, and sudden death. Fifty-five patients (aged 27±7 years) underwent LGE cardiovascular magnetic resonance and were followed for a median 7.8 (interquartile range, 3.8-9.6) years in a prospective single-center cohort study. RV LGE was present in 31 (56%) patients. The prespecified composite clinical end point comprised new-onset sustained tachyarrhythmia (atrial/ventricular) or decompensated heart failure admission/transplantation/death. Univariate predictors of the composite end point (n=22 patients; 19 atrial/2 ventricular tachyarrhythmia, 1 death) included RV LGE presence and extent, RV volumes/mass/ejection fraction, right atrial area, peak Vo(2), and age at repair. In bivariate analysis, RV LGE presence was independently associated with the composite end point (hazard ratio, 4.95 [95% confidence interval, 1.60-15.28]; P=0.005), and only percent predicted peak Vo(2) remained significantly associated with cardiac events after controlling for RV LGE (hazard ratio, 0.80 [95% confidence interval, 0.68-0.95]; P=0.009/5%). In 8 of 9 patients with >1 event, atrial tachyarrhythmia, itself a known risk factor for mortality, occurred first. There was agreement between location and extent of RV LGE at in vivo cardiovascular magnetic resonance and histologically documented focal RV fibrosis in an explanted heart. There was RV LGE progression in a different case restudied for clinical indications. Systemic RV LGE is strongly associated with adverse clinical outcome especially arrhythmia in transposition of the great arteries, thus LGE cardiovascular magnetic resonance should be incorporated in risk stratification of these patients. © 2015 American Heart

  20. A Hybrid CFHR3-1 Gene Causes Familial C3 Glomerulopathy.

    LENUS (Irish Health Repository)

    Malik, Talat H

    2012-07-01

    Controlled activation of the complement system, a key component of innate immunity, enables destruction of pathogens with minimal damage to host tissue. Complement factor H (CFH), which inhibits complement activation, and five CFH-related proteins (CFHR1-5) compose a family of structurally related molecules. Combined deletion of CFHR3 and CFHR1 is common and confers a protective effect in IgA nephropathy. Here, we report an autosomal dominant complement-mediated GN associated with abnormal increases in copy number across the CFHR3 and CFHR1 loci. In addition to normal copies of these genes, affected individuals carry a unique hybrid CFHR3-1 gene. In addition to identifying an association between these genetic observations and complement-mediated kidney disease, these results provide insight into the protective role of the combined deletion of CFHR3 and CFHR1 in IgA nephropathy.