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Sample records for 8-oxoguanine-repair-deficient mutator phenotype

  1. A MATE-family efflux pump rescues the Escherichia coli 8-oxoguanine-repair-deficient mutator phenotype and protects against H(2O(2 killing.

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    Javier R Guelfo

    2010-05-01

    Full Text Available Hypermutation may accelerate bacterial evolution in the short-term. In the long-term, however, hypermutators (cells with an increased rate of mutation can be expected to be at a disadvantage due to the accumulation of deleterious mutations. Therefore, in theory, hypermutators are doomed to extinction unless they compensate the elevated mutational burden (deleterious load. Different mechanisms capable of restoring a low mutation rate to hypermutators have been proposed. By choosing an 8-oxoguanine-repair-deficient (GO-deficient Escherichia coli strain as a hypermutator model, we investigated the existence of genes able to rescue the hypermutable phenotype by multicopy suppression. Using an in vivo-generated mini-MudII4042 genomic library and a mutator screen, we obtained chromosomal fragments that decrease the rate of mutation in a mutT-deficient strain. Analysis of a selected clone showed that the expression of NorM is responsible for the decreased mutation rate in 8-oxoguanine-repair-deficient (mutT, mutY, and mutM mutY strains. NorM is a member of the multidrug and toxin extrusion (MATE family of efflux pumps whose role in E. coli cell physiology remains unknown. Our results indicate that NorM may act as a GO-system backup decreasing AT to CG and GC to TA transversions. In addition, the ability of NorM to reduce the level of intracellular reactive oxygen species (ROS in a GO-deficient strain and protect the cell from oxidative stress, including protein carbonylation, suggests that it can extrude specific molecules-byproducts of bacterial metabolism-that oxidize the guanine present in both DNA and nucleotide pools. Altogether, our results indicate that NorM protects the cell from specific ROS when the GO system cannot cope with the damage.

  2. The Evolutionary Potential of Phenotypic Mutations.

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    Yanagida, Hayato; Gispan, Ariel; Kadouri, Noam; Rozen, Shelly; Sharon, Michal; Barkai, Naama; Tawfik, Dan S

    2015-08-01

    Errors in protein synthesis, so-called phenotypic mutations, are orders-of-magnitude more frequent than genetic mutations. Here, we provide direct evidence that alternative protein forms and phenotypic variability derived from translational errors paved the path to genetic, evolutionary adaptations via gene duplication. We explored the evolutionary origins of Saccharomyces cerevisiae IDP3 - an NADP-dependent isocitrate dehydrogenase mediating fatty acids ß-oxidation in the peroxisome. Following the yeast whole genome duplication, IDP3 diverged from a cytosolic ancestral gene by acquisition of a C-terminal peroxisomal targeting signal. We discovered that the pre-duplicated cytosolic IDPs are partially localized to the peroxisome owing to +1 translational frameshifts that bypass the stop codon and unveil cryptic peroxisomal targeting signals within the 3'-UTR. Exploring putative cryptic signals in all 3'-UTRs of yeast genomes, we found that other enzymes related to NADPH production such as pyruvate carboxylase 1 (PYC1) might be prone to peroxisomal localization via cryptic signals. Using laboratory evolution we found that these translational frameshifts are rapidly imprinted via genetic single base deletions occurring within the very same gene location. Further, as exemplified here, the sequences that promote translational frameshifts are also more prone to genetic deletions. Thus, genotypes conferring higher phenotypic variability not only meet immediate challenges by unveiling cryptic 3'-UTR sequences, but also boost the potential for future genetic adaptations.

  3. Volatility of Mutator Phenotypes at Single Cell Resolution.

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    Scott R Kennedy

    2015-04-01

    Full Text Available Mutator phenotypes accelerate the evolutionary process of neoplastic transformation. Historically, the measurement of mutation rates has relied on scoring the occurrence of rare mutations in target genes in large populations of cells. Averaging mutation rates over large cell populations assumes that new mutations arise at a constant rate during each cell division. If the mutation rate is not constant, an expanding mutator population may contain subclones with widely divergent rates of evolution. Here, we report mutation rate measurements of individual cell divisions of mutator yeast deficient in DNA polymerase ε proofreading and base-base mismatch repair. Our data are best fit by a model in which cells can assume one of two distinct mutator states, with mutation rates that differ by an order of magnitude. In error-prone cell divisions, mutations occurred on the same chromosome more frequently than expected by chance, often in DNA with similar predicted replication timing, consistent with a spatiotemporal dimension to the hypermutator state. Mapping of mutations onto predicted replicons revealed that mutations were enriched in the first half of the replicon as well as near termination zones. Taken together, our findings show that individual genome replication events exhibit an unexpected volatility that may deepen our understanding of the evolution of mutator-driven malignancies.

  4. IDH Mutations: Genotype-Phenotype Correlation and Prognostic Impact

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    Xiao-Wei Wang

    2014-01-01

    Full Text Available IDH1/2 mutation is the most frequent genomic alteration found in gliomas, affecting 40% of these tumors and is one of the earliest alterations occurring in gliomagenesis. We investigated a series of 1305 gliomas and showed that IDH mutation is almost constant in 1p19q codeleted tumors. We found that the distribution of IDH1R132H, IDH1nonR132H, and IDH2 mutations differed between astrocytic, mixed, and oligodendroglial tumors, with an overrepresentation of IDH2 mutations in oligodendroglial phenotype and an overrepresentation of IDH1nonR132H in astrocytic tumors. We stratified grade II and grade III gliomas according to the codeletion of 1p19q and IDH mutation to define three distinct prognostic subgroups: 1p19q and IDH mutated, IDH mutated—which contains mostly TP53 mutated tumors, and none of these alterations. We confirmed that IDH mutation with a hazard ratio = 0.358 is an independent prognostic factor of good outcome. These data refine current knowledge on IDH mutation prognostic impact and genotype-phenotype associations.

  5. Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical phenotype correlations.

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    Emery, Edward C; Habib, Abdella M; Cox, James J; Nicholas, Adeline K; Gribble, Fiona M; Woods, C Geoffrey; Reimann, Frank

    2015-05-20

    The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype-phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies.

  6. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.

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    Gripp, Karen W; Lin, Angela E; Stabley, Deborah L; Nicholson, Linda; Scott, Charles I; Doyle, Daniel; Aoki, Yoko; Matsubara, Yoichi; Zackai, Elaine H; Lapunzina, Pablo; Gonzalez-Meneses, Antonio; Holbrook, Jennifer; Agresta, Cynthia A; Gonzalez, Iris L; Sol-Church, Katia

    2006-01-01

    Costello syndrome is a rare condition comprising mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy, and/or atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities. Recently mutations in HRAS were identified in 12 Japanese and Italian patients with clinical information available on 7 of the Japanese patients. To expand the molecular delineation of Costello syndrome, we performed mutation analysis in 34 North American and 6 European (total 40) patients with Costello syndrome, and detected missense mutations in HRAS in 33 (82.5%) patients. All mutations affected either codon 12 or 13 of the protein product, with G12S occurring in 30 (90.9%) patients of the mutation-positive cases. In two patients, we found a mutation resulting in an alanine substitution in position 12 (G12A), and in one patient, we detected a novel mutation (G13C). Five different HRAS mutations have now been reported in Costello syndrome, however genotype-phenotype correlation remains incomplete.

  7. Polk Mutant Mice Have a Spontaneous Mutator Phenotype

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    Stancel, J. Nicole Kosarek; McDaniel, Lisa D.; Velasco, Susana; Richardson, James; Guo, Caixia; Friedberg, Errol C.

    2009-01-01

    Mice defective in the Polk gene (which encodes DNA polymerase kappa) are viable and do not manifest obvious phenotypes. The present studies document a spontaneous mutator phenotype in Polk−/− mice. The initial indication of enhanced spontaneous mutations in these mice came from the serendipitous observation of a postulated founder mutation that manifested in multiple disease states among a cohort of mice comprising all three possible Polk genotypes. Polk−/− and isogenic wild type controls carrying a reporter transgene (the λ-phage cII gene) were used for subsequent quantitative and qualitative studies on mutagenesis in various tissues. We observed significantly increased mutation frequencies in the kidney, liver, and lung of Polk−/− mice, but not in the spleen or testis. G:C base pairs dominated the mutation spectra of the kidney, liver, and lung. These results are consistent with the notion that Polκ is required for accurate translesion DNA synthesis past naturally occurring polycyclic guanine adducts, possibly generated by cholesterol and/or its metabolites. PMID:19783230

  8. Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum.

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    Moutton, Sébastien; Fergelot, Patricia; Naudion, Sophie; Cordier, Marie-Pierre; Solé, Guilhem; Guerineau, Elodie; Hubert, Christophe; Rooryck, Caroline; Vuillaume, Marie-Laure; Houcinat, Nada; Deforges, Julie; Bouron, Julie; Devès, Sylvie; Le Merrer, Martine; David, Albert; Geneviève, David; Giuliano, Fabienne; Journel, Hubert; Megarbane, André; Faivre, Laurence; Chassaing, Nicolas; Francannet, Christine; Sarrazin, Elisabeth; Stattin, Eva-Lena; Vigneron, Jacqueline; Leclair, Danielle; Abadie, Caroline; Sarda, Pierre; Baumann, Clarisse; Delrue, Marie-Ange; Arveiler, Benoit; Lacombe, Didier; Goizet, Cyril; Coupry, Isabelle

    2016-08-01

    Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.

  9. Phenotypic effect of mutations in evolving populations of RNA molecules

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    Manrubia Susanna C

    2010-02-01

    Full Text Available Abstract Background The secondary structure of folded RNA sequences is a good model to map phenotype onto genotype, as represented by the RNA sequence. Computational studies of the evolution of ensembles of RNA molecules towards target secondary structures yield valuable clues to the mechanisms behind adaptation of complex populations. The relationship between the space of sequences and structures, the organization of RNA ensembles at mutation-selection equilibrium, the time of adaptation as a function of the population parameters, the presence of collective effects in quasispecies, or the optimal mutation rates to promote adaptation all are issues that can be explored within this framework. Results We investigate the effect of microscopic mutations on the phenotype of RNA molecules during their in silico evolution and adaptation. We calculate the distribution of the effects of mutations on fitness, the relative fractions of beneficial and deleterious mutations and the corresponding selection coefficients for populations evolving under different mutation rates. Three different situations are explored: the mutation-selection equilibrium (optimized population in three different fitness landscapes, the dynamics during adaptation towards a goal structure (adapting population, and the behavior under periodic population bottlenecks (perturbed population. Conclusions The ratio between the number of beneficial and deleterious mutations experienced by a population of RNA sequences increases with the value of the mutation rate μ at which evolution proceeds. In contrast, the selective value of mutations remains almost constant, independent of μ, indicating that adaptation occurs through an increase in the amount of beneficial mutations, with little variations in the average effect they have on fitness. Statistical analyses of the distribution of fitness effects reveal that small effects, either beneficial or deleterious, are well described by a Pareto

  10. [Paternal GNAS mutations: Which phenotypes? What genetic counseling?].

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    Kottler, Marie-Laure

    2015-05-01

    Parental imprinting and the type of the genetic alteration play a determinant role in the phenotype expression of GNAS locus associated to pseudohypoparathyroidism (PHP). GNAS locus gives rise to several different messenger RNA transcripts that are derived from the paternal allele, the maternal allele, or both and can be either coding or non-coding. As a consequence, GNAS mutations lead to a wide spectrum of phenotypes. An alteration in the coding sequence of the gene leads to a haplo-insufficiency and a dysmorphic phenotype (Albright's syndrome or AHO). AHO is a clinical syndrome defined by specific physical features including short stature, obesity, round-shaped face, subcutaneous ossifications, brachymetarcapy (mainly of the 4th and 5th ray). If the alteration is on the maternal allele, there is a hormonal resistance to the PTH at the kidney level and to the TSH at the thyroid level. The phenotype is known as pseudohypoparathyroidism type 1a (PHP1a). If the alteration is on the paternal allele, there are few clinical signs with no hormonal resistance and the phenotype is known as pseudopseudo hypoparathyroidism (pseudo-PPHP). Heterozygous GNAS mutations on the paternal GNAS allele were associated with intra uterin growth retardation (IUGR). Moreover, birth weights were lower with paternal GNAS mutations affecting exon 2-13 than with exon 1/intron 1 mutations suggesting a role for loss of function XLαs. Progressive osseous heteroplasia (POH) is a rare disease of ectopic bone formation, characterized by cutaneous and subcutaneous ossifications progressing towards deep connective and muscular tissues. POH is caused by a heterozygous GNAS inactivating mutation and has been associated with paternal inheritance. However, genotype/phenotype correlations suggest that there is no direct correlation between the ossifying process and parental origin, as there is high variability in heterotopic ossification. Clinical heterogeneity makes genetic counseling a very delicate

  11. Phenotype of heterozygotes for low-density lipoprotein receptor mutations identified in different background populations

    DEFF Research Database (Denmark)

    Tybjaerg-Hansen, Anne; Jensen, Henrik Kjaerulf; Benn, Marianne

    2005-01-01

    The effect of mutations on phenotype is often overestimated because of ascertainment bias. We determined the effect of background population on cholesterol phenotype associated with specific mutations in the low-density lipoprotein (LDL) receptor and the relative importance of background population...... and type of mutation (LDL receptor [LDLR] or APOB R3500Q) for cholesterol phenotype....

  12. Phenotypic consequences of a novel SCO2 gene mutation.

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    Verdijk, Rob M; de Krijger, Ronald; Schoonderwoerd, Kees; Tiranti, Valeria; Smeets, Hubert; Govaerts, Lutgarde C P; de Coo, René

    2008-11-01

    SCO2 is a cytochrome c oxidase (COX) assembly gene. Mutations in the SCO2 gene have been associated with fatal infantile cardioencephalomyopathy. We report on the phenotype of a novel SCO2 mutation in two siblings with fatal infantile cardioencephalomyopathy. The index patient died of heart failure at 25 days of age. Muscle biopsy was performed for histology and biochemical study of the oxidative phosphorylation system complexes. The entire coding region of the SCO2 gene was sequenced. Autopsy was performed on the index patient and on a female sibling delivered at 23 weeks of gestation following termination of pregnancy during which amniocentesis and genetic testing had been performed. Muscle biopsy and biochemical analysis of heart and skeletal muscle detected a severe isolated COX-IV deficiency. Pathologic findings in both patients confirmed hypertrophic cardiomyopathy. Sequencing of the SCO2 gene showed compound heterozygous mutation; the common E140K mutation and a novel W36X nonsense mutation. Newborns with a combination of hypotonia and cardiomyopathy should be evaluated for multiple congenital anomaly syndromes, inborn errors of metabolism and mitochondrial derangements, and may require extensive diagnostic testing. Mutations in the SCO2 gene are a cause of prenatal-onset hypertrophic cardiomyopathy.

  13. Amelogenesis Imperfecta: 1 Family, 2 Phenotypes, and 2 Mutated Genes.

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    Prasad, M K; Laouina, S; El Alloussi, M; Dollfus, H; Bloch-Zupan, A

    2016-12-01

    Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterized by enamel defects. The authors have identified a large consanguineous Moroccan family segregating different clinical subtypes of hypoplastic and hypomineralized AI in different individuals within the family. Using targeted next-generation sequencing, the authors identified a novel heterozygous nonsense mutation in COL17A1 (c.1873C>T, p.R625*) segregating with hypoplastic AI and a novel homozygous 8-bp deletion in C4orf26 (c.39_46del, p.Cys14Glyfs*18) segregating with hypomineralized-hypoplastic AI in this family. This study highlights the phenotypic and genotypic heterogeneity of AI that can exist even within a single consanguineous family. Furthermore, the identification of novel mutations in COL17A1 and C4orf26 and their correlation with distinct AI phenotypes can contribute to a better understanding of the pathophysiology of AI and the contribution of these genes to amelogenesis.

  14. Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes.

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    Machida, Keigo; Cheng, Kevin T-N; Sung, Vicky M-H; Shimodaira, Shigetaka; Lindsay, Karen L; Levine, Alexandra M; Lai, Ming-Yang; Lai, Michael M C

    2004-03-23

    Hepatitis C virus (HCV) is a nonretroviral oncogenic RNA virus, which is frequently associated with hepatocellular carcinoma (HCC) and B cell lymphoma. We demonstrated here that acute and chronic HCV infection caused a 5- to 10-fold increase in mutation frequency in Ig heavy chain, BCL-6, p53, and beta-catenin genes of in vitro HCV-infected B cell lines and HCV-associated peripheral blood mononuclear cells, lymphomas, and HCCs. The nucleotide-substitution pattern of p53 and beta-catenin was different from that of Ig heavy chain in HCV-infected cells, suggesting two different mechanisms of mutation. In addition, the mutated protooncogenes were amplified in HCV-associated lymphomas and HCCs, but not in lymphomas of nonviral origin or HBV-associated HCC. HCV induced error-prone DNA polymerase zeta, polymerase iota, and activation-induced cytidine deaminase, which together, contributed to the enhancement of mutation frequency, as demonstrated by the RNA interference experiments. These results indicate that HCV induces a mutator phenotype and may transform cells by a hit-and-run mechanism. This finding provides a mechanism of oncogenesis for an RNA virus.

  15. Association of PRPS1 Mutations with Disease Phenotypes

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    Rahul Mittal

    2015-01-01

    Full Text Available Phosphoribosylpyrophosphate synthetase 1 (PRPS1 codes for PRS-I enzyme that catalyzes the first step of nucleotide synthesis. PRPS1 gene mutations have been implicated in a number of human diseases. Recently, new mutations in PRPS1 have been identified that have been associated with novel phenotypes like diabetes insipidus expanding the spectrum of PRPS1-related diseases. The purpose of this review is to evaluate current literature on PRPS1-related syndromes and summarize potential therapies. The overexpression of PRPS1 results in PRS-I superactivity resulting in purine overproduction. Patients with PRS-I superactivity demonstrate uric acid overproduction, hypotonia, ataxia, neurodevelopment abnormalities, and postlingual hearing impairment. On the other hand, decreased activity leads to X-linked nonsyndromic sensorineural deafness (DFNX-2, Charcot-Marie-Tooth disease-5 (CMTX5, and Arts syndrome depending on the residual activity of PRS-I. Mild PRS-I deficiency (DFNX-2 results in non-syndromic progressive hearing loss whereas moderate PRS-I deficiency (CMTX5 and severe PRS-I deficiency (Arts syndrome present with peripheral or optic neuropathy, prelingual progressive sensorineural hearing loss, and central nervous system impairment. Currently, purine replacement via S-adenosylmethionine (SAM supplementation in patients with Arts syndrome appears to improve their condition. This suggests that SAM supplementation can alleviate symptoms of PRPS1 deficient patients and open new avenues of therapeutic intervention.

  16. Novel Mutations and Mutation Combinations of TMPRSS3 Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment

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    Wang, Guo-Jian; Xu, Jin-Cao; Su, Yu

    2017-01-01

    Autosomal recessive hearing impairment with postlingual onset is rare. Exceptions are caused by mutations in the TMPRSS3 gene, which can lead to prelingual (DFNB10) as well as postlingual deafness (DFNB8). TMPRSS3 mutations can be classified as mild or severe, and the phenotype is dependent on the combination of TMPRSS3 mutations. The combination of two severe mutations leads to profound hearing impairment with a prelingual onset, whereas severe mutations in combination with milder TMPRSS3 mutations lead to a milder phenotype with postlingual onset. We characterized a Chinese family (number FH1523) with not only prelingual but also postlingual hearing impairment. Three mutations in TMPRSS3, one novel mutation c.36delC [p.(Phe13Serfs⁎12)], and two previously reported pathogenic mutations, c.916G>A (p.Ala306Thr) and c.316C>T (p.Arg106Cys), were identified. Compound heterozygous mutations of p.(Phe13Serfs⁎12) and p.Ala306Thr manifest as prelingual, profound hearing impairment in the patient (IV: 1), whereas the combination of p.Arg106Cys and p.Ala306Thr manifests as postlingual, milder hearing impairment in the patient (II: 2, II: 3, II: 5), suggesting that p.Arg106Cys mutation has a milder effect than p.(Phe13Serfs⁎12). We concluded that different combinations of TMPRSS3 mutations led to different hearing impairment phenotypes (DFNB8/DFNB10) in this family. PMID:28246597

  17. Phenotype of heterozygotes for low-density lipoprotein receptor mutations identified in different background populations

    DEFF Research Database (Denmark)

    Tybjaerg-Hansen, Anne; Jensen, Henrik Kjaerulf; Benn, Marianne;

    2005-01-01

    The effect of mutations on phenotype is often overestimated because of ascertainment bias. We determined the effect of background population on cholesterol phenotype associated with specific mutations in the low-density lipoprotein (LDL) receptor and the relative importance of background population...

  18. Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

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    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

  19. A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations

    NARCIS (Netherlands)

    Munot, Pinki; Saunders, Dawn E.; Milewicz, Dianna M.; Regalado, Ellen S.; Ostergaard, John R.; Braun, Kees P.; Kerr, Timothy; Lichtenbelt, Klaske D.; Philip, Sunny; Rittey, Christopher; Jacques, Thomas S.; Cox, Timothy C.; Ganesan, Vijeya

    2012-01-01

    Mutations in the ACTA2 gene lead to diffuse and diverse vascular diseases; the Arg179His mutation is associated with an early onset severe phenotype due to global smooth muscle dysfunction. Cerebrovascular disease associated with ACTA2 mutations has been likened to moyamoya disease, but appears to h

  20. Analysis of haploinsufficiency in women carrying germline mutations in the BRCA1 gene: Different mutations, different phenotypes ?

    OpenAIRE

    Vaclová, Tereza

    2015-01-01

    Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 30-01-2015 BRCA1 germline mutations are associated with significantly increased lifetime risk of developing breast and ovarian cancers. However, taking into account considerable differences in disease manifestation among mutation carriers, it is probable that various BRCA1 mutations lead to formation of distinct phenotypes and haploinsufficiency ef...

  1. Transmission of the P250R mutation of the FGFR3 gene in four generations with highly variable phenotype

    DEFF Research Database (Denmark)

    Hove, Hanne Buciek; Dunø, Morten; Daugaard-Jensen, Jette;

    Transmission of the P250R mutation of the FGFR3 gene in four generations with highly variable phenotype.......Transmission of the P250R mutation of the FGFR3 gene in four generations with highly variable phenotype....

  2. Do cell junction protein mutations cause an airway phenotype in mice or humans?

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    Chang, Eugene H; Pezzulo, Alejandro A; Zabner, Joseph

    2011-08-01

    Cell junction proteins connect epithelial cells to each other and to the basement membrane. Genetic mutations of these proteins can cause alterations in some epithelia leading to varied phenotypes such as deafness, renal disease, skin disorders, and cancer. This review examines if genetic mutations in these proteins affect the function of lung airway epithelia. We review cell junction proteins with examples of disease mutation phenotypes in humans and in mouse knockout models. We also review which of these genes are expressed in airway epithelium by microarray expression profiling and immunocytochemistry. Last, we present a comprehensive literature review to find the lung phenotype when cell junction and adhesion genes are mutated or subject to targeted deletion. We found that in murine models, targeted deletion of cell junction and adhesion genes rarely result in a lung phenotype. Moreover, mutations in these genes in humans have no obvious lung phenotype. Our research suggests that simply because a cell junction or adhesion protein is expressed in an organ does not imply that it will exhibit a drastic phenotype when mutated. One explanation is that because a functioning lung is critical to survival, redundancy in the system is expected. Therefore mutations in a single gene might be compensated by a related function of a similar gene product. Further studies in human and animal models will help us understand the overlap in the function of cell junction gene products. Finally, it is possible that the human lung phenotype is subtle and has not yet been described.

  3. A novel Italian presenilin 2 gene mutation with prevalent behavioral phenotype.

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    Marcon, Gabriella; Di Fede, Giuseppe; Giaccone, Giorgio; Rossi, Giacomina; Giovagnoli, Anna Rita; Maccagnano, Elio; Tagliavini, Fabrizio

    2009-01-01

    Presenilin mutations are the main cause of familial Alzheimer's disease. So far, more than 160 mutations in the Presenilin 1 gene (PSEN1) and approximately 10 mutations in the homologous Presenilin 2 gene (PSEN2) have been identified. Some PSEN1 mutations are associated with a phenotype fulfilling the clinical criteria of frontotemporal dementia. In PSEN2, T122P and M239V mutations presented with severe behavioral disturbances. We describe an Italian patient with a novel PSEN2 mutation (Y231C) who showed behavioral abnormalities and language impairment as presenting symptoms, with later involvement of other cognitive abilities, particularly of posterior functions.

  4. A phenotype of atypical apraxia of speech in a family carrying SQSTM1 mutation.

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    Boutoleau-Bretonnière, Claire; Camuzat, Agnès; Le Ber, Isabelle; Bouya-Ahmed, Kawtar; Guerreiro, Rita; Deruet, Anne-Laure; Evrard, Christelle; Bras, José; Lamy, Estelle; Auffray-Calvier, Elisabeth; Pallardy, Amandine; Hardy, John; Brice, Alexis; Derkinderen, Pascal; Vercelletto, Martine

    2015-01-01

    SQSTM1 mutations, coding for the p62 protein, were identified as a monogenic cause of Paget disease of bone and of amyotrophic lateral sclerosis. More recently, SQSTM1 mutations were identified in few families with frontotemporal dementia. We report a new family carrying SQSTM1 mutation and presenting with a clinical phenotype of speech apraxia or atypical behavioral disorders, associated with early visuo-contructional deficits. This study further supports the implication of SQSTM1 in frontotemporal dementia, and enlarges the phenotypic spectrum associated with SQSTM1 mutations.

  5. Familial adenomatous polyposis patients without an identified APC germline mutation have a severe phenotype

    DEFF Research Database (Denmark)

    Bisgaard, M L; Ripa, R; Knudsen, Anne Louise;

    2004-01-01

    BACKGROUND: Development of more than 100 colorectal adenomas is diagnostic of the dominantly inherited autosomal disease familial adenomatous polyposis (FAP). Germline mutations can be identified in the adenomatous polyposis coli (APC) gene in approximately 80% of patients. The APC protein...... comprises several regions and domains for interaction with other proteins, and specific clinical manifestations are associated with the mutation assignment to one of these regions or domains. AIMS: The phenotype in patients without an identified causative APC mutation was compared with the phenotype...... in patients with a known APC mutation and with the phenotypes characteristic of patients with mutations in specific APC regions and domains. PATIENTS: Data on 121 FAP probands and 149 call up patients from 70 different families were extracted from the Danish Polyposis register. METHODS: Differences in 16...

  6. Mutational and phenotypical spectrum of phenylalanine hydroxylase deficiency in Denmark

    DEFF Research Database (Denmark)

    Bayat, Allan; Yasmeen, Saiqa; Lund, Allan

    2016-01-01

    We describe the genotypes of the complete cohort, from 1967-2014, of phenylketonuria (PKU) patients in Denmark, in total 376 patients. A total of 752 independent alleles were investigated. Mutations were identified on 744 PKU alleles (98.9%). In total 82 different mutations were present in the co...

  7. Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly

    NARCIS (Netherlands)

    Bear, Kelly A.; Solomon, Benjamin D.; Antonini, Sonir; Arnhold, Ivo J. P.; Franca, Marcela M.; Gerkes, Erica H.; Grange, Dorothy K.; Hadley, Donald W.; Jaaskelainen, Jarmo; Paulo, Sabrina S.; Rump, Patrick; Stratakis, Constantine A.; Thompson, Elizabeth M.; Willis, Mary; Winder, Thomas L.; Jorge, Alexander A. L.; Roessler, Erich; Muenke, Maximilian

    2014-01-01

    Background Mutations in GLI2 have been associated with holoprosencephaly (HPE), a neuroanatomic anomaly resulting from incomplete cleavage of the developing forebrain, and an HPE-like phenotype involving pituitary anomalies and polydactyly. Objective To characterise the genotypic and phenotypic find

  8. The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer

    DEFF Research Database (Denmark)

    Hartung, Anne-Mette; Swensen, Jeff; Uriz, Inaki E;

    2016-01-01

    Costello syndrome (CS) may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We ident...

  9. Splice mutations preserve myophosphorylase activity that ameliorates the phenotype in McArdle disease

    DEFF Research Database (Denmark)

    Vissing, John; Duno, Morten; Schwartz, Marianne;

    2009-01-01

    Over 100 mutations in the myophosphorylase gene, which cause McArdle disease, are known. All these mutations have resulted in a complete block of muscle glycogenolysis, and accordingly, no genotype-phenotype correlation has been identified in this condition. We evaluated physiologic and genetic...

  10. Computational genes: a tool for molecular diagnosis and therapy of aberrant mutational phenotype

    Directory of Open Access Journals (Sweden)

    Ignatova Zoya

    2007-09-01

    Full Text Available Abstract Background A finite state machine manipulating information-carrying DNA strands can be used to perform autonomous molecular-scale computations at the cellular level. Results We propose a new finite state machine able to detect and correct aberrant molecular phenotype given by mutated genetic transcripts. The aberrant mutations trigger a cascade reaction: specific molecular markers as input are released and induce a spontaneous self-assembly of a wild type protein or peptide, while the mutational disease phenotype is silenced. We experimentally demostrated in in vitro translation system that a viable protein can be autonomously assembled. Conclusion Our work demostrates the basic principles of computational genes and particularly, their potential to detect mutations, and as a response thereafter administer an output that suppresses the aberrant disease phenotype and/or restores the lost physiological function.

  11. Expanding the phenotypic and mutational spectrum in microcephalic osteodysplastic primordial dwarfism type I.

    Science.gov (United States)

    Abdel-Salam, Ghada M H; Abdel-Hamid, Mohamed S; Issa, Mahmoud; Magdy, Ahmed; El-Kotoury, Ahmed; Amr, Khalda

    2012-06-01

    Mutations in the RNU4ATAC gene cause microcephalic osteodysplastic primordial dwarfism type I. It encodes U4atac, a small nuclear RNA that is a component of the minor spliceosome. Six distinct mutations in 30 patients diagnosed as microcephalic osteodysplastic primordial dwarfism type I have been described. We report on three additional patients from two unrelated families presenting with a milder phenotype of microcephalic osteodysplastic primordial dwarfism type I and metopic synostosis. Patient 1 had two novel heterozygous mutations in the 3' prime stem-loop, g.66G > C and g.124G > A while Patients 2 and 3 had a homozygous mutation g.55G > A in the 5' prime stem-loop. Although they manifested the known spectrum of clinical features of microcephalic osteodysplastic primordial dwarfism type I, they lacked evidence of severe developmental delay and neurological symptoms. These findings expand the mutational and phenotypic spectrum of this syndrome.

  12. The cardiac phenotype in patients with a CHD7 mutation

    DEFF Research Database (Denmark)

    Corsten-Janssen, Nicole; Kerstjens-Frederikse, Wilhelmina S; du Marchie Sarvaas, Gideon J

    2013-01-01

    Loss-of-function mutations in CHD7 cause Coloboma, Heart Disease, Atresia of Choanae, Retardation of Growth and/or Development, Genital Hypoplasia, and Ear Abnormalities With or Without Deafness (CHARGE) syndrome, a variable combination of multiple congenital malformations including heart defects...

  13. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype

    NARCIS (Netherlands)

    K. Tatton-Brown (Katrina); A. Murray (Anna); S. Hanks (Sandra); J. Douglas (Jenny); R. Armstrong (Ruth); S. Banka (Siddharth); L.M. Bird (Lynne); C.L. Clericuzio (Carol); V. Cormier-Daire (Valerie); T. Cushing (Tom); F. Flinter (Frances); S. Jacquemont (Sébastien); S. Joss (Shelagh); E. Kinning (Esther); S.A. Lynch; A. Magee (Alex); V. Mcconnell (Vivienne); A. Medeira (Ana); K. Ozono (Keiichi); M. Patton (Michael); J. Rankin (Julia); D.J. Shears (Deborah); M.E.H. Simon (Marleen); M. Splitt (M.); V. Strenger (Volker); K.E. Stuurman (Kyra); C. Taylor (Clare); H. Titheradge (Hannah); L. van Maldergem (Lionel); I.K. Temple; T.J. Cole (Trevor); S. Seal (Sheila); N. Rahman (Nazneen)

    2013-01-01

    textabstractWeaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with E

  14. Clinical phenotype of 5 females with a CDKL5 mutation

    NARCIS (Netherlands)

    Stalpers, X.L.; Spruijt, L.; Yntema, H.G.; Verrips, A.

    2012-01-01

    Mutations in the X-linked cyclin dependent kinase like 5 (CDKL5) gene have been reported in approximately 80 patients since the first description in 2003. The clinical presentation partly corresponds with Rett syndrome, considering clinical features as intellectual disability, hypotonia, and poor vi

  15. The Cardiac Phenotype in Patients With a CHD7 Mutation

    NARCIS (Netherlands)

    Corsten-Janssen, Nicole; Kerstjens-Frederikse, Wilhelmina S.; du Marchie Sarvaas, Gideon J.; Baardman, Maria E.; Bakker, Marian K.; Bergman, Jorieke E. H.; Hove, Hanne D.; Heimdal, Ketil R.; Rustad, Cecilie F.; Hennekam, Raoul C. M.; Hofstra, Robert M. W.; Hoefsloot, Lies H.; Van Ravenswaaij-Arts, Conny M. A.; Kapusta, Livia

    2013-01-01

    Background- Loss-of-function mutations in CHD7 cause Coloboma, Heart Disease, Atresia of Choanae, Retardation of Growth and/or Development, Genital Hypoplasia, and Ear Abnormalities With or Without Deafness (CHARGE) syndrome, a variable combination of multiple congenital malformations including hear

  16. A structure-function study of MID1 mutations associated with a mild Opitz phenotype.

    Science.gov (United States)

    Mnayer, Laila; Khuri, Sawsan; Merheby, Hassan Al-Ali; Meroni, Germana; Elsas, Louis J

    2006-03-01

    The X-linked form of Opitz syndrome (OS) affects midline structures and produces a characteristic, but heterogeneous, phenotype that may include severe mental retardation, hypertelorism, broad nasal bridge, widow's peak, cleft lip/cleft palate, congenital heart disease, laryngotracheal defects, and hypospadias. The MID1 gene was implicated in OS by linkage to Xp22. It encodes a 667 amino acid protein that contains a RING finger motif, two B-box zinc fingers, a coiled-coil, a fibronectin type III (FNIII) domain, and a B30.2 domain. Several mutations in MID1 are associated with severe OS. Here, we describe an intelligent male with a milder phenotype characterized by hypertelorism, broad nasal bridge, widow's peak, mild hypospadias, pectus excavatum, and a surgically corrected tracheo-esophageal fistula. He has an above average intelligence and no cleft lip/palate or heart disease. We identified a novel mutation in MID1 (P441L) which is in exon 8 and functionally associated with the FNIII domain. While OS phenotypes have been attributed to mutations in the C-terminal part of MID1, little is currently known about the structure-function relationships of MID1 mutations, and how they affect phenotype. We find from a literature review that missense mutations within the FNIII domain of MID1 are associated with a milder presentation of OS than missense mutations elsewhere in MID1. All truncating mutations (frameshift, insertions/deletions) lead to severe OS. We used homology analysis of the MID1 FNIII domain to investigate structure-function changes caused by our missense mutation. This and other missense mutations probably cause disruption of protein-protein interactions, either within MID1 or between MID1 and other proteins. We correlate these protein structure-function findings to the absence of CNS or palatal changes and conclude that the FNIII domain of the MID1 protein may be involved in midline differentiation after neural tube and palatal structures are completed.

  17. Infrequent microsatellite instability mutator phenotype in Chinese hepatocellular carcinomas

    Institute of Scientific and Technical Information of China (English)

    方丽; 房殿春; 汪荣泉; 杨仕明; 吴凯

    2003-01-01

    Objective:In order to elucidate the molecular mechanisms that might be responsible for hepatocarcinogenesis,we examined microsatellite instability(MSI),mismatch repair gene hMLH1 mutation and methylation in hepatocellular carcinoma.Methods:Fifty-two cases of surgically resected sporadic hepatocellular carcinoma(HCC)were studied.hMLH1 mutation was examined by two-dimensional electrophoresis and DNA sequencing; hMLH1 methylation was determined by methylation-specific PCR(MSP); and MSI at BAT26 was analyzed by PCR-based methods.Results:MSI at BAT26 was found in 3 of 52 cases(5.8%)of the tumors analyzed.No hMLH1 mutation or hypermethylation was found in these 52 cancerous tissues.No correlation existed between MSI and clinico-pathological characteristics of the patients.Conclusion:Our results suggest that MSI at BAT26 is rarely associated with carcinogenesis of chinese HCC.The genesis of sporadic HCC may occur in an alternative pathway that is probably different from MSI pathway.

  18. Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation.

    Science.gov (United States)

    Kato, Mitsuhiro; Das, Soma; Petras, Kristin; Kitamura, Kunio; Morohashi, Ken-ichirou; Abuelo, Diane N; Barr, Mason; Bonneau, Dominique; Brady, Angela F; Carpenter, Nancy J; Cipero, Karen L; Frisone, Francesco; Fukuda, Takayuki; Guerrini, Renzo; Iida, Eri; Itoh, Masayuki; Lewanda, Amy Feldman; Nanba, Yukiko; Oka, Akira; Proud, Virginia K; Saugier-Veber, Pascale; Schelley, Susan L; Selicorni, Angelo; Shaner, Rachel; Silengo, Margherita; Stewart, Fiona; Sugiyama, Noriyuki; Toyama, Jun; Toutain, Annick; Vargas, Ana Lía; Yanazawa, Masako; Zackai, Elaine H; Dobyns, William B

    2004-02-01

    We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.

  19. Glucokinase gene mutations: structural and genotype-phenotype analyses in MODY children from South Italy.

    Directory of Open Access Journals (Sweden)

    Nadia Tinto

    Full Text Available BACKGROUND: Maturity onset diabetes of the young type 2 (or GCK MODY is a genetic form of diabetes mellitus provoked by mutations in the glucokinase gene (GCK. METHODOLOGY/PRINCIPAL FINDINGS: We screened the GCK gene by direct sequencing in 30 patients from South Italy with suspected MODY. The mutation-induced structural alterations in the protein were analyzed by molecular modeling. The patients' biochemical, clinical and anamnestic data were obtained. Mutations were detected in 16/30 patients (53%; 9 of the 12 mutations identified were novel (p.Glu70Asp, p.Phe123Leu, p.Asp132Asn, p.His137Asp, p.Gly162Asp, p.Thr168Ala, p.Arg392Ser, p.Glu290X, p.Gln106_Met107delinsLeu and are in regions involved in structural rearrangements required for catalysis. The prevalence of mutation sites was higher in the small domain (7/12: approximately 59% than in the large (4/12: 33% domain or in the connection (1/12: 8% region of the protein. Mild diabetic phenotypes were detected in almost all patients [mean (SD OGTT = 7.8 mMol/L (1.8] and mean triglyceride levels were lower in mutated than in unmutated GCK patients (p = 0.04. CONCLUSIONS: The prevalence of GCK MODY is high in southern Italy, and the GCK small domain is a hot spot for MODY mutations. Both the severity of the GCK mutation and the genetic background seem to play a relevant role in the GCK MODY phenotype. Indeed, a partial genotype-phenotype correlation was identified in related patients (3 pairs of siblings but not in two unrelated children bearing the same mutation. Thus, the molecular approach allows the physician to confirm the diagnosis and to predict severity of the mutation.

  20. Somatic mosaicism and the phenotypic expression of COL2A1 mutations.

    Science.gov (United States)

    Nagendran, Sonali; Richards, Allan J; McNinch, Annie; Sandford, Richard N; Snead, Martin P

    2012-05-01

    Mutations in COL2A1, the gene for type II-collagen, can result in a wide variety of phenotypes depending upon the nature of the mutation. Dominant negative mutations tend to result in severe and often lethal skeletal dysplasias such as achondrogenesis type 2, Kniest dysplasia, and spondyloepiphyseal dysplasia congenita. Stickler syndrome, a condition characterized by ophthalmological and orofacial features, deafness and arthritis, usually, but not exclusively, results from haploinsufficiency. Overlapping features of all these disorders can also be seen in the same family. Rare reports have demonstrated that phenotypic variability can be explained in some families by somatic mosaicism. Here, we describe five further examples of somatic mosaicism of COL2A1 mutations illustrating the importance of detailed clinical evaluation and molecular testing even in clinically normal parents of affected individuals.

  1. Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene.

    Science.gov (United States)

    Bercovich, Dani; Elimelech, Arava; Zlotogora, Joel; Korem, Sigal; Yardeni, Tal; Gal, Nurit; Goldstein, Nurit; Vilensky, Bela; Segev, Roni; Avraham, Smadar; Loewenthal, Ron; Schwartz, Gerard; Anikster, Yair

    2008-01-01

    The aims of our research were to define the genotype-phenotype correlations of mutations in the phenylalanine hydroxylase (PAH) gene that cause phenylketonuria (PKU) among the Israeli population. The mutation spectrum of the PAH gene in PKU patients in Israel is described, along with a discussion on genotype-phenotype correlations. By using polymerase chain reaction/denaturing high-performance liquid chromatography (PCR/dHPLC) and DNA sequencing, we screened all exons of the PAH gene in 180 unrelated patients with four different PKU phenotypes [classic PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia (MHP)]. In 63.2% of patient genotypes, the metabolic phenotype could be predicted, though evidence is also found for both phenotypic inconsistencies among subjects with more than one type of mutation in the PAH gene. Data analysis revealed that about 25% of patients could participate in the future in (6R)-L: -erythro-5, 6, 7, 8-tetrahydrobiopterin (BH4) treatment trials according to their mutation genotypes. This study enables us to construct a national database in Israel that will serve as a valuable tool for genetic counseling and a prognostic evaluation of future cases of PKU.

  2. Mutations Conferring a Noncytotoxic Phenotype on Chikungunya Virus Replicons Compromise Enzymatic Properties of Nonstructural Protein 2

    OpenAIRE

    Utt, Age; Das, Pratyush Kumar; Varjak, Margus; Lulla, Valeria; Lulla, Aleksei; Merits, Andres

    2014-01-01

    Chikungunya virus (CHIKV) (genus Alphavirus) has a positive-sense RNA genome. CHIKV nonstructural protein 2 (nsP2) proteolytically processes the viral nonstructural polyprotein, possesses nucleoside triphosphatase (NTPase), RNA triphosphatase, and RNA helicase activities, and induces cytopathic effects in vertebrate cells. Although alphaviral nsP2 mutations can result in a noncytotoxic phenotype, the effects of such mutations on nsP2 enzymatic activities are not well understood. In this study...

  3. Phenotypic Suppression of Streptomycin Resistance by Mutations in Multiple Components of the Translation Apparatus

    Science.gov (United States)

    Carr, Jennifer F.; Lee, Hannah J.; Jaspers, Joshua B.; Dahlberg, Albert E.; Jogl, Gerwald

    2015-01-01

    ABSTRACT The bacterial ribosome and its associated translation factors are frequent targets of antibiotics, and antibiotic resistance mutations have been found in a number of these components. Such mutations can potentially interact with one another in unpredictable ways, including the phenotypic suppression of one mutation by another. These phenotypic interactions can provide evidence of long-range functional interactions throughout the ribosome and its functional complexes and potentially give insights into antibiotic resistance mechanisms. In this study, we used genetics and experimental evolution of the thermophilic bacterium Thermus thermophilus to examine the ability of mutations in various components of the protein synthesis apparatus to suppress the streptomycin resistance phenotypes of mutations in ribosomal protein S12, specifically those located distant from the streptomycin binding site. With genetic selections and strain constructions, we identified suppressor mutations in EF-Tu or in ribosomal protein L11. Using experimental evolution, we identified amino acid substitutions in EF-Tu or in ribosomal proteins S4, S5, L14, or L19, some of which were found to also relieve streptomycin resistance. The wide dispersal of these mutations is consistent with long-range functional interactions among components of the translational machinery and indicates that streptomycin resistance can result from the modulation of long-range conformational signals. IMPORTANCE The thermophilic bacterium Thermus thermophilus has become a model system for high-resolution structural studies of macromolecular complexes, such as the ribosome, while its natural competence for transformation facilitates genetic approaches. Genetic studies of T. thermophilus ribosomes can take advantage of existing high-resolution crystallographic information to allow a structural interpretation of phenotypic interactions among mutations. Using a combination of genetic selections, strain constructions

  4. Somatic frameshift mutations in the Bloom syndrome BLM gene are frequent in sporadic gastric carcinomas with microsatellite mutator phenotype

    Directory of Open Access Journals (Sweden)

    Matei Irina

    2001-08-01

    Full Text Available Abstract Background Genomic instability has been reported at microsatellite tracts in few coding sequences. We have shown that the Bloom syndrome BLM gene may be a target of microsatelliteinstability (MSI in a short poly-adenine repeat located in its coding region. To further characterize the involvement of BLM in tumorigenesis, we have investigated mutations in nine genes containing coding microsatellites in microsatellite mutator phenotype (MMP positive and negative gastric carcinomas (GCs. Methods We analyzed 50 gastric carcinomas (GCs for mutations in the BLM poly(A tract aswell as in the coding microsatellites of the TGFβ1-RII, IGFIIR, hMSH3, hMSH6, BAX, WRN, RECQL and CBL genes. Results BLM mutations were found in 27% of MMP+ GCs (4/15 cases but not in any of the MMP negative GCs (0/35 cases. The frequency of mutations in the other eight coding regions microsatellite was the following: TGFβ1-RII (60 %, BAX (27%, hMSH6 (20%,hMSH3 (13%, CBL (13%, IGFIIR (7%, RECQL (0% and WRN (0%. Mutations in BLM appear to be more frequently associated with frameshifts in BAX and in hMSH6and/or hMSH3. Tumors with BLM alterations present a higher frequency of unstable mono- and trinucleotide repeats located in coding regions as compared with mutator phenotype tumors without BLM frameshifts. Conclusions BLM frameshifts are frequent alterations in GCs specifically associated with MMP+tumors. We suggest that BLM loss of function by MSI may increase the genetic instability of a pre-existent unstable genotype in gastric tumors.

  5. Autosomal recessive transmission of MYBPC3 mutation results in malignant phenotype of hypertrophic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Yilu Wang

    Full Text Available BACKGROUND: Hypertrophic cardiomyopathy (HCM due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved. METHODS: A pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls. RESULTS: A novel missense mutation (c.1469G>T, p.Gly490Val in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM. CONCLUSIONS: Our data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.

  6. Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations.

    Directory of Open Access Journals (Sweden)

    Bruno Francou

    Full Text Available CONTEXT: TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH (OMIM #146110. In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher the pathophysiology of this signaling pathway. OBJECTIVE: To evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations. RESULTS: From a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%. We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn probably caused by the misfolding of the mutated NK3R protein. We found a statistically significant (p<0.0001 higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio. CONCLUSION: The gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of alpha-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations.

  7. The hemoglobin O mutation in Indonesia: distribution and phenotypic expression.

    Science.gov (United States)

    Daud, D; Harahap, A; Setianingsih, I; Nainggolan, I; Tranggana, S; Pakasi, R; Marzuki, S

    2001-01-01

    We have investigated hemoglobin O Indonesia (HbOIna) in related ethnic populations of the Indonesian archipelago: 1725 individuals of the five ethnic populations of South Sulawesi (Bugis, Toraja, Makassar, Mandar, and Kajang) and 959 individuals of the neighboring islands, who were divided into five phylogenetic groups: (a) Batak; (b) Malay from Padang, Pakanbaru, and Palembang in the island of Sumatra; (c) Javanese-related populations (Java, Tengger, and Bali) from the islands of Java and Bali; (d) populations of the Lesser Sunda Islands of Lombok, Sumba, and Sumbawa; and (e) the Papuan-languagespeaking population of Alor Island. Nineteen individuals heterozygous for HbO(Ina) were identified from the Bugis, Toraja, Makassar, and Kajang ethnic populations, but none from the other populations. In all cases, the underlying mutation was found to be in codon 116 (GAG to AAG) of the alpha1-globin gene, resulting in the Glull6Lys amino acid change. The level of HbO in the 17 individuals plus 12 additional family members carrying the mutation was found to be 11.6 +/- 1.0%, significantly lower than the expected 17%-22%, indicating the instability of HbO.

  8. Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes.

    Science.gov (United States)

    Lee, Winston; Xie, Yajing; Zernant, Jana; Yuan, Bo; Bearelly, Srilaxmi; Tsang, Stephen H; Lupski, James R; Allikmets, Rando

    2016-01-01

    Over 800 mutations in the ABCA4 gene cause autosomal recessive Stargardt disease. Due to extensive genetic heterogeneity, observed variant-associated phenotypes can manifest tremendous variability of expression. Furthermore, the high carrier frequency of pathogenic ABCA4 alleles in the general population (~1:20) often results in pseudo-dominant inheritance patterns further complicating the diagnosis and characterization of affected individuals. This study describes a genotype/phenotype analysis of an unusual family with multiple macular disease phenotypes spanning across two generations and segregating four distinct ABCA4 mutant alleles. Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Array comparative genomic hybridization revealed a large novel deletion combined with a small insertion, c.6148-698_c.6670del/insTGTGCACCTCCCTAG, and complete sequencing of the entire ABCA4 genomic locus uncovered a new deep intronic variant, c.302+68C>T. Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. This family epitomizes the clinical and genetic complexity of ABCA4-associated diseases. It contained variants from all classes of mutations, in the coding region, deep intronic, both single nucleotide variants and copy number variants that accounted for varying phenotypes segregating in an apparent dominant fashion. Unequivocally defining disease-associated alleles in the ABCA4 locus requires a multifaceted approach that includes advanced mutation detection methods and a thorough analysis of clinical phenotypes.

  9. A novel progranulin mutation causing frontotemporal lobar degeneration with heterogeneous phenotypic expression.

    Science.gov (United States)

    Rossi, Giacomina; Piccoli, Elena; Benussi, Luisa; Caso, Francesca; Redaelli, Veronica; Magnani, Giuseppe; Binetti, Giuliano; Ghidoni, Roberta; Perani, Daniela; Giaccone, Giorgio; Tagliavini, Fabrizio

    2011-01-01

    Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by behavioural disturbances and cognitive decline. Here we describe an Italian family with FTLD showing remarkable phenotypic heterogeneity. Based on low plasma levels of progranulin, we analyzed the progranulin gene (GRN) in two patients with early onset and found the novel frame-shift mutation T278SfsX7. mRNA analysis confirmed the null effect of the mutation. The patients were homozygous for H1 MAPT haplotype, a disease modifier factor that can account for early age at onset. Being predictive for GRN null mutations, plasma progranulin dosage should be included in diagnostic work-up of dementia.

  10. Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Ionasescu, V.; Ionasescu, R.; Searby, C. [Univ. of Iowa Hospitals and Clinics, Iowa City, IA (United States)

    1996-06-14

    We studied the relationship between the genotype and clinical phenotype in 27 families with dominant X-linked Charcot-Marie-Tooth (CMTX1) neuropathy. Twenty-two families showed mutations in the coding region of the connexin32 (cx32) gene. The mutations include four nonsense mutations, eight missense mutations, two medium size deletions, and one insertion. Most missense mutations showed a mild clinical phenotype (five out of eight), whereas all nonsense mutations, the larger of the two deletions, and the insertion that produced frameshifts showed severe phenotypes. Five CMTX1 families with mild clinical phenotype showed no point mutations of the cx32 gene coding region. Three of these families showed positive genetic linkage with the markers of the Xq13.1 region. The genetic linkage of the remaining two families could not be evaluated because of their small size. 25 refs., 1 fig., 1 tab.

  11. Frameshift mutations in dentin phosphoprotein and dependence of dentin disease phenotype on mutation location

    NARCIS (Netherlands)

    P. Nieminen; L. Papagiannoulis-Lascarides; J. Waltimo-Siren; P. Ollila; S. Karjalainen; S. Arte; J. Veerkamp; V. Tallon Walton; E. Chimenos Küstner; T. Siltanen; H. Holappa; P.L. Lukinmaa; S. Alaluusua

    2011-01-01

    We describe results from a mutational analysis of the region of the dentin sialophosphoprotein (DSPP) gene encoding dentin phosphoprotein (DPP) in 12 families with dominantly inherited dentin diseases. In eight families (five mutations in the N-terminal third of DPP), the clinical and radiologic fea

  12. Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort.

    Science.gov (United States)

    Lindquist, S G; Schwartz, M; Batbayli, M; Waldemar, G; Nielsen, J E

    2009-08-01

    Autosomal dominantly transmitted Alzheimer's disease (AD) and frontotemporal dementia (FTD) are genetically heterogeneous disorders. To date, three genes have been identified in which mutations cause early-onset autosomal dominant inherited AD: APP, PSEN1, and PSEN2. Mutations in two genes on chromosome 17, the MAPT and the PGRN genes, are associated with autosomal dominant inherited FTD. The aim of this study was to characterize the mutation spectrum and describe genotype-phenotype correlations in families with inherited dementia. The identification of novel mutations and/or atypical genotype-phenotype correlations contributes to further characterizing the disorders. DNA-samples from the 90 index cases from a Danish referral-based cohort representing families with presumed autosomal dominant inherited AD or FTD were screened for mutations in the known genes with sequencing, denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) techniques. Seven presumed pathogenic mutations (two PSEN1, one PSEN2, one APP, one MAPT, and two PGRN) were identified, including a novel PSEN2 mutation (V393M). No dosage aberrations were identified.

  13. A Systematic Review of Phenotypic Features Associated With Cardiac Troponin I Mutations in Hereditary Cardiomyopathies

    DEFF Research Database (Denmark)

    Mogensen, Jens; Hey, Thomas; Lambrecht, Sascha

    2015-01-01

    , before genetic testing can be used for individual risk assessment and prediction of prognosis, it is important to investigate if there is a relation between the clinical disease expression (phenotype) of the condition and mutations in specific disease genes (genotype). METHODS: We reviewed the literature...

  14. Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability

    NARCIS (Netherlands)

    L. Santoro (Lucio); G.J. Breedveld (Guido); F. Manganelli (Fiore); R. Iodice (Rosa); C. Pisciotta (Chiara); M. Nolano (Maria); F. Punzo (Francesca); M. Quarantelli (Mario); S. Pappatà (Sabina); A. Di Fonzo (Alessio); B.A. Oostra (Ben); V. Bonifati (Vincenzo)

    2011-01-01

    textabstractMutations in the ATP13A2 (PARK9) and FBXO7 (PARK15) genes are linked to different forms of autosomal recessive juvenile-onset neurodegenerative diseases with overlapping phenotypes, including levodopa-responsive parkinsonism, pyramidal disturbances, cognitive decline, and supranuclear ga

  15. Mutational spectrum of APC and genotype-phenotype correlations in Greek FAP patients

    Directory of Open Access Journals (Sweden)

    Fountzilas George

    2010-07-01

    Full Text Available Abstract Background Familial adenomatous polyposis, an autosomal dominant inherited disease caused by germline mutations within the APC gene, is characterized by early onset colorectal cancer as a consequence of the intrinsic phenotypic feature of multiple colorectal adenomatic polyps. The genetic investigation of Greek adenomatous polyposis families was performed in respects to APC and MUTYH germline mutations. Additionally, all available published mutations were considered in order to define the APC mutation spectrum in Greece. Methods A cohort of 25 unrelated adenomatous polyposis families of Greek origin has been selected. Genetic testing included direct sequencing of APC and MUTYH genes. APC gene was also checked for large genomic rearrangements by MLPA. Results Analysis of the APC gene performed in a Greek cohort of twenty five FAP families revealed eighteen different germline mutations in twenty families (80%, four of which novel. Mutations were scattered between exon 3 and codon 1503 of exon 15, while no large genomic rearrangements were identified. Conclusion This concise report describes the spectrum of all APC mutations identified in Greek FAP families, including four novel mutations. It is concluded that the Greek population is characterized by genetic heterogeneity, low incidence of genomic rearrangements in APC gene and lack of founder mutation in FAP syndrome.

  16. Clinical and molecular characterization of a novel INS mutation identified in patients with MODY phenotype.

    Science.gov (United States)

    Piccini, Barbara; Artuso, Rosangela; Lenzi, Lorenzo; Guasti, Monica; Braccesi, Giulia; Barni, Federica; Casalini, Emilio; Giglio, Sabrina; Toni, Sonia

    2016-11-01

    Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family. First genetic tests performed identified two heterozygous silent nucleotide substitutions in MODY3/HNF1α gene. An ineffective attempt to suspend insulin therapy, administering repaglinide and sulphonylureas, was made. DNA was re-sequenced by NGS investigating a set of 102 genes. Genes implicated in the pathway of pancreatic β-cells, candidate genes for type 2 diabetes mellitus and genes causative of diabetes in mice were selected. A novel heterozygous variant in human preproinsulin INS gene (c.125T > C) was found in the affected family members. The new INS mutation broadens the spectrum of possible INS phenotypes. Screening for INS mutations is warranted not only in neonatal diabetes but also in MODYx patients and in selected patients with type 1 diabetes mellitus negative for autoantibodies. Subjects with complex diseases without a specific phenotype should be studied by NGS because Sanger sequencing is ineffective and time consuming in detecting rare variants.

  17. Mutation spectrum and genotype-phenotype correlation of hearing loss patients caused by SLC26A4 mutations in the Japanese: a large cohort study.

    Science.gov (United States)

    Miyagawa, Maiko; Nishio, Shin-Ya; Usami, Shin-Ichi

    2014-05-01

    Mutations in SLC26A4 cause a broad phenotypic spectrum, from typical Pendred syndrome to nonsyndromic hearing loss associated with enlarged vestibular aqueduct. Identification of these mutations is important for accurate diagnosis, proper medical management and appropriate genetic counseling and requires updated information regarding spectrum, clinical characteristics and genotype-phenotype correlations, based on a large cohort. In 100 patients with bilateral enlarged vestibular aqueduct among 1511 Japanese hearing loss probands registered in our gene bank, goiter data were available for 79, of whom 15 had Pendred syndrome and 64 had nonsyndromic hearing loss. We clarified the mutation spectrum for the SLC26A4 mutations and also summarized hearing levels, progression, fluctuation and existence of genotype-phenotype correlation. SLC26A4 mutations were identified in 82 of the 100 patients (82.0%). Of the Pendred syndrome patients, 93% (14/15) were carriers, as were 77% (49/64) of the nonsyndromic hearing loss patients. Clinical characteristics of patients with SLC26A4 mutations were congenital, fluctuating and progressive hearing loss usually associated with vertigo and/or goiter. We found no genotype-phenotype correlations, indicating that, unlike in the case of GJB2 mutations, the phenotype cannot be predicted from the genotype. Our mutation analysis confirmed the importance of mutations in the SLC26A4 gene among hearing loss patients with enlarged vestibular aqueduct and revealed the mutation spectrum, essential information when performing genetic testing.

  18. Molecular phenotype of the np 7472 deafness-associated mitochondrial mutation in osteosarcoma cell cybrids.

    Science.gov (United States)

    Toompuu, M; Tiranti, V; Zeviani, M; Jacobs, H T

    1999-11-01

    The nucleotide pair (np) 7472 insC mitochondrial DNA mutation in the tRNA(Ser)(UCN) gene is associated with sensorineural deafness, combined in some individuals with a wider syndrome including ataxia and myo-clonus. Previous studies in osteosarcoma cell cybrids revealed only a mild respiratory defect linked to the mutation. We have investigated the biochemical and molecular consequences of the mutation, using a panel of seven osteosarcoma cell cybrids containing 100% mutant mtDNA, plus two cybrids carrying 100% wild-type mtDNA from the same patient. The mutation is associated with a mild growth deficit in selective (galactose) medium that is only significant in combination with a reduced mtDNA copy number, suggesting a mechanism that might modulate clinical phenotype. The mutation results in a 65% drop in the steady-state level of tRNA(Ser)(UCN), but causes at most only a very mild and quantitative abnormality of mitochondrial protein synthesis, associated with modest hypersensitivity to doxycyclin. No evidence for a specific defect in aminoacylation was obtained, and unlike the case with the np 7445 mutation, the pattern of RNA processing of light strand transcripts of the ND6 region was not systematically altered. Comparing the np 7472 and np 7445 mutant phenotypes in cultured cells suggests that sensorineural deafness can result from a functional insufficiency of mitochondrial tRNA(Ser)(UCN), to which some cells of the auditory system are especially vulnerable.

  19. Darier disease in Slovenia: spectrum of ATP2A2 mutations and relation to patients' phenotypes.

    Science.gov (United States)

    Godic, Aleksandar; Strazisar, Mojca; Zupan, Andrej; Korosec, Branka; Kansky, Aleksej; Glavac, Damjan

    2010-01-01

    ATP2A2 encodes the sarco/endoplasmic reticulum Ca2+- ATPase (SERCA2) and has been identified as a defective gene in Darier disease (DD). It is an autosomal dominant genodermatosis, which is characterized by loss of adhesion between suprabasal epidermal keratinocytes (acantholysis) and abnormal keratinization (dyskeratosis). We examined 28 Slovenian patients with DD (the cohort of patients represents over 50% of all DD patients in Slovenia) and screened genomic DNA for ATP2A2 mutations and RNA for splice site mutations. We identified 7 different ATP2A2 mutations, 4 of which are novel: A516P, R559G, 544+1del6, and 1762-6del18. We also found two previously described polymorphisms 2741+54 G>A in intron XVIII and 2172 G>A (A724A) in exon 15, with allele frequencies of 64.2% and 11.3%, respectively. The mutations are scattered throughout the gene and affect the actuator, phosphorylation, stalk and transmembrane domains of SERCA2. A P160L mutation in a Slovene patient with severe DD and a history of deafness is another consistent genotype-phenotype correlation. It seems that mutations of the ATP2A2 gene may also play a role in the pathogenesis of deafness, which seems to be a new phenotypic characteristic of DD patients.

  20. Interplay between DMD point mutations and splicing signals in Dystrophinopathy phenotypes.

    Directory of Open Access Journals (Sweden)

    Jonàs Juan-Mateu

    Full Text Available DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements.

  1. Regenerant arabidopsis lineages display a distinct genome-wide spectrum of mutations conferring variant phenotypes

    KAUST Repository

    Jiang, Caifu

    2011-07-28

    Multicellular organisms can be regenerated from totipotent differentiated somatic cell or nuclear founders [1-3]. Organisms regenerated from clonally related isogenic founders might a priori have been expected to be phenotypically invariant. However, clonal regenerant animals display variant phenotypes caused by defective epigenetic reprogramming of gene expression [2], and clonal regenerant plants exhibit poorly understood heritable phenotypic ("somaclonal") variation [4-7]. Here we show that somaclonal variation in regenerant Arabidopsis lineages is associated with genome-wide elevation in DNA sequence mutation rate. We also show that regenerant mutations comprise a distinctive molecular spectrum of base substitutions, insertions, and deletions that probably results from decreased DNA repair fidelity. Finally, we show that while regenerant base substitutions are a likely major genetic cause of the somaclonal variation of regenerant Arabidopsis lineages, transposon movement is unlikely to contribute substantially to that variation. We conclude that the phenotypic variation of regenerant plants, unlike that of regenerant animals, is substantially due to DNA sequence mutation. 2011 Elsevier Ltd. All rights reserved.

  2. A novel mutation in the AGXT gene causing primary hyperoxaluria type I: genotype–phenotype correlation

    Indian Academy of Sciences (India)

    SAOUSSEN M’DIMEGH; CÉCILE AQUAVIVA- BOURDAIN; ASMA OMEZZINE; IBTIHEL M’BAREK; GENEVIÉVE SOUCHE; DORSAF ZELLAMA; KAMEL ABIDI; ABDELATTIF ACHOUR; TAHAR GARGAH; SAOUSSEN ABROUG; ALI BOUSLAMA

    2016-09-01

    Primary hyperoxaluria type I (PH1) is an autosomal recessive metabolic disorder caused by inherited mutations in the AGXT gene encoding liver peroxisomal alanine : glyoxylate aminotransferase (AGT) which is deficient or mistargeted to mitochon-dria. PH1 shows considerable phenotypic and genotypic heterogeneity. The incidence and severity of PH1 varies in different geographic regions. DNA samples of the affected members from two unrelated Tunisian families were tested by amplifying and sequencing each of the AGXT exons and intron–exon junctions. We identified a novel frameshift mutation in the AGXT gene, the c.406_410dupACTGC resulting in a truncated protein (p.Gln137Hisfs*19). It is found in homozygous state in two nonconsanguineous unrelated families from Tunisia. These molecular findings provide genotype/phenotype correlations in the intrafamilial phenotypic and permit accurate carrier detection, and prenatal diagnosis. The novel p.G ln137Hisfs*19 mutation detected in our study extend the spectrum of knownAGXT gene mutations in Tunisia.

  3. Mutations in the BLOC-1 Subunits Dysbindin and Muted Generate Divergent and Dosage-dependent Phenotypes*

    Science.gov (United States)

    Larimore, Jennifer; Zlatic, Stephanie A.; Gokhale, Avanti; Tornieri, Karine; Singleton, Kaela S.; Mullin, Ariana P.; Tang, Junxia; Talbot, Konrad; Faundez, Victor

    2014-01-01

    Post-mortem analysis has revealed reduced levels of the protein dysbindin in the brains of those suffering from the neurodevelopmental disorder schizophrenia. Consequently, mechanisms controlling the cellular levels of dysbindin and its interacting partners may participate in neurodevelopmental processes impaired in that disorder. To address this question, we studied loss of function mutations in the genes encoding dysbindin and its interacting BLOC-1 subunits. We focused on BLOC-1 mutants affecting synapse composition and function in addition to their established systemic pigmentation, hematological, and lung phenotypes. We tested phenotypic homogeneity and gene dosage effects in the mouse null alleles muted (Bloc1s5mu/mu) and dysbindin (Bloc1s8sdy/sdy). Transcripts of NMDA receptor subunits and GABAergic interneuron markers, as well as expression of BLOC-1 subunit gene products, were affected differently in the brains of Bloc1s5mu/mu and Bloc1s8sdy/sdy mice. Unlike Bloc1s8sdy/sdy, elimination of one or two copies of Bloc1s5 generated indistinguishable pallidin transcript phenotypes. We conclude that monogenic mutations abrogating the expression of a protein complex subunit differentially affect the expression of other complex transcripts and polypeptides as well as their downstream effectors. We propose that the genetic disruption of different subunits of protein complexes and combinations thereof diversifies phenotypic presentation of pathway deficiencies, contributing to the wide phenotypic spectrum and complexity of neurodevelopmental disorders. PMID:24713699

  4. Mutations in Hirschsprung disease : When does a mutation contribute to the phenotype

    NARCIS (Netherlands)

    Hofstra, RMW; Osinga, J; Buys, CHCM

    1997-01-01

    Hirschsprung disease is a congenital disorder clinically characterized by the absence of colonic ganglia and genetically by extensive heterogeneity. Genes involved include RET, GDNF, EDNRB and EDN3. Mutations of these genes may give dominant, recessive, or polygenic patterns of inheritance. In parti

  5. Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations.

    Science.gov (United States)

    Alcalay, Roy N; Mirelman, Anat; Saunders-Pullman, Rachel; Tang, Ming-X; Mejia Santana, Helen; Raymond, Deborah; Roos, Ernest; Orbe-Reilly, Martha; Gurevich, Tanya; Bar Shira, Anat; Gana Weisz, Mali; Yasinovsky, Kira; Zalis, Maayan; Thaler, Avner; Deik, Andres; Barrett, Matthew James; Cabassa, Jose; Groves, Mark; Hunt, Ann L; Lubarr, Naomi; San Luciano, Marta; Miravite, Joan; Palmese, Christina; Sachdev, Rivka; Sarva, Harini; Severt, Lawrence; Shanker, Vicki; Swan, Matthew Carrington; Soto-Valencia, Jeannie; Johannes, Brooke; Ortega, Robert; Fahn, Stanley; Cote, Lucien; Waters, Cheryl; Mazzoni, Pietro; Ford, Blair; Louis, Elan; Levy, Oren; Rosado, Llency; Ruiz, Diana; Dorovski, Tsvyatko; Pauciulo, Michael; Nichols, William; Orr-Urtreger, Avi; Ozelius, Laurie; Clark, Lorraine; Giladi, Nir; Bressman, Susan; Marder, Karen S

    2013-12-01

    The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P 5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

  6. Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation.

    Science.gov (United States)

    Spivak, Jerry L

    2010-03-02

    The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus.

  7. Familial adenomatous polyposis patients without an identified APC germline mutation have a severe phenotype

    DEFF Research Database (Denmark)

    Bisgaard, M L; Ripa, R; Knudsen, Anne Louise;

    2004-01-01

    BACKGROUND: Development of more than 100 colorectal adenomas is diagnostic of the dominantly inherited autosomal disease familial adenomatous polyposis (FAP). Germline mutations can be identified in the adenomatous polyposis coli (APC) gene in approximately 80% of patients. The APC protein compri...... they do not themselves more often represent an isolated case. CONCLUSIONS: The severe phenotype should be considered when counselling FAP families in which attenuated FAP is excluded and in which a causative APC mutation has not been identified.......BACKGROUND: Development of more than 100 colorectal adenomas is diagnostic of the dominantly inherited autosomal disease familial adenomatous polyposis (FAP). Germline mutations can be identified in the adenomatous polyposis coli (APC) gene in approximately 80% of patients. The APC protein...... in patients with a known APC mutation and with the phenotypes characteristic of patients with mutations in specific APC regions and domains. PATIENTS: Data on 121 FAP probands and 149 call up patients from 70 different families were extracted from the Danish Polyposis register. METHODS: Differences in 16...

  8. Progressive skeletal myopathy, a phenotypic variant of desmin myopathy associated with desmin mutations.

    Science.gov (United States)

    Dalakas, Marinos C; Dagvadorj, Ayush; Goudeau, Bertrand; Park, Kye-Yoon; Takeda, Kazuyo; Simon-Casteras, Monique; Vasconcelos, Olavo; Sambuughin, Nyamkhishig; Shatunov, Alexey; Nagle, James W; Sivakumar, Kumaraswamy; Vicart, Patrick; Goldfarb, Lev G

    2003-03-01

    Desmin myopathy is a familial or sporadic disorder characterized by the presence of desmin mutations that cause skeletal muscle weakness associated with cardiac conduction block, arrhythmia and heart failure. Distinctive histopathologic features include intracytoplasmic accumulation of desmin-reactive deposits and electron-dense granular aggregates in skeletal and cardiac muscle cells. We describe two families with features of adult-onset slowly progressive skeletal myopathy without cardiomyopathy. N342D point mutation was present in the desmin helical rod domain in patients of family 1, and I451M mutation was found in the non-helical tail domain in patients of family 2. Of interest, the same I451M mutation has previously been reported in patients with cardiomyopathy and no signs of skeletal myopathy. Some carriers of the I451M mutation did not develop any disease, suggesting incomplete penetrance. Expression studies demonstrated inability of the N342D mutant desmin to form cellular filamentous network, confirming the pathogenic role of this mutation, but the network was not affected by the tail-domain I451M mutation. Progressive skeletal myopathy is a rare phenotypic variant of desmin myopathy allelic to the more frequent cardio-skeletal form.

  9. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations.

    Science.gov (United States)

    Juan-Mateu, Jonas; Gonzalez-Quereda, Lidia; Rodriguez, Maria Jose; Baena, Manel; Verdura, Edgard; Nascimento, Andres; Ortez, Carlos; Baiget, Montserrat; Gallano, Pia

    2015-01-01

    Recent advances in molecular therapies for Duchenne muscular dystrophy (DMD) require precise genetic diagnosis because most therapeutic strategies are mutation-specific. To understand more about the genotype-phenotype correlations of the DMD gene we performed a comprehensive analysis of the DMD mutational spectrum in a large series of families. Here we provide the clinical, pathological and genetic features of 576 dystrophinopathy patients. DMD gene analysis was performed using the MLPA technique and whole gene sequencing in blood DNA and muscle cDNA. The impact of the DNA variants on mRNA splicing and protein functionality was evaluated by in silico analysis using computational algorithms. DMD mutations were detected in 576 unrelated dystrophinopathy families by combining the analysis of exonic copies and the analysis of small mutations. We found that 471 of these mutations were large intragenic rearrangements. Of these, 406 (70.5%) were exonic deletions, 64 (11.1%) were exonic duplications, and one was a deletion/duplication complex rearrangement (0.2%). Small mutations were identified in 105 cases (18.2%), most being nonsense/frameshift types (75.2%). Mutations in splice sites, however, were relatively frequent (20%). In total, 276 mutations were identified, 85 of which have not been previously described. The diagnostic algorithm used proved to be accurate for the molecular diagnosis of dystrophinopathies. The reading frame rule was fulfilled in 90.4% of DMD patients and in 82.4% of Becker muscular dystrophy patients (BMD), with significant differences between the mutation types. We found that 58% of DMD patients would be included in single exon-exon skipping trials, 63% from strategies directed against multiexon-skipping exons 45 to 55, and 14% from PTC therapy. A detailed analysis of missense mutations provided valuable information about their impact on the protein structure.

  10. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations.

    Directory of Open Access Journals (Sweden)

    Jonas Juan-Mateu

    Full Text Available Recent advances in molecular therapies for Duchenne muscular dystrophy (DMD require precise genetic diagnosis because most therapeutic strategies are mutation-specific. To understand more about the genotype-phenotype correlations of the DMD gene we performed a comprehensive analysis of the DMD mutational spectrum in a large series of families. Here we provide the clinical, pathological and genetic features of 576 dystrophinopathy patients. DMD gene analysis was performed using the MLPA technique and whole gene sequencing in blood DNA and muscle cDNA. The impact of the DNA variants on mRNA splicing and protein functionality was evaluated by in silico analysis using computational algorithms. DMD mutations were detected in 576 unrelated dystrophinopathy families by combining the analysis of exonic copies and the analysis of small mutations. We found that 471 of these mutations were large intragenic rearrangements. Of these, 406 (70.5% were exonic deletions, 64 (11.1% were exonic duplications, and one was a deletion/duplication complex rearrangement (0.2%. Small mutations were identified in 105 cases (18.2%, most being nonsense/frameshift types (75.2%. Mutations in splice sites, however, were relatively frequent (20%. In total, 276 mutations were identified, 85 of which have not been previously described. The diagnostic algorithm used proved to be accurate for the molecular diagnosis of dystrophinopathies. The reading frame rule was fulfilled in 90.4% of DMD patients and in 82.4% of Becker muscular dystrophy patients (BMD, with significant differences between the mutation types. We found that 58% of DMD patients would be included in single exon-exon skipping trials, 63% from strategies directed against multiexon-skipping exons 45 to 55, and 14% from PTC therapy. A detailed analysis of missense mutations provided valuable information about their impact on the protein structure.

  11. Bilateral frontoparietal polymicrogyria: a novel GPR56 mutation and an unusual phenotype.

    Science.gov (United States)

    Santos-Silva, Rita; Passas, Armanda; Rocha, Carla; Figueiredo, Rita; Mendes-Ribeiro, Jose; Fernandes, Susana; Biskup, Saskia; Leão, Miguel

    2015-04-01

    Loss of function of GPR56 causes a specific brain malformation called the bilateral frontoparietal polymicrogyria (BFPP), which has typical clinical and neuroradiological findings. So far, 35 families and 26 independent mutations have been described.We present a Portuguese 5-year-old boy, born from nonconsanguineous parents, with BFPP. This patient has a novel GPR56 mutation (R271X) and an unusual phenotype, because he presents hot water epilepsy.To the best of our knowledge, this is the first reported case of BFPP evolving hot water epilepsy.

  12. A rare CYP21A2 mutation in a congenital adrenal hyperplasia kindred displaying genotype–phenotype non-concordance

    Science.gov (United States)

    Khattab, Ahmed; Yuen, Tony; Almalki, Sultan; Yau, Mabel; Kazmi, Diya; Sun, Li; Harbison, Madeleine; Haider, Shozeb; Zaidi, Mone; New, Maria I.

    2015-01-01

    Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is caused by the autosomal recessive inheritance of mutations in the gene CYP21A2. CYP21A2 mutations lead to variable impairment of the 21-hydroxylase enzyme, which, in turn, is associated with three clinical phenotypes, namely, salt wasting, simple virilizing, and non-classical CAH. However, it is known that a given mutation can associate with different clinical phenotypes, resulting in a high rate of genotype–phenotype non-concordance. We aimed to study the genotype–phenotype non-concordance in a family with three sibs affected with non-classical CAH. All had hormonal evidence of non-classical CAH, but this phenotype could not be explained by the genotype obtained from commercial CYP21A2 genetic testing, which revealed heterozygosity for the maternal 30 kb deletion mutation. We performed Sanger sequencing of the entire CYP21A2 gene in this family to search for a rare mutation that was not covered by commercial testing and found in the three sibs a second, rare c.1097G>A (p.R366H) mutation in exon 8. Computational modeling confirmed that this was a mild mutation consistent with non-classical CAH. We recommend that sequencing of entire genes for rare mutations should be carried out when genotype–phenotype non-concordance is observed in patients with autosomal recessive monogenic disorders, including CAH. PMID:26291314

  13. Novel truncating mutations in PKP1 and DSP cause similar skin phenotypes in two Brazilian families.

    Science.gov (United States)

    Tanaka, A; Lai-Cheong, J E; Café, M E M; Gontijo, B; Salomão, P R; Pereira, L; McGrath, J A

    2009-03-01

    Inherited mutations in components of desmosomes result in a spectrum of syndromes characterized by variable abnormalities in the skin and its appendages, including blisters and erosions, palmoplantar hyperkeratosis, woolly hair or hypotrichosis and, in some cases, extracutaneous features such as cardiomyopathy. We investigated the molecular basis of two Brazilian patients presenting with clinical features consistent with ectodermal dysplasia-skin fragility syndrome. In patient 1 we identified a homozygous nonsense mutation, p.R672X, in the PKP1 gene (encoding plakophilin 1). This particular mutation has not been reported previously but is similar to the molecular pathology underlying other cases of this syndrome. In patient 2 we found compound heterozygosity for two frameshift mutations, c.2516del4 and c.3971del4, in the DSP gene (encoding desmoplakin). Although there was considerable clinical overlap in the skin and hair abnormalities in these two cases, patient 2 also had early-onset cardiomyopathy. The mutation c.3971del4 occurs in the longer desmoplakin-I isoform (which is the major cardiac transcript) but not in the more ubiquitous desmoplakin-II. In contrast, PKP1 is not expressed in the heart, which accounts for the lack of cardiomyopathy in patient 1. Collectively, these cases represent the first desmosomal genodermatoses to be reported from Brazil and add to genotype-phenotype correlation in this group of inherited disorders. Loss-of-function mutations in the DSP gene can result in a phenotype similar to ectodermal dysplasia-skin fragility syndrome resulting from PKP1 mutations but only DSP pathology is associated with cardiac disease.

  14. A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients.

    Science.gov (United States)

    Choi, B-O; Nakhro, K; Park, H J; Hyun, Y S; Lee, J H; Kanwal, S; Jung, S-C; Chung, K W

    2015-06-01

    Charcot-Marie-Tooth disease 2A (CMT2A) is the most common axonal form of peripheral neuropathy caused by a defect in the mitofusin 2 (MFN2) gene, which encodes an outer mitochondrial membrane GTPase. MFN2 mutations result in a large range of phenotypes. This study analyzed the prevalence of MFN2 mutation in Korean families with their assorted phenotypes (607 CMT families and 160 CMT2 families). Direct sequencing of the MFN2 coding exons or whole-exome sequencing has been applied to identify causative mutations. A total of 21 mutations were found in 36 CMT2 families. Comparative genotype-phenotype correlations impacting severity, onset age, and specific symptoms were assessed. Most mutations were seen in the GTPase domain (∼86%). A deletion mutation found in the transmembrane helices is reported for the first time, as well as five novel mutations at other domains. MFN2 mutations made up 5.9% of total CMT families, whereas 22.9% in CMT2 families, of which 27.8% occurred de novo. Interestingly, patient phenotypes ranged from mild to severe even for the same mutation, suggesting other factors influenced phenotype and penetrance. This CMT2A cohort study will be useful for molecular diagnosis and treatment of axonal neuropathy.

  15. Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene

    OpenAIRE

    Straub, Volker; Sarkozy, Anna; Windpassinger, Christian; Hudson, Judith; Dougan, Charlotte F; Lecky, Brian; Hilton-Jones, David; Eagle, Michelle; Charlton, Richard; Barresi, Rita; Lochmuller, Hans; Bushby, Kate

    2011-01-01

    Abstract Mutations in the four-and-a-half LIM domain 1 (FHL1) gene, which encodes a 280 amino acid protein containing 4 LIM domains and a single zinc finger domain in the N-terminal region, have been associated with a broad clinical spectrum of X-linked muscle diseases encompassing a variety of different phenotypes. Patients might either present with a scapuloperoneal myopathy, a myopathy with postural muscle atrophy and generalized hypertrophy, an Emery-Dreifuss muscular dystrophy...

  16. Mutations distribution and correlation with phenotypes in steroid 21-hydroxylase deficiency Italian patients

    Energy Technology Data Exchange (ETDEWEB)

    Carrera, P.; Volorio, S.; Ferran, M. [and others

    1994-09-01

    Steroid 21-hydroxylase deficiency is recessively inherited and accounts for over 90% of the genetic disorders of steroidogenesis (CAH). We previously described the distribution of the whole deletion (14.4%) and large scale gene conversion (7.8%) at the P450c21-B locus in our population. In this study we determined the distribution of seven point mutations and searched for new mutations in patients where large rearrangements were not found. For this purpose we have studied 45 Italian families using a P450c21-B-specific PCR in combination with either dot blot analysis and allele-specific oligonucleotide hybridization or by cloning and sequencing. Molecular results have indicated a high frequency of point mutations (61%) corresponding to deleterious sequences normally present in the pseudogene. In particular, only 3 of them were prominent: the splicing mutation at codon 281 (9/16) was the most common within the non-classic form. By cloning and sequencing we detected a deletion of the C2029 residue causing a frameshift and the downstream insertion of a stop codon (2124-2126). This mutation was found in a non-classical patient who is a compound heterozygote for the mutation 281. Family genotyping revealed 5 de novo mutations, and in 8 asymptomatic parents, we detected causative mutations in both alleles. These data suggest that phenotype is not always correlated to allelic variations in P450c21-B genes. For this reason, in these families prenatal diagnosis should be performed by direct detection of mutations instead of linkage analysis.

  17. Particular Mal de Meleda Phenotypes in Tunisia and Mutations Founder Effect in the Mediterranean Region

    Directory of Open Access Journals (Sweden)

    Mbarka Bchetnia

    2013-01-01

    Full Text Available Mal de Meleda (MDM is a rare, autosomal recessive form of palmoplantar keratoderma. It is characterized by erythema and hyperkeratosis of the palms and soles that progressively extend to the dorsal surface of the hands and feet. It is caused by mutations in SLURP-1 gene encoding for secreted mammalian Ly-6/uPAR-related protein 1 (SLURP-1. We performed mutational analysis by direct sequencing of SLURP-1 gene in order to identify the genetic defect in three unrelated families (families MDM-12, MDM-13, and MDM-14 variably affected with transgressive palmoplantar keratoderma. A spectrum of clinical presentations with variable features has been observed from the pronounced to the transparent hyperkeratosis. We identified the 82delT frame shift mutation in the SLURP-1 gene in both families MDM-12 and MDM-13 and the missense variation p.Cys99Tyr in family MDM-14. To date, the 82delT variation is the most frequent cause of MDM in the world which is in favour of a recurrent molecular defect. The p.Cys99Tyr variation is only described in Tunisian families making evidence of founder effect mutation of likely Tunisian origin. Our patients presented with very severe to relatively mild phenotypes, including multiple keratolytic pits observed for one patient in the hyperkeratotic area which was not previously reported. The phenotypic variability may reflect the influence of additional factors on disease characteristics. This report further expands the spectrum of clinical phenotypes associated with mutations in SLURP1 in the Mediterranean population.

  18. SCN4A mutation as modifying factor of myotonic dystrophy type 2 phenotype.

    Science.gov (United States)

    Bugiardini, E; Rivolta, I; Binda, A; Soriano Caminero, A; Cirillo, F; Cinti, A; Giovannoni, R; Botta, A; Cardani, R; Wicklund, M P; Meola, G

    2015-04-01

    In myotonic dystrophy type 2 (DM2), an association has been reported between early and severe myotonia and recessive chloride channel (CLCN1) mutations. No DM2 cases have been described with sodium channel gene (SCN4A) mutations. The aim is to describe a DM2 patient with severe and early onset myotonia and co-occurrence of a novel missense mutation in SNC4A. A 26-year-old patient complaining of hand cramps and difficulty relaxing her hands after activity was evaluated at our department. Neurophysiology and genetic analysis for DM1, DM2, CLCN1 and SCN4A mutations were performed. Genetic testing was positive for DM2 (2650 CCTG repeat) and for a variant c.215C>T (p.Pro72Leu) in the SCN4A gene. The variation affects the cytoplasmic N terminus domain of Nav1.4, where mutations have never been reported. The biophysical properties of the mutant Nav1.4 channels were evaluated by whole-cell voltage-clamp analysis of heterologously expressed mutant channel in tsA201 cells. Electrophysiological studies of the P72L variant showed a hyperpolarizing shift (-5 mV) of the voltage dependence of activation that may increase cell excitability. This case suggests that SCN4A mutations may enhance the myotonic phenotype of DM2 patients and should be screened for atypical cases with severe myotonia.

  19. WDR35 mutation in siblings with Sensenbrenner syndrome: a ciliopathy with variable phenotype.

    Science.gov (United States)

    Bacino, Carlos A; Dhar, Shweta U; Brunetti-Pierri, Nicola; Lee, Brendan; Bonnen, Penelope E

    2012-11-01

    Sensenbrenner syndrome and unclassified short rib-polydactyly conditions are ciliopathies with overlapping phenotypes and genetic heterogeneity. Mutations in WDR35 were identified recently in a sub-group of patients with Sensenbrenner syndrome and in a single family that presented with an unclassified form of short-rib polydactyly (SRP) syndrome. We report on siblings with an unusual combination of phenotypes: narrow thorax, short stature, minor anomalies, developmental delay, and severe hepatic fibrosis leading to liver failure and early death in two of the children. Both parents were unaffected suggesting autosomal recessive inheritance. The family and their affected children were followed over a decade. Exome sequencing was performed in one affected individual. It showed a homozygous missense mutation in a highly conserved position of the WDR35 gene. This family represents a WDR35-ciliopathy with a complex clinical presentation that includes significant overlap of the phenotypes described in Sensenbrenner syndrome and the unclassified SRPs. The accurate molecular diagnosis of this family exemplifies the power of exome sequencing in the diagnosis of Mendelian disorders and enabled us to broaden and refine our understanding of Sensenbrenner syndrome and SRP. Detailed genotype-phenotype information is provided as well as discussion of previously reported cases.

  20. The Stability of G6PD Is Affected by Mutations with Different Clinical Phenotypes

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    Saúl Gómez-Manzo

    2014-11-01

    Full Text Available Glucose-6-phosphate dehydrogenase (G6PD deficiency is the most common enzyme deficiency worldwide, causing a wide spectrum of conditions with severity classified from the mildest (Class IV to the most severe (Class I. To correlate mutation sites in the G6PD with the resulting phenotypes, we studied four naturally occurring G6PD variants: Yucatan, Nashville, Valladolid and Mexico City. For this purpose, we developed a successful over-expression method that constitutes an easier and more precise method for obtaining and characterizing these enzymes. The kcat (catalytic constant of all the studied variants was lower than in the wild-type. The structural rigidity might be the cause and the most evident consequence of the mutations is their impact on protein stability and folding, as can be observed from the protein yield, the T50 (temperature where 50% of its original activity is retained values, and differences on hydrophobic regions. The mutations corresponding to more severe phenotypes are related to the structural NADP+ region. This was clearly observed for the Classes III and II variants, which became more thermostable with increasing NADP+, whereas the Class I variants remained thermolabile. The mutations produce repulsive electric charges that, in the case of the Yucatan variant, promote increased disorder of the C-terminus and consequently affect the binding of NADP+, leading to enzyme instability.

  1. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome.

    Science.gov (United States)

    Brown, Kyla; Selfridge, Jim; Lagger, Sabine; Connelly, John; De Sousa, Dina; Kerr, Alastair; Webb, Shaun; Guy, Jacky; Merusi, Cara; Koerner, Martha V; Bird, Adrian

    2016-02-01

    Rett syndrome is caused by mutations in the X-linked MECP2 gene, which encodes a chromosomal protein that binds to methylated DNA. Mouse models mirror the human disorder and therefore allow investigation of phenotypes at a molecular level. We describe an Mecp2 allelic series representing the three most common missense Rett syndrome (RTT) mutations, including first reports of Mecp2[R133C] and Mecp2[T158M] knock-in mice, in addition to Mecp2[R306C] mutant mice. Together these three alleles comprise ∼25% of all RTT mutations in humans, but they vary significantly in average severity. This spectrum is mimicked in the mouse models; R133C being least severe, T158M most severe and R306C of intermediate severity. Both R133C and T158M mutations cause compound phenotypes at the molecular level, combining compromised DNA binding with reduced stability, the destabilizing effect of T158M being more severe. Our findings contradict the hypothesis that the R133C mutation exclusively abolishes binding to hydroxymethylated DNA, as interactions with DNA containing methyl-CG, methyl-CA and hydroxymethyl-CA are all reduced in vivo. We find that MeCP2[T158M] is significantly less stable than MeCP2[R133C], which may account for the divergent clinical impact of the mutations. Overall, this allelic series recapitulates human RTT severity, reveals compound molecular aetiologies and provides a valuable resource in the search for personalized therapeutic interventions.

  2. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes

    NARCIS (Netherlands)

    Ruijs, M.W.G.; Verhoef, S.; Rookus, M.A.; Pruntel, R.; van der Hout, A.H.; Hogervorst, F.B.L.; Kluijt, I.; Sijmons, R.H.; Aalfs, C.M.; Wagner, A.; Ausems, M.G.E.M.; Hoogerbrugge, N.; van Asperen, C.J.; Gómez García, E.B.; Meijers-Heijboer, H.; ten Kate, L.P.; Menko, F.H.; van 't Veer, L.J.

    2010-01-01

    Background Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations. However, TP53 germline mutations may also occur in less obvious phenotypes. As a result, different criteria a

  3. A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations

    Science.gov (United States)

    Munot, Pinki; Saunders, Dawn E.; Milewicz, Dianna M.; Regalado, Ellen S.; Ostergaard, John R.; Braun, Kees P.; Kerr, Timothy; Lichtenbelt, Klaske D.; Philip, Sunny; Rittey, Christopher; Jacques, Thomas S.; Cox, Timothy C.

    2012-01-01

    Mutations in the ACTA2 gene lead to diffuse and diverse vascular diseases; the Arg179His mutation is associated with an early onset severe phenotype due to global smooth muscle dysfunction. Cerebrovascular disease associated with ACTA2 mutations has been likened to moyamoya disease, but appears to have distinctive features. This study involved the analysis of neuroimaging of 13 patients with heterozygous missense mutations in ACTA2 disrupting Arg179. All patients had persistent ductus arteriosus and congenital mydriasis, and variable presentation of pulmonary hypertension, bladder and gastrointestinal problems associated with this mutation. Distinctive cerebrovascular features were dilatation of proximal internal carotid artery, occlusive disease of terminal internal carotid artery, an abnormally straight course of intracranial arteries, and absent basal ‘moyamoya’ collaterals. Patterns of brain injury supported both large and small vessel disease. Key differences from moyamoya disease were more widespread arteriopathy, the combination of arterial ectasia and stenosis and, importantly, absence of the typical basal ‘moyamoya’ collaterals. Evaluation of previously published cases suggests some of these features are also seen in the ACTA2 mutations disrupting Arg258. The observation that transition from dilated to normal/stenotic arterial calibre coincides with where the internal carotid artery changes from an elastic to muscular artery supports the hypothesis that abnormal smooth muscle cell proliferation caused by ACTA2 mutations is modulated by arterial wall components. Patients with persistent ductus arteriosus or congenital mydriasis with a label of ‘moyamoya’ should be re-evaluated to ensure the distinctive neuroimaging features of an ACTA2 mutation have not been overlooked. This diagnosis has prognostic and genetic implications, and mandates surveillance of other organ systems, in particular the aorta, to prevent life-threatening aortic dissection

  4. Alzheimer disease-like clinical phenotype in a family with FTDP-17 caused by a MAPT R406W mutation

    DEFF Research Database (Denmark)

    Lindquist, S.G.; Holm, I.E.; Schwartz, M.

    2008-01-01

    We report clinical, molecular, neuroimaging and neuropathological features of a Danish family with autosomal dominant inherited dementia, a clinical phenotype resembling Alzheimer's disease and a pathogenic mutation (R406W) in the microtubule associated protein tau (MAPT) gene. Pre-symptomatic an......We report clinical, molecular, neuroimaging and neuropathological features of a Danish family with autosomal dominant inherited dementia, a clinical phenotype resembling Alzheimer's disease and a pathogenic mutation (R406W) in the microtubule associated protein tau (MAPT) gene. Pre...

  5. Mutations in genes involved in nonsense mediated decay ameliorate the phenotype of sel-12 mutants with amber stop mutations in Caenorhabditis elegans

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    Aubert Sylvie

    2009-03-01

    Full Text Available Abstract Background Presenilin proteins are part of a complex of proteins that can cleave many type I transmembrane proteins, including Notch Receptors and the Amyloid Precursor Protein, in the middle of the transmembrane domain. Dominant mutations in the human presenilin genes PS1 and PS2 lead to Familial Alzheimer's disease. Mutations in the Caenorhabditis elegans sel-12 presenilin gene cause a highly penetrant egg-laying defect due to reduction of signalling through the lin-12/Notch receptor. Mutations in six spr genes (for suppressor of presenilin are known to strongly suppress sel-12. Mutations in most strong spr genes suppress sel-12 by de-repressing the transcription of the largely functionally equivalent hop-1 presenilin gene. However, how mutations in the spr-2 gene suppress sel-12 is unknown. Results We show that spr-2 mutations increase the levels of sel-12 transcripts with Premature translation Termination Codons (PTCs in embryos and L1 larvae. mRNA transcripts from sel-12 alleles with PTCs undergo degradation by a process known as Nonsense Mediated Decay (NMD. However, spr-2 mutations do not appear to affect NMD. Mutations in the smg genes, which are required for NMD, can restore sel-12(PTC transcript levels and ameliorate the phenotype of sel-12 mutants with amber PTCs. However, the phenotypic suppression of sel-12 by smg genes is nowhere near as strong as the effect of previously characterized spr mutations including spr-2. Consistent with this, we have identified only two mutations in smg genes among the more than 100 spr mutations recovered in genetic screens. Conclusion spr-2 mutations do not suppress sel-12 by affecting NMD of sel-12(PTC transcripts and appear to have a novel mechanism of suppression. The fact that mutations in smg genes can ameliorate the phenotype of sel-12 alleles with amber PTCs suggests that some read-through of sel-12(amber alleles occurs in smg backgrounds.

  6. A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Garza, Rene [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); Hudson, Robert A. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); McMahan, C. Alex [Department of Pathology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); Walter, Christi A. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); South Texas Veterans Healthcare System, San Antonio, TX 78229 (United States); Vogel, Kristine S. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States)]. E-mail: vogelk@uthscsa.edu

    2007-02-03

    Defects in genes that control DNA repair, proliferation, and apoptosis can increase genomic instability, and thus promote malignant progression. Although most tumors that arise in humans with neurofibromatosis type 1 (NF1) are benign, these individuals are at increased risk for malignant peripheral nerve sheath tumors (MPNST). To characterize additional mutations required for the development of MPNST from benign plexiform neurofibromas, we generated a mouse model for these tumors by combining targeted null mutations in Nf1 and p53, in cis. CisNf1+/-; p53+/- mice spontaneously develop PNST, and these tumors exhibit loss-of-heterozygosity at both the Nf1 and p53 loci. Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies. To quantitate spontaneous mutant frequencies (MF), we crossed the Big Blue mouse, which harbors a lacI transgene, to the cisNf1+/-; p53+/- mice, and isolated genomic DNA from both tumor and normal tissues in compound heterozygotes and wild-type siblings. Many of the PNST exhibited increased mutant frequencies (MF = 4.70) when compared to normal peripheral nerve and brain (MF = 2.09); mutations occurred throughout the entire lacI gene, and included base substitutions, insertions, and deletions. Moreover, the brains, spleens, and livers of these cisNf1+/-; p53+/- animals exhibited increased mutant frequencies when compared to tissues from wild-type littermates. We conclude that a mild mutator phenotype arises in the tumors and tissues of cisNf1+/-; p53+/- mice, and propose that genomic instability influences NF1 tumor progression and disease severity.

  7. The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer.

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    Anne-Mette Hartung

    2016-05-01

    Full Text Available Costello syndrome (CS may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We identified an unusual, new germline p.Gly12Val mutation, c.35_36GC>TG, in a 12-year-old boy with attenuated CS. Analysis of his HRAS cDNA showed high levels of exon 2 skipping. Using wild type and mutant HRAS minigenes, we confirmed that c.35_36GC>TG results in exon 2 skipping by simultaneously disrupting the function of a critical Exonic Splicing Enhancer (ESE and creation of an Exonic Splicing Silencer (ESS. We show that this vulnerability of HRAS exon 2 is caused by a weak 3' splice site, which makes exon 2 inclusion dependent on binding of splicing stimulatory proteins, like SRSF2, to the critical ESE. Because the majority of cancer- and CS- causing mutations are located here, they affect splicing differently. Therefore, our results also demonstrate that the phenotype in CS and somatic cancers is not only determined by the different transforming potentials of mutant HRAS proteins, but also by the efficiency of exon 2 inclusion resulting from the different HRAS mutations. Finally, we show that a splice switching oligonucleotide (SSO that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells. This unravels a potential for development of new anti-cancer therapies based on SSO-mediated HRAS exon 2 skipping.

  8. Comprehensive analysis of gene mutation and phenotype of tuberous sclerosis complex in China

    Directory of Open Access Journals (Sweden)

    Guo-qiang HUANG

    2015-04-01

    Full Text Available Objective To summarize the clinical features of tuberous sclerosis complex (TSC, the distribution and description of TSC gene, and to probe into the correlation of genotype with phenotype.  Methods According to the 1998 International Tuberous Sclerosis Complex Diagnostic Criteria, a total of 163 TSC patients with pathogenic mutation in TSC gene (3 cases were detected in our hospital, and the other 160 cases were collected from other institutions in China were enrolled, and their gene detection results and clinical data were analyzed.  Results Among 163 cases, TSC1 mutation (31 cases accounted for 19.02% [32.26% (10/31 in exon 15, 16.13% (5/31 in exon 21, 12.90% (4/31 in exon 18], and TSC2 mutation (132 cases accounted for 80.98% [9.85% (13/132 in exon 37, 7.58% (10/132 in exon 40, 6.82%(9/132 in exon 33]. The proportion of base replacement in TSC1 was 41.94% (13/31, and 52.27% (69/132 in TSC2. Male patients exhibited significantly more subependymal nodules or calcifications than thefemale patients (χ2 = 8.016, P = 0.005. Sporadic patients exhibited significantly more cortical tubers than familial patients (χ2 = 6.273, P = 0.012. Patients with TSC2 mutations had significantly higher frequencies of hypomelanotic macules than patients with TSC1 mutations (χ2 = 6.756, P = 0.009. Patients with missense mutations were more likely to have facial angiofibromas compared with patients with other mutations (χ2 = 4.438, P = 0.035.  Conclusions Exon 15, 21 and 18 of TSC1 and exon 37, 40 and 33 of TSC2 accounted for higher percentage of mutations. Correlating genotypes with phenotypes should facilitate the individualized treatment and prognostic assessment of tuberous sclerosis complex. DOI: 10.3969/j.issn.1672-6731.2015.04.013

  9. Mosaicism for dominant collagen 6 mutations as a cause for intrafamilial phenotypic variability.

    Science.gov (United States)

    Donkervoort, Sandra; Hu, Ying; Stojkovic, Tanya; Voermans, Nicol C; Foley, A Reghan; Leach, Meganne E; Dastgir, Jahannaz; Bolduc, Véronique; Cullup, Thomas; de Becdelièvre, Alix; Yang, Lin; Su, Hai; Meilleur, Katherine; Schindler, Alice B; Kamsteeg, Erik-Jan; Richard, Pascale; Butterfield, Russell J; Winder, Thomas L; Crawford, Thomas O; Weiss, Robert B; Muntoni, Francesco; Allamand, Valérie; Bönnemann, Carsten G

    2015-01-01

    Collagen 6-related dystrophies and myopathies (COL6-RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy, intermediate phenotypes, to the milder Bethlem myopathy. Both inter- and intrafamilial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6-RD families with marked intergenerational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional fifth simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild-type allele (COL6A1, COL6A2, and COL6A3) in genomic DNA from various tissues, including blood, dermal fibroblasts, and saliva. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild-type allele compared with the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intrafamilial/intergenerational variability of COL6-RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected.

  10. [Novel TSC1 mutation associated with variable phenotypes in tuberous sclerosis].

    Science.gov (United States)

    Kövesdi, Erzsébet; Hadzsiev, Kinga; Komlósi, Katalin; Kassay, Mária; Barsi, Péter; Melegh, Béla

    2013-06-01

    Tuberous sclerosis is an autosomal dominant disorder, caused by mutations of the TSC1 or TSC2 genes resulting in tumor predisposition. Clinical signs include non-malignant brain tumors, skin, eye, heart and kidney abnormalities. The authors report a Hungarian family with broad phenotypic variability. First, the 5-year-old boy, showing the most symptoms was examined, whose first seizure occurred at 15 months and a cranial magnetic resonance imaging revealed numerous intracerebral calcareous foci. Except of hypopigmented skin spots, no other abnormality was found on physical examination. The mother was completely asymptomatic. Epilepsy of the maternal uncle started at the age of 3 years, of his sister at the age of 17 years and of the maternal grandmother at the age of 39 years. At the age of 52 years the grandmother developed renal cysts. Molecular genetic analysis of the family confirmed a de novo heterozygous point mutation (c.2524 C\\>T) [corrected] in exon 20 of the TSC1 gene. The mutation was detected in all examined family members. Despite increasing data on the pathomechanism of tuberous sclerosis, there is still little known about the genetic modifying factors influencing the broad intra- and interfamilial phenotypic variability.

  11. Disintegrating the fly: A mutational perspective on phenotypic integration and covariation.

    Science.gov (United States)

    Haber, Annat; Dworkin, Ian

    2017-01-01

    The structure of environmentally induced phenotypic covariation can influence the effective strength and magnitude of natural selection. Yet our understanding of the factors that contribute to and influence the evolutionary lability of such covariation is poor. Most studies have either examined environmental variation without accounting for covariation, or examined phenotypic and genetic covariation without distinguishing the environmental component. In this study, we examined the effect of mutational perturbations on different properties of environmental covariation, as well as mean shape. We use strains of Drosophila melanogaster bearing well-characterized mutations known to influence wing shape, as well as naturally derived strains, all reared under carefully controlled conditions and with the same genetic background. We find that mean shape changes more freely than the covariance structure, and that different properties of the covariance matrix change independently from each other. The perturbations affect matrix orientation more than they affect matrix eccentricity or total variance. Yet, mutational effects on matrix orientation do not cluster according to the developmental pathway that they target. These results suggest that it might be useful to consider a more general concept of "decanalization," involving all aspects of variation and covariation.

  12. Homozygous N396T mutation in Gaucher disease: Portuguese sisters with markedly different phenotypes

    Directory of Open Access Journals (Sweden)

    Samantha Kimball

    2011-03-01

    Full Text Available Samantha Kimball1,2, Francis Choy4, Agnes Zay5, Dominick Amato31Department of Nutritional Sciences, University of Toronto, Canada; 2Department of Laboratory Medicine and Pathology, 3Department of Medicine, Division of Hematology, Mt Sinai Hospital, Toronto, Canada; 4Department of Biology, University of Victoria, Victoria, Canada; 5MRC Center for Regenerative Medicine, University of Edinburgh, Edinburgh, ScotlandAbstract: Gaucher disease (GD is characterized by reduced activity of glucocerebrosidase leading to complications in the reticuloendothelial system. N396T, a rarer mutation of the glucocerebrosidase gene, has been encountered in Portuguese populations and has generally been associated with milder phenotypes. This report presents brief histories of two Portuguese sisters, both with homozygous N396T mutations. These patients are phenotypically very different despite the fact that in both patients residual enzyme activity is very low. The case of patient 1 is complicated by comorbid diabetes mellitus and human immunodeficiency virus (HIV infection. Enzyme replacement therapy (ERT improved this patient's clinical picture sufficiently to enable antiretroviral treatment to proceed for the HIV. This report demonstrates the poor correlation of clinical GD with genotype as well as with residual enzyme activity. It further illustrates how treatment of the underlying GD with ERT improved symptoms allowing for antiretroviral therapy thereby improving both the GD and HIV.Keywords: Gaucher disease, N396T mutation, glucocerebrosidase, HIV

  13. Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients

    DEFF Research Database (Denmark)

    Hoornaert, Kristien P; Vereecke, Inge; Dewinter, Chantal;

    2010-01-01

    Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation ...

  14. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection.

    NARCIS (Netherlands)

    Pearson, E.R.; Pruhova, S.; Tack, C.J.J.; Johansen, A.; Castleden, H.A.; Lumb, P.J.; Wierzbicki, A.S.; Clark, P.M.; Lebl, J.; Pedersen, O.; Ellard, S.; Hansen, T.; Hattersley, A.T.

    2005-01-01

    AIMS/HYPOTHESIS: Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha) are considered a rare cause of MODY with only 14 mutations reported to date. The description of the phenotype is limited to single families. We investigated the genetics and

  15. Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy

    DEFF Research Database (Denmark)

    Böhm, Johann; Biancalana, Valérie; Dechene, Elizabeth T

    2012-01-01

    regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort...... protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT....

  16. Mutations in BALB mitochondrial DNA induce CCL20 up-regulation promoting tumorigenic phenotypes

    Energy Technology Data Exchange (ETDEWEB)

    Sligh, James [Department of Medicine—Dermatology Division, University of Arizona, Tucson, AZ 857 24 (United States); University of Arizona Cancer Center, Tucson, AZ 85724 (United States); Janda, Jaroslav [University of Arizona Cancer Center, Tucson, AZ 85724 (United States); Jandova, Jana, E-mail: jjandova@email.arizona.edu [Department of Medicine—Dermatology Division, University of Arizona, Tucson, AZ 857 24 (United States); University of Arizona Cancer Center, Tucson, AZ 85724 (United States)

    2014-11-15

    Highlights: • Alterations in mitochondrial DNA are commonly found in various human cancers. • Mutations in BALB mitochondrial DNA induce up-regulation of chemokine CCL20. • Increased growth and motility of mtBALB cells is associated with CCL20 levels. • mtDNA changes in BALB induce in vivo tumor growth through CCL20 up-regulation. • Mutations in mitochondrial DNA play important roles in keratinocyte neoplasia. - Abstract: mtDNA mutations are common in human cancers and are thought to contribute to the process of neoplasia. We examined the role of mtDNA mutations in skin cancer by generating fibroblast cybrids harboring a mutation in the gene encoding the mitochondrial tRNA for arginine. This somatic mutation (9821insA) was previously reported in UV-induced hyperkeratotic skin tumors in hairless mice and confers specific tumorigenic phenotypes to mutant cybrids. Microarray analysis revealed and RT-PCR along with Western blot analysis confirmed the up-regulation of CCL20 and its receptor CCR6 in mtBALB haplotype containing the mt-Tr 9821insA allele compared to wild type mtB6 haplotype. Based on reported role of CCL20 in cancer progression we examined whether the hyper-proliferation and enhanced motility of mtBALB haplotype would be associated with CCL20 levels. Treatment of both genotypes with recombinant CCL20 (rmCCL20) resulted in enhanced growth and motility of mtB6 cybrids. Furthermore, the acquired somatic alteration increased the in vivo tumor growth of mtBALB cybrids through the up-regulation of CCL20 since neutralizing antibody significantly decreased in vivo tumor growth of these cells; and tumors from anti-CCL20 treated mice injected with mtBALB cybrids showed significantly decreased CCL20 levels. When rmCCL20 or mtBALB cybrids were used as chemotactic stimuli, mtB6 cybrids showed increased motility while anti-CCL20 antibody decreased the migration and in vivo tumor growth of mtBALB cybrids. Moreover, the inhibitors of MAPK signaling and NF

  17. Neuroimaging features in C9orf72 and TARDBP double mutation with FTD phenotype.

    Science.gov (United States)

    Origone, Paola; Accardo, Jennifer; Verdiani, Simonetta; Lamp, Merit; Arnaldi, Dario; Bellone, Emilia; Picco, Agnese; Morbelli, Silvia; Mandich, Paola; Nobili, Flavio

    2015-01-01

    Increasing evidence has shown that morphological and functional neuroimaging may help to understand the pathophysiological mechanisms leading to behavioral disturbances in patients with genetic or sporadic frontotemporal dementia (FTD). The C9orf72 expansion was found in association with the N267S TARDBP mutation in two siblings with behavioral-variant FTD (bvFTD). In one of them with very mild dementia, MRI showed symmetric atrophy of temporal, inferolateral and orbital frontal cortex, while [18F]FDG-PET disclosed more extended hypometabolism in dorsolateral and inferolateral frontal cortex, anterior cingulate, and caudate nucleus. Hypometabolism in right lateral and orbital frontal cortex was confirmed also in comparison with a group of sporadic bvFTD patients. These findings appear as the neuroimaging hallmark of double C9orf72 and TARDBP gene mutation with a bvFTD phenotype.

  18. Phenotype characterization and DSPP mutational analysis of three Brazilian dentinogenesis imperfecta type II families.

    Science.gov (United States)

    Acevedo, A C; Santos, L J S; Paula, L M; Dong, J; MacDougall, M

    2009-01-01

    The aim of this study was to perform phenotype analysis and dentin sialophosphoprotein (DSPP) mutational analysis on 3 Brazilian families diagnosed with dentinogenesis imperfecta type II (DGI-II) attending the Dental Anomalies Clinic in Brasilia, Brazil. Physical and oral examinations, as well as radiographic and histopathological analyses, were performed on 28 affected and unaffected individuals. Clinical, radiographic and histopathological analyses confirmed the diagnosis of DGI-II in 19 individuals. Pulp stones were observed in ground sections of several teeth in 2 families, suggesting that obliteration of pulp chambers and root canals results from the growth of these nodular structures. Mutational DSPP gene analysis of representative affected family members revealed 7 various non-disease-causing alterations in exons 1-4 within the dentin sialoprotein domain. Further longitudinal studies are necessary to elucidate the progression of pulpal obliteration in the DGI-II patients studied as well as the molecular basis of their disease.

  19. Prediction of phenotypes of missense mutations in human proteins from biological assemblies.

    Science.gov (United States)

    Wei, Qiong; Xu, Qifang; Dunbrack, Roland L

    2013-02-01

    Single nucleotide polymorphisms (SNPs) are the most frequent variation in the human genome. Nonsynonymous SNPs that lead to missense mutations can be neutral or deleterious, and several computational methods have been presented that predict the phenotype of human missense mutations. These methods use sequence-based and structure-based features in various combinations, relying on different statistical distributions of these features for deleterious and neutral mutations. One structure-based feature that has not been studied significantly is the accessible surface area within biologically relevant oligomeric assemblies. These assemblies are different from the crystallographic asymmetric unit for more than half of X-ray crystal structures. We find that mutations in the core of proteins or in the interfaces in biological assemblies are significantly more likely to be disease-associated than those on the surface of the biological assemblies. For structures with more than one protein in the biological assembly (whether the same sequence or different), we find the accessible surface area from biological assemblies provides a statistically significant improvement in prediction over the accessible surface area of monomers from protein crystal structures (P = 6e-5). When adding this information to sequence-based features such as the difference between wildtype and mutant position-specific profile scores, the improvement from biological assemblies is statistically significant but much smaller (P = 0.018). Combining this information with sequence-based features in a support vector machine leads to 82% accuracy on a balanced dataset of 50% disease-associated mutations from SwissVar and 50% neutral mutations from human/primate sequence differences in orthologous proteins.

  20. A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype.

    Science.gov (United States)

    Romaniello, Romina; Saettini, Francesco; Panzeri, Elena; Arrigoni, Filippo; Bassi, Maria T; Borgatti, Renato

    2015-03-25

    This study reports on a 9-year-old girl who developed West syndrome and showed clinical features fulfilling the main revised diagnostic criteria for typical Rett syndrome (hand washing, severe cognitive impairment with absence of language, ataxic gait, progressive scoliosis and autistic features). Mutation analyses for methyl-CpG-binding protein 2 (MECP2), cyclin-dependent kinase-like 5 (CDKL5/STK9), ARX and Forkhead box G1 (FOXG1) genes were carried out, with negative results. A known de-novo c.1217G>A missense mutation in exon 14 leading to the substitution of a conserved residue, p.R406H in domain3b of the syntaxin-binding protein 1 (STXBP1) gene, was detected. The STXBP1 gene encodes the syntaxin-binding protein 1, a neuron-specific protein involved in synaptic vesicle release at both glutaminergic and GABAergic synapses. This function is also affected by MECP2 gene mutations, which are known to lead to a decrease in glutamate and GABA receptors' density. It is possible to speculate that the impairment in synaptic plasticity represents the pathogenic link between MECP2 and STXBP1 gene mutations. On reviewing the clinical features of the reported patients with the same mutation in the STXBP1 gene, it has been observed that poor eye contact, tremour, dyskinesia, head/hand stereotypies and both cognitive and motor progressive deterioration are common symptoms, although never considered as indicative of a Rett syndrome phenotype. In conclusion, the case described here suggests a relationship between the Rett syndrome and the STXBP1 gene not described so far, making the search for STXBP1 gene mutations advisable in patients with Rett syndrome and early onset of epilepsy.

  1. Different attenuated phenotypes of GM2 gangliosidosis variant B in Japanese patients with HEXA mutations at codon 499, and five novel mutations responsible for infantile acute form.

    Science.gov (United States)

    Tanaka, Akemi; Hoang, Lan Thi Ngcok; Nishi, Yasuaki; Maniwa, Satoshi; Oka, Makio; Yamano, Tsunekazu

    2003-01-01

    Eight mutations of the alpha subunit of beta-hexosaminidase A gene ( HEXA) were identified in eight patients with GM2 gangliosidosis variant B. They were five missense mutations, two splice-site mutations, and one two-base deletion. Five of them, R252L (CGT-->CTT), N295S (AAT-->AAC), W420C (TGG-->TGT), IVS 13, +2A-->C, and del 265-266AC (exon 2), were novel mutations responsible for infantile acute form of GM2 gangliosidosis. Two missense mutations, R499H and R499C, were found in one allele of two patients with attenuated phenotypes. The patient with R499C showed a late infantile form, and the other patient with R499H showed a juvenile form. These two mutations have been reported previously in the patients of other ethnic groups, and they have been known to cause attenuated phenotypes. The milder phenotypes of GM2 gangliosidosis variant B, different from the infantile acute form, have not been reported so far in Japan, and this is the first report of Japanese patients with attenuated phenotypes and their molecular analysis.

  2. XPD Helicase Structures and Activities: Insights into the Cancer and Aging Phenotypes from XPD Mutations

    Energy Technology Data Exchange (ETDEWEB)

    Tainer, John; Fan, Li; Fuss, Jill O.; Cheng, Quen J.; Arvai, Andrew S.; Hammel, Michal; Roberts, Victoria A.; Cooper, Priscilla K.; Tainer, John A.

    2008-06-02

    Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicase activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.

  3. XPD Helicase Structures And Activities: Insights Into the Cancer And Aging Phenotypes From XPD Mutations

    Energy Technology Data Exchange (ETDEWEB)

    Fan, L.; Fuss, J.O.; Cheng, Q.J.; Arvai, A.S.; Hammel, M.; Roberts, V.A.; Cooper, P.K.; Tainer, J.A.

    2009-05-18

    Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicase activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.

  4. Further defining the phenotypic spectrum of B4GALT7 mutations.

    Science.gov (United States)

    Salter, Claire G; Davies, Justin H; Moon, Rebecca J; Fairhurst, Joanna; Bunyan, David; Foulds, Nicola

    2016-06-01

    Proteoglycans are components of the extracellular matrix with diverse biological functions. Defects in proteoglycan synthesis have been linked to several human diseases with common features of short stature, hypermobility, joint dislocations, and skeletal dysplasia. B4GALT7 encodes galactosyltransferase-I that catalyzes the addition of a galactose moiety to a xylosyl group in the tetrasaccharide linker of proteoglycans. Mutations in this gene have been associated with the rare progeroid form of Ehlers Danlos syndrome and in addition more recently found to underlie Larsen of Reunion Island syndrome. Nine individuals have been reported with a diagnosis of the progeroid form of Ehlers Danlos syndrome, four of whom have had molecular characterization showing homozygous or compound heterozygous mutations in B4GALT7. We report two newly described patients with compound heterozygous mutations in B4GALT7, and show that the six individuals with confirmed mutations do not have the progeroid features described in the original five patients with a clinical diagnosis of the progeroid form of Ehlers Danlos syndrome. We suggest that galactosyltransferase-I deficiency does not cause the progeroid form of Ehlers Danlos syndrome, but instead results in a clinically recognizable syndrome comprising short stature, joint hypermobility, radioulnar synostosis, and severe hypermetropia. This group of syndromic patients are on a phenotypic spectrum with individuals who have Larsen of Reunion Island syndrome, although the key features of osteopenia, fractures and hypermetropia have not been reported in patients from Reunion Island. © 2016 Wiley Periodicals, Inc.

  5. Analysis of phenotype, enzyme activity and genotype of Chinese patients with POMT1 mutation.

    Science.gov (United States)

    Yang, Haipo; Manya, Hiroshi; Kobayashi, Kazuhiro; Jiao, Hui; Fu, Xiaona; Xiao, Jiangxi; Li, Xiaoqing; Wang, Jingmin; Jiang, Yuwu; Toda, Tatsushi; Endo, Tamao; Wu, Xiru; Xiong, Hui

    2016-08-01

    Protein O-mannosyltransferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan glycosylation. POMT1 mutations cause a wide spectrum of clinical conditions from Walker-Warburg syndrome (WWS), which involves muscle, eye and brain abnormalities, to mild forms of limb-girdle muscular dystrophy with mental retardation. We aimed to elucidate the impact of different POMT1 mutations on the clinical phenotype. We report five Chinese patients with POMT1 mutations: one had a typical clinical manifestation of WWS, and the other four were diagnosed with congenital muscular dystrophy with mental retardation of varying severity. We analyzed the influence of the POMT1 mutations on POMT activity by assaying the patients' muscles and cultured skin fibroblasts. We demonstrated different levels of decreased POMT activity that correlated highly with decreased α-dystroglycan glycosylation. Our results suggest that POMT activity is inversely proportional to clinical severity, and demonstrate that skin fibroblasts can be used for differential diagnosis of patients with α-dystroglycanopathies. We have provided clinical, histological, enzymatic and genetic evidence of POMT1 involvement in five unrelated Chinese patients.

  6. Novel phenotype associated with a mutation in the KCNA1(Kv1.1 gene

    Directory of Open Access Journals (Sweden)

    Maria Cristina D'Adamo

    2015-01-01

    Full Text Available Episodic ataxia type 1 (EA1 is an autosomal dominant K+ channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G was identified that changes a highly conserved residue (p.C185W in the first transmembrane segment of the voltage-gated K+ channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K+ channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1.

  7. Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene

    Science.gov (United States)

    D'Adamo, Maria C.; Gallenmüller, Constanze; Servettini, Ilenio; Hartl, Elisabeth; Tucker, Stephen J.; Arning, Larissa; Biskup, Saskia; Grottesi, Alessandro; Guglielmi, Luca; Imbrici, Paola; Bernasconi, Pia; Di Giovanni, Giuseppe; Franciolini, Fabio; Catacuzzeno, Luigi; Pessia, Mauro; Klopstock, Thomas

    2015-01-01

    Episodic ataxia type 1 (EA1) is an autosomal dominant K+ channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G) was identified that changes a highly conserved residue (p.C185W) in the first transmembrane segment of the voltage-gated K+ channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K+ channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1. PMID:25642194

  8. Diverse Phenotypic Expression of Cardiomyopathies in a Family with TNNI3 p.Arg145Trp Mutation

    Science.gov (United States)

    Hwang, Ji-won; Jang, Mi-Ae; Jang, Shin Yi; Seo, Soo Hyun; Seong, Moon-Woo; Park, Sung Sup; Ki, Chang-Seok

    2017-01-01

    Genetic diagnosis of cardiomyopathies is challenging, due to the marked genetic and allelic heterogeneity and the lack of knowledge of the mutations that lead to clinical phenotypes. Here, we present the case of a large family, in which a single TNNI3 mutation caused variable phenotypic expression, ranging from restrictive cardiomyopathy (RCMP) to hypertrophic cardiomyopathy (HCMP) to near-normal phenotype. The proband was a 57-year-old female with HCMP. Examining the family history revealed that her elder sister had expired due to severe RCMP. Using a next-generation sequencing-based gene panel to analyze the proband, we identified a known TNNI3 gene mutation, c.433C>T, which is predicted to cause an amino acid substitution (p.Arg145Trp) in the highly conserved inhibitory region of the cardiac troponin I protein. Sanger sequencing confirmed that six relatives with RCMP or near-normal phenotypes also carried this mutation. To our knowledge, this is the first genetically confirmed family with diverse phenotypic expression of cardiomyopathies in Korea. Our findings demonstrate familial implications, where a single mutation in a sarcomere protein can cause diverse phenotypic expression of cardiomyopathies.

  9. Further insight into the phenotype associated with a mutation in the ORC6 gene, causing Meier-Gorlin syndrome 3.

    Science.gov (United States)

    Shalev, Stavit Allon; Khayat, Morad; Etty, Daniel-Spiegl; Elpeleg, Orly

    2015-03-01

    Mutations in genes encoding the origin recognition complex subunits cause Meier-Gorlin syndrome. The disease manifests a triad of short stature, small ears, and small and/or absent patellae with variable expressivity. We report on the identification of a homozygous deleterious mutation in the ORC6 gene in previously described fetuses at the severe end of the Meier-Gorlin spectrum. The phenotype included severe intrauterine growth retardation, dislocation of knees, gracile bones, clubfeet, and small mandible and chest. To date, the clinical presentation of ORC6-associated Meier-Gorlin syndrome has been mild compared to other the phenotype associated with other loci. The present report expands the clinical phenotype associated with ORC6 mutations to include severely abnormal embryological development suggesting a possible genotype-phenotype correlation.

  10. Relation between poor persistance of a mutant phenotype and mutational spectra using the aprt system

    Energy Technology Data Exchange (ETDEWEB)

    Dion, P.A.; Belouchi, A.; Gaudreault, N. [Institut du Cancer Montreal (Canada)] [and others

    1994-09-01

    In the last fifteen years our laboratory has characterized a response to DNA damage which is called loss of persistance of a mutant phenotype. Mutants of Chinese hamster ovary cells (CHO), induced by ethylmethane sulfonate (EMS), are nearly always underrepresented in the population following 5-10 generations of growth in non-selective media. However several variant lines exist for which the number of progeny mutants, following the same protocol, is up to ten-fold higher. Different explanations for this have been tested. Mutational spectra have been used in many studies to yield information about the mechanism of action of mutagens. They can also be exploited to give information about how cells respond to a specific mutagen. Previously our laboratory has shown that following EMS treatment, two mutational hotspots existed within the third exon of the aprt gene: one at nucleotide 1365 (Mspl site) and a second between nucleotides 1303 to 1309. These results were obtained using normal CHO cell lines. We have now generated high density mutational spectra of the same exon following treatment with EMS, using variant cell lines. The spectra obtained were different in a variety of aspects. The hotspot at nucleotide 1365 was substantially reduced in variant cell lines. A possible explanation for this and other differences could be that the different form taken by various mutants act as different signals to the mechanism rendering some mutants undetectable in normal cells. So the relative accumulation of mutants at 1365 in normal cells would be due to a poor signaling toward such a system, while other mutations would be more efficient signals. This unknown mechanism could be something similar to molecular chaperones, which are more and more recognized as being able to distinguish the unfolded or mutated form of a protein.

  11. Oncometabolic mutation IDH1 R132H confers a metformin-hypersensitive phenotype.

    Science.gov (United States)

    Cuyàs, Elisabet; Fernández-Arroyo, Salvador; Corominas-Faja, Bruna; Rodríguez-Gallego, Esther; Bosch-Barrera, Joaquim; Martin-Castillo, Begoña; De Llorens, Rafael; Joven, Jorge; Menendez, Javier A

    2015-05-20

    Metabolic flexibility might be particularly constrained in tumors bearing mutations in isocitrate dehydrogenase 1 (IDH1) leading to the production of the oncometabolite 2-hydroxygluratate (2HG). To test the hypothesis that IDH1 mutations could generate metabolic vulnerabilities for therapeutic intervention, we utilized an MCF10A cell line engineered with an arginine-to-histidine conversion at position 132 (R132H) in the catalytic site of IDH1, which equips the enzyme with a neomorphic α-ketoglutarate to 2HG reducing activity in an otherwise isogenic background. IDH1 R132H/+ and isogenic IDH1 +/+ parental cells were screened for their ability to generate energy-rich NADH when cultured in a standardized high-throughput Phenotype MicroArrayplatform comprising >300 nutrients. A radical remodeling of the metabotype occurred in cells carrying the R132H mutation since they presented a markedly altered ability to utilize numerous carbon catabolic fuels. A mitochondria toxicity-screening modality confirmed a severe inability of IDH1-mutated cells to use various carbon substrates that are fed into the electron transport chain at different points. The mitochondrial biguanide poisons, metformin and phenformin, further impaired the intrinsic weakness of IDH1-mutant cells to use certain carbon-energy sources. Additionally, metabolic reprogramming of IDH1-mutant cells increased their sensitivity to metformin in assays of cell proliferation, clonogenic potential, and mammosphere formation. Targeted metabolomics studies revealed that the ability of metformin to interfere with the anaplerotic entry of glutamine into the tricarboxylic acid cycle could explain the hypersensitivity of IDH1-mutant cells to biguanides. Moreover, synergistic interactions occurred when metformin treatment was combined with the selective R132H-IDH1 inhibitor AGI-5198. Together, these results suggest that therapy involving the simultaneous targeting of metabolic vulnerabilities with metformin, and 2HG

  12. Highly prevalent LIPH founder mutations causing autosomal recessive woolly hair/hypotrichosis in Japan and the genotype/phenotype correlations.

    Directory of Open Access Journals (Sweden)

    Kana Tanahashi

    Full Text Available Mutations in LIPH cause of autosomal recessive woolly hair/hypotrichosis (ARWH, and the 2 missense mutations c.736T>A (p.Cys246Ser and c.742C>A (p.His248Asn are considered prevalent founder mutations for ARWH in the Japanese population. To reveal genotype/phenotype correlations in ARWH cases in Japan and the haplotypes in 14 Japanese patients from 14 unrelated Japanese families. 13 patients had woolly hair, and 1 patient had complete baldness since birth. An LIPH mutation search revealed homozygous c.736T>A mutations in 10 of the patients. Compound heterozygous c.736T>A and c.742C>A mutations were found in 3 of the patients, and homozygous c.742C>A mutation in 1 patient. The phenotype of mild hypotrichosis with woolly hair was restricted to the patients with the homozygous c.736T>A mutation. The severe phenotype of complete baldness was seen in only 1 patient with homozygous c.742C>A. Haplotype analysis revealed that the alleles containing the LIPH c.736T>A mutation had a haplotype identical to that reported previously, although 4 alleles out of 5 chromosomes containing the LIPH c.742C>A mutation had a different haplotype from the previously reported founder allele. These alleles with c.742C>A are thought to be the third founder LIPH mutation causing ARWH. To accurately determine the prevalence of the founder mutations, we investigated allele frequencies of those mutations in 819 Japanese controls. Heterozygous c.736T>A mutations were found in 13 controls (allele frequency: 0.0079; carrier rate: 0.016, and heterozygous c.742C>A mutations were found in 2 controls (allele frequency: 0.0012; carrier rate: 0.0024. In conclusion, this study confirms the more accurate allele frequencies of the pathogenic founder mutations of LIPH and shows that there is a third founder mutation in Japan. In addition, the present findings suggest that the mutation patterns of LIPH might be associated with hypotrichosis severity in ARWH.

  13. CYP24A1 loss of function: Clinical phenotype of monoallelic and biallelic mutations.

    Science.gov (United States)

    Carpenter, Thomas O

    2017-01-16

    CYP24A1, encoding the vitamin D-24-hydroxylase, is of major clinical and physiologic importance, serving to regulate the catabolism of 1,25-(OH)2D, the physiologically active vitamin D metabolite. In addition to facilitating catabolism of 1,25-(OH)2D, CYP24A1 also enhances the turnover and elimination of 25-OHD, the abundant precursor metabolite and storage form of the vitamin. CYP24A1 can be stimulated hormonally by 1,25-(OH)2D and by FGF23, whereas CYP27B1, encoding the vitamin D-1α-hydroxylase, is stimulated hormonally by parathyroid hormone (PTH) and downregulated by FGF23. Thus CYP24A1 and CYP27B1, together, provide for alternate and regulated fates of 25-OHD, and control the availability of the active metabolite, 1,25-(OH)2D, depending upon physiologic needs. These two enzymes, are therefore central to the homeostatic control of vitamin D metabolism, and as a result affect calcium metabolism in critical ways. Disruption of CYP24A1 in mice results in elevated circulating 1,25-(OH)2D, substantiating the importance of the enzyme in the maintenance of vitamin D metabolism. The consequential skeletal phenotype in these mice further demonstrates the biologic sequelae of the disruption of the vitamin D pathway, and illustrates a specific developmental pathology mediated largely by oversupply of 1,25-(OH)2D. More recent evidence has identified loss of function mutations in CYP24A1 in association with hypercalcemia, hypercalciuria and nephrolithiasis in humans. Initial reports described certain variant mutations in CYP24A1 as an unrecognized cause of "Idiopathic Infantile Hypercalcemia," and more recently older children and adults have been identified with a similar phenotype. Over 25 likely disease-causing variants are described. Homozygous and compound heterozygote mutations account for the overwhelming majority of cases, however the heterozygous loss-of-function mutations of CYP24A1 do not appear to consistently result in symptomatic hypercalcemia. Considerations

  14. Novel mutation in Sjogren-Larsson syndrome is associated with divergent neurologic phenotypes.

    Science.gov (United States)

    Davis, Kathleen; Holden, Kenton R; S'Aulis, Dana; Amador, Claudia; Matheus, M Gisele; Rizzo, William B

    2013-10-01

    Sjögren-Larsson syndrome is an inherited disorder of lipid metabolism caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase, which results in accumulation of fatty aldehydes and alcohols and is characterized by ichthyosis, intellectual disability, and spastic diplegia/quadriplegia. The authors describe 2 unrelated Honduran patients who carried the same novel homozygous nonsense mutation (c.1309A>T, p.K437X) and ALDH3A2 DNA haplotype, but widely differed in disease severity. One patient exhibited spastic quadriplegia with unusual neuroregression, whereas the other patient had the usual static form of spastic diplegia with neurodevelopmental disabilities. Biochemical analyses showed a similar profound deficiency of fatty aldehyde dehydrogenase activity and impaired fatty alcohol metabolism in both patients' cultured fibroblasts. These results indicate that variation in the neurologic phenotype of Sjögren-Larsson syndrome is not strictly determined by the ALDH3A2 mutation or the biochemical defect as expressed in cultured fibroblasts, but by unidentified epigenetic/environmental factors, gene modifiers, or other mechanisms.

  15. Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter

    Science.gov (United States)

    Borzutzky, Arturo; Crompton, Brian; Bergmann, Anke K.; Giliani, Silvia; Baxi, Sachin; Martin, Madelena; Neufeld, Ellis J.; Notarangelo, Luigi D.

    2009-01-01

    Hereditary folate malabsorption is a rare inborn error of metabolism due to mutations in the proton-coupled folate transporter (PCFT). Clinical presentation of PCFT deficiency may mimic severe combined immune deficiency (SCID). We report a 4-month-old female who presented with failure to thrive, normocytic anemia, Pneumocystis jirovecii pneumonia and systemic cytomegalovirus infection. Immunological evaluation revealed hypogammaglobulinemia, absent antibody responses, and lack of mitogen-induced lymphocyte proliferative responses. However, the absolute number and distribution of lymphocyte subsets, including naïve T cells and recent thymic emigrants, were normal, arguing against primary SCID. Serum and cerebrospinal fluid folate levels were undetectable. A homozygous 1082-1G>A mutation of the PCFT gene was found, resulting in skipping of exon 3. Parenteral folinic acid repletion resulted in normalization of anemia, humoral and cellular immunity, and full clinical recovery. PCFT mutations should be considered in infants with SCID-like phenotype, as the immunodeficiency is reversible with parenteral folinic acid repletion. PMID:19740703

  16. Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum

    Science.gov (United States)

    Thorwarth, Anne; Schnittert-Hübener, Sarah; Schrumpf, Pamela; Müller, Ines; Jyrch, Sabine; Dame, Christof; Biebermann, Heike; Kleinau, Gunnar; Katchanov, Juri; Schuelke, Markus; Ebert, Grit; Steininger, Anne; Bönnemann, Carsten; Brockmann, Knut; Christen, Hans-Jürgen; Crock, Patricia; deZegher, Francis; Griese, Matthias; Hewitt, Jacqueline; Ivarsson, Sten; Hübner, Christoph; Kapelari, Klaus; Plecko, Barbara; Rating, Dietz; Stoeva, Iva; Ropers, Hans-Hilger; Grüters, Annette; Ullmann, Reinhard; Krude, Heiko

    2017-01-01

    Background NKX2-1 encodes a transcription factor with large impact on the development of brain, lung and thyroid. Germline mutations of NKX2-1 can lead to dysfunction and malformations of these organs. Starting from the largest coherent collection of patients with a suspected phenotype to date, we systematically evaluated frequency, quality and spectrum of phenotypic consequences of NKX2-1 mutations. Methods After identifying mutations by Sanger sequencing and array CGH, we comprehensively reanalysed the phenotype of affected patients and their relatives. We employed electrophoretic mobility shift assay (EMSA) to detect alterations of NKX2-1 DNA binding. Gene expression was monitored by means of in situ hybridisation and compared with the expression level of MBIP, a candidate gene presumably involved in the disorders and closely located in close genomic proximity to NKX2-1. Results Within 101 index patients, we detected 17 point mutations and 10 deletions. Neurological symptoms were the most consistent finding (100%), followed by lung affection (78%) and thyroidal dysfunction (75%). Novel symptoms associated with NKX2-1 mutations comprise abnormal height, bouts of fever and cardiac septum defects. In contrast to previous reports, our data suggest that missense mutations in the homeodomain of NKX2-1 not necessarily modify its DNA binding capacity and that this specific type of mutations may be associated with mild pulmonary phenotypes such as asthma. Two deletions did not include NKX2-1, but MBIP, whose expression spatially and temporarily coincides with NKX2-1 in early murine development. Conclusions The high incidence of NKX2-1 mutations strongly recommends the routine screen for mutations in patients with corresponding symptoms. However, this analysis should not be confined to the exonic sequence alone, but should take advantage of affordable NGS technology to expand the target to adjacent regulatory sequences and the NKX2-1 interactome in order to maximise the

  17. Mutation frequency and genotype/phenotype correlation among phenylketonuria patients from Georgia

    Energy Technology Data Exchange (ETDEWEB)

    Woo, S.L.C.; Martinez, D.; Kuozmine, A. [Baylor College of Medicine, Houston, TX (United States)] [and others

    1994-09-01

    Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). To determine the molecular basis of PKU in the state of Georgia, thirty-five Georgian PKU patients representing sixty independent alleles were examined by a combination of DGGE and direct sequence analysis. At present, this approach has led to the identification of 55/60 or about 92% of all mutant alleles. The relatively high frequencies of mutations common to the British Isles (R408W, I65T and L348V) are compatible with 1990 census data showing that 34% of the general Georgian population claim Irish, English or Scottish ancestors. Three new mutations, E76A (1/60), R241L (2/60), and R400R (2/60), were also detected in this study. Although the nucleotide substitution in codon 400 (AGG{r_arrow}CGG) did not change the amino acid sequence, it was the only base change detected in a scan of all 13 exons of two independent alleles. Since codon 400 is split between exons 11 and 12, this change may exert some effect on splicing, as has previously been seen in the PAH gene for the silent mutation Q304Q and the nonsense mutation Y356X, each of which effect codons immediately adjacent to splicing signals. This hypothesis remains to be tested by expression analysis or studies of ectopic transcripts. The remaining 19 characterized alleles contained one of 15 previously identified mutations. Twenty-five of the thirty non-related patients examined in this study were completely genotyped, and there was a strong correlation between mutant PAH genotype, PAH activity predicted from in vitro expression studies where known, and PKU or HPA phenotype. For mutations not yet studied by expression analysis, this correlation suggests that L213P, R241L, Y277D may drastically reduce residual PAH activity while F39L and E76A may retain significant amounts of PAH activity.

  18. A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A.

    Science.gov (United States)

    Lederer, Damien; Shears, Debbie; Benoit, Valérie; Verellen-Dumoulin, Christine; Maystadt, Isabelle

    2014-05-01

    Kabuki syndrome is a rare malformation syndrome characterized by a typical facial appearance, skeletal anomalies, cardiac malformation, and mild to moderate intellectual disability. In 55-80% of patients with Kabuki syndrome, a mutation in MLL2 is identified. Recently, eight patients with Kabuki syndrome and a mutation in KDM6A were described. In this report, we describe two brothers with a mutation in KDM6A inherited from their mother and maternal grandmother. The two boys have Kabuki-like phenotypes whereas the mother and grandmother present with attenuated phenotypes. This family represents the first instance of hereditary X-linked Kabuki syndrome. We present a short literature review of the patients described with a mutation in KDM6A.

  19. Deep intronic mis-splicing mutation in JAK3 gene underlies T-B+NK- severe combined immunodeficiency phenotype.

    Science.gov (United States)

    Stepensky, Polina; Keller, Baerbel; Shamriz, Oded; NaserEddin, Adeeb; Rumman, Nisreen; Weintraub, Michael; Warnatz, Klaus; Elpeleg, Orly; Barak, Yaacov

    2016-02-01

    Severe combined immune deficiency (SCID) is a group of genetically heterogeneous diseases caused by an early block in T cell differentiation and present with life threatening infections, often within the first year of life. Janus kinase (JAK)3 gene mutations have been found to cause autosomal recessive T-B+ SCID phenotype. In this study we describe three patients with a novel deep intronic mis-splicing mutation in JAK3 as a cause of T-B+NK- SCID highlighting the need for careful evaluation of intronic regulatory elements of known genes associated with clearly defined clinical phenotypes. We present the cases and discuss the current literature.

  20. Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene

    Energy Technology Data Exchange (ETDEWEB)

    Putnam, E.A.; Cho, M.; Milewicz, D.M. [Univ. of Texas-Houston Medical School, Houston, TX (United States)] [and others

    1996-03-29

    Marfan syndrome is a dominantly inherited connective tissue disorder with a wide range of phenotypic severity. The condition is the result of mutations in FBN1, a large gene composed of 65 exons encoding the fibrillin-1 protein. While mutations causing classic manifestations of Marfan syndrome have been identified throughout the FBN1 gene, the six previously characterized mutations resulting in the severe, perinatal lethal form of Marfan syndrome have clustered in exons 24-32 of the gene. We screened 8 patients with either neonatal Marfan syndrome or severe cardiovascular complications of Marfan syndrome for mutations in this region of the gene. Using intron-based exon-specific primers, we amplified exons 23-32 from genomic DNAs, screened these fragments by single-stranded conformational polymorphism analysis, and sequenced indicated exons. This analysis documented mutations in exons 25-27 of the FBN1 mutations in 6 of these patients. These results, taken together with previously published FBN1 mutations in this region, further define the phenotype associated with mutations in exons 24-32 of the FBN1 gene, information important for the development of possible diagnostic tests and genetic counseling. 49 refs., 4 figs., 2 tabs.

  1. Mutation of the diamond-blackfan anemia gene Rps7 in mouse results in morphological and neuroanatomical phenotypes.

    Directory of Open Access Journals (Sweden)

    Dawn E Watkins-Chow

    Full Text Available The ribosome is an evolutionarily conserved organelle essential for cellular function. Ribosome construction requires assembly of approximately 80 different ribosomal proteins (RPs and four different species of rRNA. As RPs co-assemble into one multi-subunit complex, mutation of the genes that encode RPs might be expected to give rise to phenocopies, in which the same phenotype is associated with loss-of-function of each individual gene. However, a more complex picture is emerging in which, in addition to a group of shared phenotypes, diverse RP gene-specific phenotypes are observed. Here we report the first two mouse mutations (Rps7(Mtu and Rps7(Zma of ribosomal protein S7 (Rps7, a gene that has been implicated in Diamond-Blackfan anemia. Rps7 disruption results in decreased body size, abnormal skeletal morphology, mid-ventral white spotting, and eye malformations. These phenotypes are reported in other murine RP mutants and, as demonstrated for some other RP mutations, are ameliorated by Trp53 deficiency. Interestingly, Rps7 mutants have additional overt malformations of the developing central nervous system and deficits in working memory, phenotypes that are not reported in murine or human RP gene mutants. Conversely, Rps7 mouse mutants show no anemia or hyperpigmentation, phenotypes associated with mutation of human RPS7 and other murine RPs, respectively. We provide two novel RP mouse models and expand the repertoire of potential phenotypes that should be examined in RP mutants to further explore the concept of RP gene-specific phenotypes.

  2. Hypo- and hypermorphic FOXC1 mutations in dominant glaucoma: transactivation and phenotypic variability.

    Directory of Open Access Journals (Sweden)

    Cristina Medina-Trillo

    Full Text Available Dominant glaucoma, a heterogeneous, infrequent and irreversible optic neuropathy, is often associated with elevated intraocular pressure and early-onset. The role of FOXC1 in this type of glaucoma was investigated in twelve Spanish probands via nucleotide variation screening of its proximal promoter and unique exon. Functional evaluations of the identified variants included analyses of the transcriptional activity, protein stability, DNA binding ability and subcellular localization. Four different mutations that were identified in four probands (33.3% were associated with remarkable phenotypic variability and were functionally classified as either hypermorphic (p.Y47X, p.Q106X and p.G447_G448insDG or hypomorphic (p.I126S alleles. To the best of our knowledge, three of the variants are novel (p.Y47X, p.I126S and p.G447_G448insDG and, in addition, hypermorphic FOXC1 mutations are reported herein for the first time. The presence of an intact N-terminal activation domain in the truncated proteins p.Y47X and p.Q106X may underlie their associated transactivation hyperactivity by a gain-of-function mechanism involving dysregulated protein-protein interactions. Similarly, altered molecular interactions may also lead to increased p.G447_G448insDG activity. In contrast, the partial loss-of-function associated with p.I126S was due to impaired protein stability, DNA binding, protein phosphorylation and subcellular distribution. These results support that moderate and variable FOXC1 transactivation changes are associated with moderate goniodysgenesis, dominant glaucoma and remarkable phenotypic variability.

  3. Oncometabolic mutation IDH1 R132H confers a metformin-hypersensitive phenotype

    Science.gov (United States)

    Cuyàs, Elisabet; Fernández-Arroyo, Salvador; Corominas-Faja, Bruna; Rodríguez-Gallego, Esther; Bosch-Barrera, Joaquim; Martin-Castillo, Begoña; De Llorens, Rafael; Joven, Jorge; Menendez, Javier A.

    2015-01-01

    Metabolic flexibility might be particularly constrained in tumors bearing mutations in isocitrate dehydrogenase 1 (IDH1) leading to the production of the oncometabolite 2-hydroxygluratate (2HG). To test the hypothesis that IDH1 mutations could generate metabolic vulnerabilities for therapeutic intervention, we utilized an MCF10A cell line engineered with an arginine-to-histidine conversion at position 132 (R132H) in the catalytic site of IDH1, which equips the enzyme with a neomorphic α-ketoglutarate to 2HG reducing activity in an otherwise isogenic background. IDH1 R132H/+ and isogenic IDH1 +/+ parental cells were screened for their ability to generate energy-rich NADH when cultured in a standardized high-throughput Phenotype MicroArrayplatform comprising >300 nutrients. A radical remodeling of the metabotype occurred in cells carrying the R132H mutation since they presented a markedly altered ability to utilize numerous carbon catabolic fuels. A mitochondria toxicity-screening modality confirmed a severe inability of IDH1-mutated cells to use various carbon substrates that are fed into the electron transport chain at different points. The mitochondrial biguanide poisons, metformin and phenformin, further impaired the intrinsic weakness of IDH1-mutant cells to use certain carbon-energy sources. Additionally, metabolic reprogramming of IDH1-mutant cells increased their sensitivity to metformin in assays of cell proliferation, clonogenic potential, and mammosphere formation. Targeted metabolomics studies revealed that the ability of metformin to interfere with the anaplerotic entry of glutamine into the tricarboxylic acid cycle could explain the hypersensitivity of IDH1-mutant cells to biguanides. Moreover, synergistic interactions occurred when metformin treatment was combined with the selective R132H-IDH1 inhibitor AGI-5198. Together, these results suggest that therapy involving the simultaneous targeting of metabolic vulnerabilities with metformin, and 2HG

  4. Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association.

    Directory of Open Access Journals (Sweden)

    Slađana Andrejević

    Full Text Available Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T. Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444 or group 2 (missense, excluding mutations at Arg444. Significant differences were found in the clinical severity score (P = 0.005, prevalence of laryngeal (P = 0.040 and facial (P = 0.013 oedema, and long-term prophylaxis (P = 0.023 between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038. Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a

  5. Mutator Phenotype and DNA Double-Strand Break Repair in BLM Helicase-Deficient Human Cells

    Science.gov (United States)

    Suzuki, Tetsuya; Yasui, Manabu

    2016-01-01

    Bloom syndrome (BS), an autosomal recessive disorder of the BLM gene, predisposes sufferers to various cancers. To investigate the mutator phenotype and genetic consequences of DNA double-strand breaks (DSBs) in BS cells, we developed BLM helicase-deficient human cells by disrupting the BLM gene. Cells with a loss of heterozygosity (LOH) due to homologous recombination (HR) or nonhomologous end joining (NHEJ) can be restored with or without site-directed DSB induction. BLM cells exhibited a high frequency of spontaneous interallelic HR with crossover, but noncrossover events with long-tract gene conversions also occurred. Despite the highly interallelic HR events, BLM cells predominantly produced hemizygous LOH by spontaneous deletion. These phenotypes manifested during repair of DSBs. Both NHEJ and HR appropriately repaired DSBs in BLM cells, resulting in hemizygous and homozygous LOHs, respectively. However, the magnitude of the LOH was exacerbated in BLM cells, as evidenced by large deletions and long-tract gene conversions with crossover. BLM helicase suppresses the elongation of branch migration and crossover of double Holliday junctions (HJs) during HR repair, and a deficiency in this enzyme causes collapse, abnormal elongation, and/or preferable resolution to crossover of double HJs, resulting in a large-scale LOH. This mechanism underlies the predisposition for cancer in BS. PMID:27601585

  6. A novel mutation at the JK locus causing Jknull phenotype in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    MENG Yan; ZHOU Xueyan; LI Yang; ZHAO Dan; LIANG Shuyuan; ZHAO Xuejian; YANG Baoxue

    2005-01-01

    Urea transporters are a group of proteins that facilitate urea movement across biological membranes. Kidd blood group (JK antigen) and urea transporter of human erythrocytes are carried by the same protein UT-B. To investigate the molecular basis of the Jknull phenotype in the Chinese population, blood samples from Chinese individuals were screened using the 2 mol/L urea solution hemolysis test. Urea and water permeability of erythrocytes membrane was measured by stopped-flow light scattering. Genomic DNA was extracted from lymphocytes. UT-B gene of Jknull's family was analyzed using genomic PCR by primers designed to cover sequences of all exons and exon-intron boundaries in human UT-B gene. One Jknull subject was found from twenty thousand screened Chinese individuals, and it was confirmed that this individual did not express the erythrocyte urea transporter. Genomic sequence analysis of the Jknull individual showed that there were two point mutations, G→C, which is novel, and G→A, at the 3(-acceptor splice site (AG) of intron 5 of UT-B gene. Exon 6 is spliced out in the UT-B transcript due to either of these mutations. Water permeability in Jknull erythrocytes (Pf, ~0.00037 cm/s) was significantly lower than that in normal erythrocytes (Pf, ~0.00062 cm/s) after HgCl2 incubation, providing evidence for UT-B facilitated water transport in human erythrocytes.

  7. Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype

    OpenAIRE

    2006-01-01

    Heterozygous mutations of the homeobox genes ALX4 and MSX2 cause skull defects termed enlarged parietal foramina (PFM) and cranium bifidum (CB); a single MSX2 mutation has been documented in a unique craniosynostosis (CRS) family. However, the relative mutational contribution of these genes to PFM/CB and CRS is not known and information on genotype–phenotype correlations is incomplete. We analysed ALX4 and MSX2 in 11 new unrelated cases or families with PFM/CB, 181 cases of CRS, and a single ...

  8. Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening

    NARCIS (Netherlands)

    Haack, T.B.; Gorza, M.; Danhauser, K.; Mayr, J.A.; Haberberger, B.; Wieland, T.; Kremer, L.; Strecker, V.; Graf, E.; Memari, Y.; Ahting, U.; Kopajtich, R.; Wortmann, S.B.; Rodenburg, R.J.T.; Kotzaeridou, U.; Hoffmann, G.F.; Sperl, W.; Wittig, I.; Wilichowski, E.; Schottmann, G.; Schuelke, M.; Plecko, B.; Stephani, U.; Strom, T.M.; Meitinger, T.; Prokisch, H.; Freisinger, P.

    2014-01-01

    Defects of mitochondrial oxidative phosphorylation (OXPHOS) are associated with a wide range of clinical phenotypes and time courses. Combined OXPHOS deficiencies are mainly caused by mutations of nuclear genes that are involved in mitochondrial protein translation. Due to their genetic heterogeneit

  9. A novel phenotype of a hepatocyte nuclear factor homeobox A (HNF1A) gene mutation, presenting with neonatal cholestasis

    NARCIS (Netherlands)

    de Vries, Aleida G. M.; Bakker-van Waarde, Willie M.; Dassel, Anne C. M.; Losekoot, Monique; Duiker, Evelien W.; Gouw, Annette S. H.; Bodewes, Frank A. J. A.

    2015-01-01

    We report a novel phenotype of a hepatocyte nuclear factor homeobox A (HNF1A) mutation (heterozygote c.130dup, p.Leu44fs) presenting with transient neonatal cholestasis, subsequently followed by persistent elevation of transaminases, maturity-onset diabetes of the young (MODY) type 3 and hepatocellu

  10. Mismatch repair genes of Streptococcus pneumoniae: HexA confers a mutator phenotype in Escherichia coli by negative complementation.

    Science.gov (United States)

    Prudhomme, M; Méjean, V; Martin, B; Claverys, J P

    1991-11-01

    DNA repair systems able to correct base pair mismatches within newly replicated DNA or within heteroduplex molecules produced during recombination are widespread among living organisms. Evidence that such generalized mismatch repair systems evolved from a common ancestor is particularly strong for two of them, the Hex system of the gram-positive Streptococcus pneumoniae and the Mut system of the gram-negative Escherichia coli and Salmonella typhimurium. The homology existing between HexA and MutS and between HexB and MutL prompted us to investigate the effect of expressing hex genes in E. coli. Complementation of mutS or mutL mutations, which confer a mutator phenotype, was assayed by introducing on a multicopy plasmid the hexA and hexB genes, under the control of an inducible promoter, either individually or together in E. coli strains. No decrease in mutation rate was conferred by either hexA or hexB gene expression. However, a negative complementation effect was observed in wild-type E. coli cells: expression of hexA resulted in a typical Mut- mutator phenotype. hexB gene expression did not increase the mutation rate either individually or in conjunction with hexA. Since expression of hexA did not affect the mutation rate in mutS mutant cells and the hexA-induced mutator effect was recA independent, it is concluded that this effect results from inhibition of the Mut system. We suggest that HexA, like its homolog MutS, binds to mismatches resulting from replication errors, but in doing so it protects them from repair by the Mut system. In agreement with this hypothesis, an increase in mutS gene copy number abolished the hexA-induced mutator phenotype. HexA protein could prevent repair either by being unable to interact with Mut proteins or by producing nonfunctional repair complexes.

  11. Splicing mutation in the ATR-X gene can lead to a dysmorphic mental retardation phenotype without {alpha}-thalassemia

    Energy Technology Data Exchange (ETDEWEB)

    Villard, L.; Lossi, A.M.; Fontes, M. [and others

    1996-03-01

    We have previously reported the isolation of a gene from Xq13 that codes for a putative regulator of transcription (XNP) and has now been shown to be the gene involved in the X-linked {alpha}-thalassemia with mental retardation (ATR-X) syndrome. The widespread expression and numerous domains present in the putative protein suggest that this gene could be involved in other phenotypes. The predominant expression of the gene in the developing brain, as well as its association with neuron differentiation, indicates that mutations of this gene might result in a mental retardation (MR) phenotype. In this paper we present a family with a splice junction mutation in XNP that results in the skipping of an exon and in the introduction of a stop codon in the middle of the XNP-coding sequence. Only the abnormal transcript is expressed in two first cousins presenting the classic ATR-X phenotype (with {alpha}-thalassemia and HbH inclusions). In a distant cousin presenting a similar dysmorphic MR phenotype but not having thalassemia, {approximately}30% of the XNP transcripts are normal. These data demonstrate that the mode of action of the XNP gene product on globin expression is distinct from its mode of action in brain development and facial morphogenesis and suggest that other dysmorphic mental retardation phenotypes, such as Juberg-Marsidi or some sporadic cases of Coffin-Lowry, could be due to mutations in XNP. 20 refs., 5 figs., 2 tabs.

  12. Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a danish five-generation family with a novel FAM83H nonsense mutation

    DEFF Research Database (Denmark)

    Haubek, Dorte; Gjørup, Hans; Jensen, Lillian Gryesten

    2011-01-01

    Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a danish five-generation family with a novel FAM83H nonsense mutation......Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a danish five-generation family with a novel FAM83H nonsense mutation...

  13. Genetic and structural analyses suggest that a novel SPG3A mutation causes severe phenotypes of hereditary spastic paraplegia

    Institute of Scientific and Technical Information of China (English)

    CHEN Suqin; ZHOU Yan; LI Xunhua; Labu; HUANG Shuang; HUANG Weijun; ZHOU Chunlong; liu; WANG Yiming

    2006-01-01

    Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases. The genotypes and phenotypes of HSP are extremely heterogenous. SPG3A is one of the identified genes underlying HSP, and codes for a GTPase, atlastin. Mutations in SPG3A are currently believed to be associated with early onset and mild phenotypes. And most structural predictions could not detect gross changes in the mutant protein. However, in a severely affected HSP family we have identified a novel SPG3A mutation, c.1228G>A (p.G410R), in a Tibetan kindred. The mutation occurred at the highly conserved nucleotide and co-segregated with the disease, and was absent in the control subjects. Structural predictions showed that the Tibetan mutation occurred at the linking part between the guanylate-binding protein domain (GB, the ball region) and the transmembrane helices (TM, the rod region) at the start point of an α-helix, which may disrupt the helix, and cause changes in the overall structure of the transmembrane region of the molecule. Our results indicate that severe phenotypes can also arise from SPG3A mutations and the linking part of the guanylate-binding protein domain and the transmembrane helices might be crucial in determining the severity of the disease. This paper not only presents the first SPG3A mutational report from the Chinese population, but also provides potential evidence for a possible correlation between the severity of the phenotypes of HSP with the extension of the changes in the protein structures of atlastin.

  14. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I.

    Science.gov (United States)

    Li, Kairong; Turner, Ashley N; Chen, Min; Brosius, Stephanie N; Schoeb, Trenton R; Messiaen, Ludwine M; Bedwell, David M; Zinn, Kurt R; Anastasaki, Corina; Gutmann, David H; Korf, Bruce R; Kesterson, Robert A

    2016-07-01

    Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing patient-specific mutations. In order to test therapeutic approaches that might restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C>T; p.Arg681*) and a missense mutation (c.2542G>C; p.Gly848Arg). The latter is associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1(Arg681*) and missense NF1(Gly848Arg) mutations have different effects on neurofibromin expression in the mouse and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1(Gly848Arg) mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1(Arg681*) mutation are not viable. Mice with one Nf1(Arg681*) allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf1(4F/Arg681*); DhhCre) display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for preclinical testing of novel nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in individuals with NF1.

  15. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I

    Directory of Open Access Journals (Sweden)

    Kairong Li

    2016-07-01

    Full Text Available Neurofibromatosis type 1 (NF1 is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing patient-specific mutations. In order to test therapeutic approaches that might restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C>T; p.Arg681* and a missense mutation (c.2542G>C; p.Gly848Arg. The latter is associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1Arg681* and missense NF1Gly848Arg mutations have different effects on neurofibromin expression in the mouse and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1Gly848Arg mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1Arg681* mutation are not viable. Mice with one Nf1Arg681* allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf14F/Arg681*; DhhCre display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for preclinical testing of novel nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in individuals with NF1.

  16. Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype.

    Science.gov (United States)

    Mavrogiannis, Lampros A; Taylor, Indira B; Davies, Sally J; Ramos, Feliciano J; Olivares, José L; Wilkie, Andrew O M

    2006-02-01

    Heterozygous mutations of the homeobox genes ALX4 and MSX2 cause skull defects termed enlarged parietal foramina (PFM) and cranium bifidum (CB); a single MSX2 mutation has been documented in a unique craniosynostosis (CRS) family. However, the relative mutational contribution of these genes to PFM/CB and CRS is not known and information on genotype-phenotype correlations is incomplete. We analysed ALX4 and MSX2 in 11 new unrelated cases or families with PFM/CB, 181 cases of CRS, and a single family segregating a submicroscopic deletion of 11p11.2, including ALX4. We explored the correlations between skull defect size and age, gene, and mutation type, and reviewed additional phenotypic manifestations. Four PFM cases had mutations in either ALX4 or MSX2; including previous families, we have identified six ALX4 and six MSX2 mutations, accounting for 11/13 familial, but only 1/6 sporadic cases. The deletion family confirms the delineation of a mental retardation locus to within 1.1 Mb region of 11p11.2. Overall, no significant size difference was found between ALX4- and MSX2-related skull defects, but the ALX4 mutation p.R218Q tends to result in persistent CB and is associated with anatomical abnormalities of the posterior fossa. We conclude that PFM caused by mutations in ALX4 and MSX2 have a similar prevalence and are usually clinically indistinguishable. Mutation screening has a high pickup rate in PFM, especially in familial cases, but is not indicated in CRS.

  17. Phenotype-genotype correlations in mouse models of amelogenesis imperfecta caused by Amelx and Enam mutations.

    Science.gov (United States)

    Coxon, Thomas Liam; Brook, Alan Henry; Barron, Martin John; Smith, Richard Nigel

    2012-01-01

    Mutations in human and in mouse orthologous genes Amelx and Enam result in a diverse range of enamel defects. In this study we aimed to investigate the phenotype-genotype correlation between the mutants and the wild-type controls in mouse models of amelogenesis imperfecta using novel measurement approaches. Ten hemi-mandibles and incisors were dissected from each group of Amelx(WT), Amelx(X/Y64H), Amelx(Y/Y64H), Amelx(Y64H/Y64H), and Enam(WT), Enam(Rgsc395) heterozygous and Enam(Rgsc395) homozygous mice. Their macro-morphology, colour and micro-topography were assessed using bespoke 2D and 3D image analysis systems and customized colour and whiteness algorithms. The novel methods identified significant differences (p ≤ 0.05) between the Amelx groups for mandible and incisor size and enamel colour and between the Enam groups for incisor size and enamel colour. The Amelx(WT) mice had the largest mandibles and incisors, followed in descending order of size by the Amelx(X/Y64H), Amelx(Y/Y64H) and Amelx(Y64H/Y64H) mice. Within the Enam groups the Enam(WT) incisors were largest and the Enam(Rgsc395) heterozygous mice were smallest. The effect on tooth morphology was also reflected by the severity of the enamel defects in the colour and whiteness assessment. Amelogenin affected mandible morphology and incisor enamel formation, while enamelin only affected incisors, supporting the multifunctional role of amelogenin. The enamelin mutation was associated with earlier forming enamel defects. The study supported the critical involvement of amelogenin and enamelin in enamel mineralization.

  18. Different mutations at V363 MAPT codon are associated with atypical clinical phenotypes and show unusual structural and functional features.

    Science.gov (United States)

    Rossi, Giacomina; Bastone, Antonio; Piccoli, Elena; Morbin, Michela; Mazzoleni, Giulia; Fugnanesi, Valeria; Beeg, Marten; Del Favero, Elena; Cantù, Laura; Motta, Simona; Salsano, Ettore; Pareyson, Davide; Erbetta, Alessandra; Elia, Antonio Emanuele; Del Sorbo, Francesca; Silani, Vincenzo; Morelli, Claudia; Salmona, Mario; Tagliavini, Fabrizio

    2014-02-01

    Microtubule-associated protein tau gene (MAPT) is one of the major genes linked to frontotemporal lobar degeneration, a group of neurodegenerative diseases clinically, pathologically, and genetically heterogeneous. In particular, MAPT mutations give rise to the subgroup of tauopathies. The pathogenetic mechanisms underlying the MAPT mutations so far described are the decreased ability of tau protein to promote microtubule polymerization (missense mutations) or the altered ratio of tau isoforms (splicing mutations), both leading to accumulation of hyperphosphorylated filamentous tau protein. Following a genetic screening of patients affected by frontotemporal lobar degeneration, we identified 2 MAPT mutations, V363I and V363A, leading to atypical clinical phenotypes, such as posterior cortical atrophy. We investigated in vitro features of the recombinant mutated tau isoforms and revealed unusual functional and structural characteristics such as an increased ability to promote microtubule polymerization and a tendency to form oligomeric instead of filamentous aggregates. Thus, we disclosed a greater than expected complexity of abnormal features of mutated tau isoforms. Overall our findings suggest a high probability that these mutations are pathogenic.

  19. Impaired mechanical response of an EDMD mutation leads to motility phenotypes that are repaired by loss of prenylation.

    Science.gov (United States)

    Zuela, Noam; Zwerger, Monika; Levin, Tal; Medalia, Ohad; Gruenbaum, Yosef

    2016-05-01

    There are roughly 14 distinct heritable autosomal dominant diseases associated with mutations in lamins A/C, including Emery-Dreifuss muscular dystrophy (EDMD). The mechanical model proposes that the lamin mutations change the mechanical properties of muscle nuclei, leading to cell death and tissue deterioration. Here, we developed an experimental protocol that analyzes the effect of disease-linked lamin mutations on the response of nuclei to mechanical strain in living Caenorhabditis elegans We found that the EDMD mutation L535P disrupts the nuclear mechanical response specifically in muscle nuclei. Inhibiting lamin prenylation rescued the mechanical response of the EDMD nuclei, reversed the muscle phenotypes and led to normal motility. The LINC complex and emerin were also required to regulate the mechanical response of C. elegans nuclei. This study provides evidence to support the mechanical model and offers a potential future therapeutic approach towards curing EDMD.

  20. Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes.

    Science.gov (United States)

    Nouioua, Sonia; Hamadouche, Tarik; Funalot, Benoit; Bernard, Rafaëlle; Bellatache, Nora; Bouderba, Radia; Grid, Djamel; Assami, Salima; Benhassine, Traki; Levy, Nicolas; Vallat, Jean-Michel; Tazir, Meriem

    2011-08-01

    Autosomal recessive Charcot-Marie-Tooth diseases, relatively common in Algeria due to high prevalence of consanguineous marriages, are clinically and genetically heterogeneous. We report on two consanguineous families with demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMT4) associated with novel homozygous mutations in the MTMR2 gene, c.331dupA (p.Arg111LysfsX24) and PRX gene, c.1090C>T (p.Arg364X) respectively, and peculiar clinical phenotypes. The three patients with MTMR2 mutations (CMT4B1 family) had a typical phenotype of severe early onset motor and sensory neuropathy with typical focally folded myelin on nerve biopsy. Associated clinical features included vocal cord paresis, prominent chest deformities and claw hands. Contrasting with the classical presentation of CMT4F (early-onset Dejerine-Sottas phenotype), the four patients with PRX mutations (CMT4F family) had essentially a late age of onset and a protracted and relatively benign evolution, although they presented marked spine deformities. These observations broaden the spectrum of clinical phenotypes associated with these two CMT4 forms.

  1. The Spectrum of SLC17A5-Gene Mutations Resulting in Free Sialic Acid–Storage Diseases Indicates Some Genotype-Phenotype Correlation

    Science.gov (United States)

    Aula, Nina; Salomäki, Pirjo; Timonen, Ritva; Verheijen, Frans; Mancini, Grazia; Månsson, Jan-Eric; Aula, Pertti; Peltonen, Leena

    2000-01-01

    Lysosomal free sialic acid–storage diseases include the allelic disorders Salla disease (SD) and infantile sialic acid–storage disease (ISSD). The defective gene, SLC17A5, coding for the lysosomal free sialic acid transporter was recently isolated by positional cloning. In the present study, we have identified a large number of mutations in SLC17A5 in patients presenting with either Salla disease or the ISSD phenotype. We also report for the first time the exon-intron boundaries of SLC17A5. All Finnish patients with SD (n=80) had a missense mutation changing a highly conserved arginine to cysteine (R39C); 91% of them were homozygotes for this old founder mutation. The compound-heterozygote patients, with the founder mutation in only one allele, presented with a more severe phenotype than did the homozygote patients. The same R39C mutation was also found both in most of the Swedish patients with SD and in a heterozygous form in five patients from central Europe who presented with an unusually severe (intermediate) SD phenotype. Ten different mutations, including deletions, insertions, and missense and nonsense mutations, were identified in patients with the most severe ISSD phenotype, most of whom were compound heterozygotes. Our results indicate some genotype-phenotype correlation in free sialic acid–storage diseases, suggesting that the phenotype associated with the homozygote R39C mutation is milder than that associated with other mutations. PMID:10947946

  2. Incidence of the mask phenotype M264V mutation in Labrador Retrievers.

    Science.gov (United States)

    Conant, E K; Juras, R; Cothran, E G

    2011-12-01

    The introduction of SNP (Single Nucleotide Polymorphism) chips allows for the rapid typing of multiple markers for many individuals at one time. Our lab routinely types dogs using a custom designed combined panel of SNPs for parentage verification and a number of genes for diagnostic tests using an OpenArray platform manufactured by BioTrove (Woburn, MA, USA). By utilizing the same SNP panel across a wide array of canine breeds it is possible to detect trait-associated SNPs in breeds not thought to carry those traits. We genotyped 245 Labrador Retrievers on the canine SNP chip and found 13 animals heterozygous for the M264V mutation associated with autosomal dominant mask trait, and one animal homozygous for this trait. The color genotypes for these animals were further examined. In standard colored Labradors (black, chocolate, and yellow), the mask phenotype would never be distinguishable. As illustrated by this example, we feel this SNP panel is a valuable method for discovering traits not known to exist in a breed.

  3. A unique mutation in a MYB gene cosegregates with the nectarine phenotype in peach.

    Directory of Open Access Journals (Sweden)

    Elisa Vendramin

    Full Text Available Nectarines play a key role in peach industry; the fuzzless skin has implications for consumer acceptance. The peach/nectarine (G/g trait was described as monogenic and previously mapped on chromosome 5. Here, the position of the G locus was delimited within a 1.1 cM interval (635 kb based on linkage analysis of an F2 progeny from the cross 'Contender' (C, peach x 'Ambra' (A, nectarine. Careful inspection of the genes annotated in the corresponding genomic sequence (Peach v1.0, coupled with variant discovery, led to the identification of MYB gene PpeMYB25 as a candidate for trichome formation on fruit skin. Analysis of genomic re-sequencing data from five peach/nectarine accessions pointed to the insertion of a LTR retroelement in exon 3 of the PpeMYB25 gene as the cause of the recessive glabrous phenotype. A functional marker (indelG developed on the LTR insertion cosegregated with the trait in the CxA F2 progeny and was validated on a broad panel of genotypes, including all known putative donors of the nectarine trait. This marker was shown to efficiently discriminate between peach and nectarine plants, indicating that a unique mutational event gave rise to the nectarine trait and providing a useful diagnostic tool for early seedling selection in peach breeding programs.

  4. Identification of a novel lethal fibrillin-1 gene mutation in a Chinese Marfan family and correlation of 3'fibrillin-1 gene mutations with phenotype

    Institute of Scientific and Technical Information of China (English)

    GAO Ling-gen; ZHANG Lin; SONG Lei; WANG Hu; CHANG Qian; WU Yong-bo; HUI Ru-tai; ZHOU Xian-liang

    2010-01-01

    Background Mutations in the fibrillin-1 gene have been identified in patients with Marfan syndrome (MFS). This study aimed to identify the molecular defects in the fibrillin-1 gene in a Chinese family with Marfan syndrome, accompanied by aortic aneurysms/dissection.Methods Two patients and one non-carrier in the family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of these individuals in the family as well as 50 healthy normal controls. Polymerase chain reaction amplification and direct sequencing of all 65 coding exons of fibrillin-1 gene were analyzed.Results We found a novel mutation (c.8547T>G, p. Tyr2849X) in exon 65 of fibrillin-1 gene in a Chinese proband with Marfan syndrome, accompanied by aortic aneurysms/dissection. Sudden death at a young age of affected members was seen due to aortic aneurysms/dissection. By evaluating genotype-phenotype correlations of patients with mutations in the 3'end of fibrillin-1 gene (exons 64 and 65), we also found that the presence of nonsense mutations occurring in exons 64 and 65 appeared to be an indicator of early-onset aortic risk and sudden death.Conclusions These results expand the mutation spectrum of fibrillin-1 gene and help in the study of the molecular pathogenesis of Marfan syndrome, indicating that mutations occurring in the 3' end of fibrillin-1 gene may play an independent functional role in the pathogenesis of Marfan syndrome.

  5. Inherited erythromelalgia due to mutations in SCN9A: natural history, clinical phenotype and somatosensory profile.

    Science.gov (United States)

    McDonnell, Aoibhinn; Schulman, Betsy; Ali, Zahid; Dib-Hajj, Sulayman D; Brock, Fiona; Cobain, Sonia; Mainka, Tina; Vollert, Jan; Tarabar, Sanela; Waxman, Stephen G

    2016-04-01

    Inherited erythromelalgia, the first human pain syndrome linked to voltage-gated sodium channels, is widely regarded as a genetic model of human pain. Because inherited erythromelalgia was linked to gain-of-function changes of sodium channel Na(v)1.7 only a decade ago, the literature has mainly consisted of reports of genetic and/or clinical characterization of individual patients. This paper describes the pattern of pain, natural history, somatosensory profile, psychosocial status and olfactory testing of 13 subjects with primary inherited erythromelalgia with mutations of SCN9A, the gene encoding Na(v)1.7. Subjects were clinically profiled using questionnaires, quantitative sensory testing and olfaction testing during the in-clinic phase of the study. In addition, a detailed pain phenotype for each subject was obtained over a 3-month period at home using diaries, enabling subjects to self-report pain attacks, potential triggers, duration and severity of pain. All subjects reported pain and heat in the extremities (usually feet and/or hands), with pain attacks triggered by heat or exercise and relieved mainly by non-pharmacological manoeuvres such as cooling. A large proportion of pain attacks (355/1099; 32%) did not involve a specific trigger. There was considerable variability in the number, duration and severity of pain attacks between subjects, even those carrying the same mutation within a family, and within individuals over the 12-13 week observation period. Most subjects (11/13) had pain between attacks. For these subjects, mean pain severity between pain attacks was usually lower than that during an attack. Olfaction testing using the Sniffin'T test did not demonstrate hyperosmia. One subject had evidence of orthostatic hypotension. Overall, there was a statistically significant correlation between total Hospital Anxiety and Depression Scale scores (P= 0.005) and pain between attacks and for Hospital Anxiety and Depression Scale Depression scores and pain

  6. Comparison of phenotypes between different vangl2 mutants demonstrates dominant effects of the Looptail mutation during hair cell development.

    Directory of Open Access Journals (Sweden)

    Haifeng Yin

    Full Text Available Experiments utilizing the Looptail mutant mouse, which harbors a missense mutation in the vangl2 gene, have been essential for studies of planar polarity and linking the function of the core planar cell polarity proteins to other developmental signals. Originally described as having dominant phenotypic traits, the molecular interactions underlying the Looptail mutant phenotype are unclear because Vangl2 protein levels are significantly reduced or absent from mutant tissues. Here we introduce a vangl2 knockout mouse and directly compare the severity of the knockout and Looptail mutant phenotypes by intercrossing the two lines and assaying the planar polarity of inner ear hair cells. Overall the vangl2 knockout phenotype is milder than the phenotype of compound mutants carrying both the Looptail and vangl2 knockout alleles. In compound mutants a greater number of hair cells are affected and changes in the orientation of individual hair cells are greater when quantified. We further demonstrate in a heterologous cell system that the protein encoded by the Looptail mutation (Vangl2(S464N disrupts delivery of Vangl1 and Vangl2 proteins to the cell surface as a result of oligomer formation between Vangl1 and Vangl2(S464N, or Vangl2 and Vangl2(S464N, coupled to the intracellular retention of Vangl2(S464N. As a result, Vangl1 protein is missing from the apical cell surface of vestibular hair cells in Looptail mutants, but is retained at the apical cell surface of hair cells in vangl2 knockouts. Similarly the distribution of Prickle-like2, a putative Vangl2 interacting protein, is differentially affected in the two mutant lines. In summary, we provide evidence for a direct physical interaction between Vangl1 and Vangl2 through a combination of in vitro and in vivo approaches and propose that this interaction underlies the dominant phenotypic traits associated with the Looptail mutation.

  7. Gaucher disease: Pseudoreversion of a disease mutation`s effects--implications for structure/function and genotype/phenotype correlations

    Energy Technology Data Exchange (ETDEWEB)

    Ponce, E.; Mear, J; Grabowski, G.A. [Children`s Hospital Research Foundation, Cincinnati, OH (United States)

    1994-09-01

    Numerous mutations ({approximately}45) of the acid {beta}-glucosidase gene have been identified in patients with Gaucher disease. Many of these have been characterized by partial sequencing of cDNAs derived by RT-PCR or PCR of genomic DNA. In addition, genotype/phenotype correlations have been based on screening for known mutations. Thus, only a part of the gene is characterized in any population of affected patients. Several Gaucher disease alleles contain multiple, authentic point mutations that raises concern about conclusions based on only partial genetic characterization. Several wild-type cDNAs for acid {beta}-glucosidase have been sequenced. One contained a cloning artifact encoding R495H. We expressed this cDNA and showed that the R495H enzyme had normal kinetic and stability properties. A disease-associated allele encoding R496H has been found by several groups. The close association and similarities of these two substitutions led us to question the disease casuality of the R496H allele. To evaluate this, we created and/or expressed cDNAs encoding R495, R496 (wild-type), (R495H, R496), (R495, R496H) and (R495H, R496H). The (wild-type) and (R495H, R496) enzymes had indistinguishable properties whereas the (R495, R496H) enzyme was essentially inactive. The introduction of both mutations (R495H, R496H) produced an enzyme whose activity was 25 to 50% of the wild-type. These results indicate that a pseudoreversion to a functional enzyme can occur by introducing a functionally neutral mutation together with a severe mutation. These results have major implications to structure/function and genotype/phenotype correlations in this disease.

  8. Long-term bezafibrate treatment improves skin and spleen phenotypes of the mtDNA mutator mouse.

    Directory of Open Access Journals (Sweden)

    Lloye M Dillon

    Full Text Available Pharmacological agents, such as bezafibrate, that activate peroxisome proliferator-activated receptors (PPARs and PPAR γ coactivator-1α (PGC-1α pathways have been shown to improve mitochondrial function and energy metabolism. The mitochondrial DNA (mtDNA mutator mouse is a mouse model of aging that harbors a proofreading-deficient mtDNA polymerase γ. These mice develop many features of premature aging including hair loss, anemia, osteoporosis, sarcopenia and decreased lifespan. They also have increased mtDNA mutations and marked mitochondrial dysfunction. We found that mutator mice treated with bezafibrate for 8-months had delayed hair loss and improved skin and spleen aging-like phenotypes. Although we observed an increase in markers of fatty acid oxidation in these tissues, we did not detect a generalized increase in mitochondrial markers. On the other hand, there were no improvements in muscle function or lifespan of the mutator mouse, which we attributed to the rodent-specific hepatomegaly associated with fibrate treatment. These results showed that despite its secondary effects in rodent's liver, bezafibrate was able to improve some of the aging phenotypes in the mutator mouse. Because the associated hepatomegaly is not observed in primates, long-term bezafibrate treatment in humans could have beneficial effects on tissues undergoing chronic bioenergetic-related degeneration.

  9. Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype.

    Science.gov (United States)

    Limberg, Maren M; Zumhagen, Sven; Netter, Michael F; Coffey, Alison J; Grace, Andrew; Rogers, Jane; Böckelmann, Doris; Rinné, Susanne; Stallmeyer, Birgit; Decher, Niels; Schulze-Bahr, Eric

    2013-05-01

    Andersen-Tawil syndrome (ATS) is characterized by dysmorphic features, periodic paralyses and abnormal ventricular repolarization. After genotyping a large set of patients with congenital long-QT syndrome, we identified two novel, heterozygous KCNJ2 mutations (p.N318S, p.W322C) located in the C-terminus of the Kir2.1 subunit. These mutations have a different localization than classical ATS mutations which are mostly located at a potential interaction face with the slide helix or at the interface between the C-termini. Mutation carriers were without the key features of ATS, causing an isolated cardiac phenotype. While the N318S mutants regularly reached the plasma membrane, W322C mutants primarily resided in late endosomes. Co-expression of N318S or W322C with wild-type Kir2.1 reduced current amplitudes only by 20-25 %. This mild loss-of-function for the heteromeric channels resulted from defective channel trafficking (W322C) or gating (N318S). Strikingly, and in contrast to the majority of ATS mutations, neither mutant caused a dominant-negative suppression of wild-type Kir2.1, Kir2.2 and Kir2.3 currents. Thus, a mild reduction of native Kir2.x currents by non dominant-negative mutants may cause ATS with an isolated cardiac phenotype.

  10. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia.

    Science.gov (United States)

    Deml, B; Reis, L M; Maheshwari, M; Griffis, C; Bick, D; Semina, E V

    2014-11-01

    Anophthalmia/microphthalmia (A/M) is a developmental ocular malformation defined as complete absence or reduction in size of the eye. A/M is a heterogenous disorder with numerous causative genes identified; however, about half the cases lack a molecular diagnosis. We undertook whole exome sequencing in an A/M family with two affected siblings, two unaffected siblings, and unaffected parents; the ocular phenotype was isolated with only mild developmental delay/learning difficulties reported and a normal brain magnetic resonance imaging (MRI) in the proband at 16 months. No pathogenic mutations were identified in 71 known A/M genes. Further analysis identified a shared heterozygous mutation in COL4A1, c.2317G>A, p.(Gly773Arg) that was not seen in the unaffected parents and siblings. Analysis of 24 unrelated A/M exomes identified a novel c.2122G>A, p.(Gly708Arg) mutation in an additional patient with unilateral microphthalmia, bilateral microcornea and Peters anomaly; the mutation was absent in the unaffected mother and the unaffected father was not available. Mutations in COL4A1 have been linked to a spectrum of human disorders; the most consistent feature is cerebrovascular disease with variable ocular anomalies, kidney and muscle defects. This study expands the spectrum of COL4A1 phenotypes and indicates screening in patients with A/M regardless of MRI findings or presumed inheritance pattern.

  11. Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities.

    Science.gov (United States)

    Mahoney, My G; Sadowski, Sara; Brennan, Donna; Pikander, Pekka; Saukko, Pekka; Wahl, James; Aho, Heikki; Heikinheimo, Kristiina; Bruckner-Tuderman, Leena; Fertala, Andrzej; Peltonen, Juha; Uitto, Jouni; Peltonen, Sirkku

    2010-04-01

    Desmoplakin (DP) anchors the intermediate filament cytoskeleton to the desmosomal cadherins and thereby confers structural stability to tissues. In this study, we present a patient with extensive mucocutaneous blisters, epidermolytic palmoplantar keratoderma, nail dystrophy, enamel dysplasia, and sparse woolly hair. The patient died at the age of 14 years from undiagnosed cardiomyopathy. The skin showed hyperplasia and acantholysis in the mid- and lower epidermal layers, whereas the heart showed extensive fibrosis and fibrofatty replacement in both ventricles. Immunofluorescence microscopy showed a reduction in the C-terminal domain of DP in the skin and oral mucosa. Sequencing of the DP gene showed undescribed mutations in the maternal and paternal alleles. Both mutations affected exon 24 encoding the C-terminal domain. The paternal mutation, c.6310delA, leads to a premature stop codon. The maternal mutation, c.7964 C to A, results in a substitution of an aspartic acid for a conserved alanine residue at amino acid 2655 (A2655D). Structural modeling indicated that this mutation changes the electrostatic potential of the mutated region of DP, possibly altering functions that depend on intermolecular interactions. To conclude, we describe a combination of DP mutation phenotypes affecting the skin, heart, hair, and teeth. This patient case emphasizes the importance of heart examination of patients with desmosomal genodermatoses.

  12. Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II.

    Science.gov (United States)

    Hermans, Monique M P; van Leenen, Dik; Kroos, Marian A; Beesley, Clare E; Van Der Ploeg, Ans T; Sakuraba, Hitoshi; Wevers, Ron; Kleijer, Wim; Michelakakis, Helen; Kirk, Edwin P; Fletcher, Janice; Bosshard, Nils; Basel-Vanagaite, Lina; Besley, Guy; Reuser, Arnold J J

    2004-01-01

    Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to acid alpha-glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the acid alpha-glucosidase gene (GAA) encoding acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on acid alpha-glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the GAA alleles. This genotype-phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease.

  13. Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation

    DEFF Research Database (Denmark)

    Nielsen, Jørgen Erik; Johnson, B; Koefoed, Pernille

    2004-01-01

    Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria...... relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations...

  14. Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype.

    Science.gov (United States)

    Alston, Charlotte L; Compton, Alison G; Formosa, Luke E; Strecker, Valentina; Oláhová, Monika; Haack, Tobias B; Smet, Joél; Stouffs, Katrien; Diakumis, Peter; Ciara, Elżbieta; Cassiman, David; Romain, Nadine; Yarham, John W; He, Langping; De Paepe, Boel; Vanlander, Arnaud V; Seneca, Sara; Feichtinger, René G; Płoski, Rafal; Rokicki, Dariusz; Pronicka, Ewa; Haller, Ronald G; Van Hove, Johan L K; Bahlo, Melanie; Mayr, Johannes A; Van Coster, Rudy; Prokisch, Holger; Wittig, Ilka; Ryan, Michael T; Thorburn, David R; Taylor, Robert W

    2016-07-01

    Complex I deficiency is the most common biochemical phenotype observed in individuals with mitochondrial disease. With 44 structural subunits and over 10 assembly factors, it is unsurprising that complex I deficiency is associated with clinical and genetic heterogeneity. Massively parallel sequencing (MPS) technologies including custom, targeted gene panels or unbiased whole-exome sequencing (WES) are hugely powerful in identifying the underlying genetic defect in a clinical diagnostic setting, yet many individuals remain without a genetic diagnosis. These individuals might harbor mutations in poorly understood or uncharacterized genes, and their diagnosis relies upon characterization of these orphan genes. Complexome profiling recently identified TMEM126B as a component of the mitochondrial complex I assembly complex alongside proteins ACAD9, ECSIT, NDUFAF1, and TIMMDC1. Here, we describe the clinical, biochemical, and molecular findings in six cases of mitochondrial disease from four unrelated families affected by biallelic (c.635G>T [p.Gly212Val] and/or c.401delA [p.Asn134Ilefs(∗)2]) TMEM126B variants. We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy. Functional experimentation including viral rescue and complexome profiling of subject cell lines has confirmed TMEM126B as the tenth complex I assembly factor associated with human disease and validates the importance of both genome-wide sequencing and proteomic approaches in characterizing disease-associated genes whose physiological roles have been previously undetermined.

  15. The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice.

    Science.gov (United States)

    Puig, Kendra L; Kulas, Joshua A; Franklin, Whitney; Rakoczy, Sharlene G; Taglialatela, Giulio; Brown-Borg, Holly M; Combs, Colin K

    2016-04-01

    APP/PS1 double transgenic mice expressing human mutant amyloid precursor protein (APP) and presenilin-1 (PS1) demonstrate robust brain amyloid beta (Aβ) peptide containing plaque deposition, increased markers of oxidative stress, behavioral dysfunction, and proinflammatory gliosis. On the other hand, lack of growth hormone, prolactin, and thyroid-stimulating hormone due to a recessive mutation in the Prop 1 gene (Prop1df) in Ames dwarf mice results in a phenotype characterized by potentiated antioxidant mechanisms, improved learning and memory, and significantly increased longevity in homozygous mice. Based on this, we hypothesized that a similar hormone deficiency might attenuate disease changes in the brains of APP/PS1 mice. To test this idea, APP/PS1 mice were crossed to the Ames dwarf mouse line. APP/PS1, wild-type, df/+, df/df, df/+/APP/PS1, and df/df/APP/PS1 mice were compared at 6 months of age through behavioral testing and assessing amyloid burden, reactive gliosis, and brain cytokine levels. df/df mice demonstrated lower brain growth hormone and insulin-like growth factor 1 concentrations. This correlated with decreased astrogliosis and microgliosis in the df/df/APP/PS1 mice and, surprisingly, reduced Aβ plaque deposition and Aβ 1-40 and Aβ 1-42 concentrations. The df/df/APP/PS1 mice also demonstrated significantly elevated brain levels of multiple cytokines in spite of the attenuated gliosis. These data indicate that the df/df/APP/PS1 line is a unique resource in which to study aging and resistance to disease and suggest that the affected pituitary hormones may have a role in regulating disease progression.

  16. A mutation in the {beta}-myosin rod associated with hypertrophic cardiomyopathy has an unexpected molecular phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Armel, Thomas Z. [Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309 (United States); Leinwand, Leslie A., E-mail: leslie.leinwand@colorado.edu [Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309 (United States)

    2010-01-01

    Hypertrophic cardiomyopathy (HCM) is a common, autosomal dominant disorder primarily characterized by left ventricular hypertrophy and is the leading cause of sudden cardiac death in youth. HCM is caused by mutations in several sarcomeric proteins, with mutations in MYH7, encoding {beta}-MyHC, being the most common. While many mutations in the globular head region of the protein have been reported and studied, analysis of HCM-causing mutations in the {beta}-MyHC rod domain has not yet been reported. To address this question, we performed an array of biochemical and biophysical assays to determine how the HCM-causing E1356K mutation affects the structure, stability, and function of the {beta}-MyHC rod. Surprisingly, the E1356K mutation appears to thermodynamically destabilize the protein, rather than alter the charge profile know to be essential for muscle filament assembly. This thermodynamic instability appears to be responsible for the decreased ability of the protein to form filaments and may be responsible for the HCM phenotype seen in patients.

  17. Motor Neuron Syndrome as a New Phenotypic Manifestation of Mutation 9185T>C in Gene MTATP6

    Directory of Open Access Journals (Sweden)

    Marisa Brum

    2014-01-01

    Full Text Available Background. The mutation 9185T>C in ATP6 gene, associated with Leigh syndrome, was reported in only few families. Motor neuron disease (MND, both clinically and electrophysiologically, was not previously described in association with this mutation. Case Report. 33-year-old male, with family history of mitochondrial disease, presented with cognitive impairment, exercise intolerance, and progressive muscle weakness. Examination revealed global hypotonia, and proximal tetraparesis, without atrophy or fasciculation, pyramidal signs, or sensory symptoms. The laboratory findings revealed an increase of lactate and lactate/pyruvate ratio; electromyogram showed chronic neurogenic compromise; muscle biopsy was suggestive of spinal muscular atrophy and mitochondriopathy; genetic study of SMN1 was negative but detected a homoplasmic mutation 9185T>C in ATP6 gene. His younger sister, with the same mutation, had cognitive impairment, ataxia, and muscle weakness. EMG showed axonal peripheral neuropathy. Conclusion. This case is unique because of the benignity and the coexistence of clinical, neurophysiological, and pathological findings suggestive of MND that, although described in mitochondrial disease, have not yet been reported in association with 9185T>C mutation. The present case contributes to the expansion of the phenotypic expressions of this particular mutation.

  18. Novel frameshift mutation in the CACNA1A gene causing a mixed phenotype of episodic ataxia and familiar hemiplegic migraine.

    Science.gov (United States)

    Kinder, S; Ossig, C; Wienecke, M; Beyer, A; von der Hagen, M; Storch, A; Smitka, M

    2015-01-01

    Episodic ataxia type 2 (EA2, MIM#108500) is the most common form of EA and an autosomal-dominant inherited disorder characterized by paroxysmal episodes of ataxia. The disease causative gene CACNA1A encodes for the alpha 1A subunit of the voltage-gated P/Q-type calcium channel. We report on a family with a novel mutation in the CACNA1A gene. The clinical symptoms within the family varied from the typical clinical presentation of EA2 with dysarthria, gait ataxia and oculomotor symptoms to migraine and dystonia. A novel nonsense mutation of the CACNA1A gene was identified in all affected family members and is most likely the disease causing molecular defect. The pharmacological treatment with acetazolamide (AAA) was successful in three family members so far. Treatment with AAA led to a reduction of migraine attacks and an improvement of the dystonia. This relationship confirmed the hypothesis that this novel mutation results in a heterogeneous phenotype and confutes the coincidence with common migraine. Dystonia is potentially included as a further part of the phenotype spectrum of CACNA1A gene mutations.

  19. p.Pro4Arg mutation in LMNA gene: a new atypical progeria phenotype without metabolism abnormalities.

    Science.gov (United States)

    Guo, Hong; Luo, Na; Hao, Fei; Bai, Yun

    2014-08-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a typical presenile disorder, with mutation in the LMNA gene. Besides HGPS, mutations in LMNA gene have also been reported in atypical progeroid syndrome (APS). The objective of the study was to investigate the phenotype and molecular basis of APS in a Chinese family. LMNA gene mutations were also reviewed to identify the phenotypic and pathogenic differences among APS. Two siblings in a non-consanguineous Chinese family with atypical progeria were reported. The clinical features were observed, including presenile manifestations such as bird-like facial appearance, generalized lipodystrophy involving the extremities and mottled hyperpigmentation on the trunk and extremities. A heterozygous mutation c.11C>G (p.Pro4Arg) of the LMNA gene was detected in the two patients. 28 different variants of the LMNA gene have been reported in APS families, spreading over almost all the 12 exons of the LMNA gene with some hot-spot regions. This is the first detailed description of an APS family without metabolism abnormalities. APS patients share most of the clinical features, but there may be some distinct features in different ethnic groups.

  20. Phenotypic diversity associated with the mitochondrial m.8313G>A point mutation.

    LENUS (Irish Health Repository)

    O'Rourke, Killian

    2012-02-01

    We report the clinical, histochemical, and molecular genetic findings in a patient with progressive mitochondrial cytopathy due to the m.8313G>A point mutation in the mitochondrial tRNA(Lys) (MTTK) gene. The clinical features in this case are severe, including short stature, myopathy, peripheral neuropathy, and osteoporosis, while extensive analysis of maternal relatives indicate that the mutation has arisen de novo and was not maternally inherited. This report of a second case, together with single muscle fiber mutation analysis that shows clear segregation of mutation load with cytochrome c oxidase deficiency, confirms that the mutation is pathologic.

  1. Frequency of mutations in Mediterranean fever gene, with gender and genotype–phenotype correlations in a Turkish population

    Indian Academy of Sciences (India)

    Salih Coşkun; Serkan Kurtgöz; Ece Keskin; Ferah Sönmez; Gökay Bozkurt

    2015-12-01

    Familial Mediterranean fever (FMF) is the most common hereditary inflammatory periodic disease, characterized by recurrent episodes of fever, abdominal pain, synovitis and pleurisy. The aim of this study was to determine the frequency and distribution of Mediterranean fever () gene mutations and to investigate the clinical characteristics and genotype–phenotype correlation in patients with FMF in Aydın, a province in western Anatolia, Turkey. Therefore, we retrospectively analysed gene mutations in 383 patients with suspected FMF and the clinical features of 327 among them. The gene mutations were investigated using the reverse dot-blot hybridization technique. We detected 26 different genotypes and 11 different mutations. The most common mutations in our cohort were p.M694V (41.15%), p.E148Q (20.35%), p.M680I(G/C) (12.39%) and p.R761H (9.73%). Abdominal pain (86.2%), fever (80.7%), arthralgia (57.2%), vomiting (36.1%), arthritis (34.6%), fatigue (31.5%), anorexia (22.9%) and chest pain (19.0%) were the most prevalent clinical features in our patients. This is the first study from Aydın in which the distribution of gene mutations and clinical features were evaluated in patients with FMF. We found that the most common mutation was p.M694V in our region, while the frequency of the p.R761H mutation was higher compared to other regions of Turkey with respect to extracted data from previous similar studies. Presented results supported the clinical findings in the literature that the homozygous p.M694V and compound heterozygous genotype were associated with more severe courses in FMF patients.

  2. Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype.

    Science.gov (United States)

    Takenouchi, Toshiki; Hida, Mariko; Sakamoto, Yoshiaki; Torii, Chiharu; Kosaki, Rika; Takahashi, Takao; Kosaki, Kenjiro

    2013-12-01

    Recently, three marfanoid patients with congenital lipodystrophy and a neonatal progeroid appearance were reported. Although their phenotype was distinct from that of classic Marfan syndrome, they all had a truncating mutation in the penultimate exon, i.e., exon 64, of FBN1, the causative gene for Marfan syndrome. These patients might represent a new entity, but the exact phenotypic and genotypic spectrum remains unknown. Here, we report on a girl born prematurely who exhibited severe congenital lipodystrophy and a neonatal progeroid appearance. The patient exhibited a characteristic growth pattern consisting of an accelerated growth in height with a discrepant poor weight gain. She had a characteristic facial appearance with craniosynostosis. A mutation analysis identified c.8175_8182del8bp, p.Arg2726Glufs*9 in exon 64 of the FBN1 gene. A review of similar, recently reported patients revealed that the cardinal features of these patients include (1) congenital lipodystrophy, (2) premature birth with an accelerated linear growth disproportionate to the weight gain, and (3) a progeroid appearance with distinct facial features. Lines of molecular evidence suggested that this new progeroid syndrome represents a neomorphic phenotype caused by truncated transcripts with an extremely charged protein motif that escapes from nonsense-mediated mRNA decay, altering FBN1-TGF beta signaling, rather than representing the severe end of the hypomorphic phenotype of the FBN1-TGF beta disorder spectrum. We propose that this marfanoid entity comprised of congenital lipodystrophy, a neonatal progeroid appearance, and a peculiar growth profile and caused by rare mutations in the penultimate exon of FBN1, be newly referred to as marfanoid-progeroid syndrome.

  3. SMA-causing missense mutations in survival motor neuron (Smn) display a wide range of phenotypes when modeled in Drosophila.

    Science.gov (United States)

    Praveen, Kavita; Wen, Ying; Gray, Kelsey M; Noto, John J; Patlolla, Akash R; Van Duyne, Gregory D; Matera, A Gregory

    2014-08-01

    Mutations in the human survival motor neuron 1 (SMN) gene are the primary cause of spinal muscular atrophy (SMA), a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of phenotypic severities, similar to the human disease. Furthermore, specific interactions with other proteins known to be important for SMN's role in RNP assembly are conserved. Intragenic complementation analyses revealed that the three most severe mutations, all of which map to the YG box self-oligomerization domain of SMN, display a stronger phenotype than the null allele and behave in a dominant fashion. In support of this finding, the severe YG box mutants are defective in self-interaction assays, yet maintain their ability to heterodimerize with wild-type SMN. When expressed at high levels, wild-type SMN is able to suppress the activity of the mutant protein. These results suggest that certain SMN mutants can sequester the wild-type protein into inactive complexes. Molecular modeling of the SMN YG box dimer provides a structural basis for this dominant phenotype. These data demonstrate that important structural and functional features of the SMN YG box are conserved between vertebrates and invertebrates, emphasizing the importance of self-interaction to the proper functioning of SMN.

  4. SMA-causing missense mutations in survival motor neuron (Smn display a wide range of phenotypes when modeled in Drosophila.

    Directory of Open Access Journals (Sweden)

    Kavita Praveen

    2014-08-01

    Full Text Available Mutations in the human survival motor neuron 1 (SMN gene are the primary cause of spinal muscular atrophy (SMA, a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs, core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of phenotypic severities, similar to the human disease. Furthermore, specific interactions with other proteins known to be important for SMN's role in RNP assembly are conserved. Intragenic complementation analyses revealed that the three most severe mutations, all of which map to the YG box self-oligomerization domain of SMN, display a stronger phenotype than the null allele and behave in a dominant fashion. In support of this finding, the severe YG box mutants are defective in self-interaction assays, yet maintain their ability to heterodimerize with wild-type SMN. When expressed at high levels, wild-type SMN is able to suppress the activity of the mutant protein. These results suggest that certain SMN mutants can sequester the wild-type protein into inactive complexes. Molecular modeling of the SMN YG box dimer provides a structural basis for this dominant phenotype. These data demonstrate that important structural and functional features of the SMN YG box are conserved between vertebrates and invertebrates, emphasizing the importance of self-interaction to the proper functioning of SMN.

  5. A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum.

    Science.gov (United States)

    Gutiérrez-Amavizca, Bianca Ethel; Brambila-Tapia, Aniel Jessica Leticia; Juárez-Vázquez, Clara Ibet; Holder-Espinasse, Muriel; Manouvrier-Hanu, Sylvie; Escande, Fabienne; Barros-Núñez, Patricio

    2012-11-01

    Brachydactyly type C (BDC), a well-recognized autosomal dominant hand malformation, displays brachymesophalangy of the second, third, and fifth fingers, a short first metacarpal, hyperphalangy, and ulnar deviation of the index finger. An "angel-shaped phalanx" is a distinctive radiological sign that can be found in BDC and other skeletal dysplasias, such as angel-shaped phalango-epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. BDC and ASPED result from mutations in the CDMP1 gene. We report here a Mexican patient with BDC and clinical features of ASPED who carries a novel mutation in CDMP1, confirming that BDC and ASPED are part of the CDMP1 mutational spectrum. Based on the large number of clinical features in common, we suggest that both anomalies are part of the same clinical spectrum. Supported by an extensive review of the literature, a possible genotype-phenotype correlation in the mutational spectrum of this gene is proposed.

  6. The phenotypes of temperature-sensitive mini-RK2 replicons carrying mutations in the replication control gene trfA are suppressed nonspecifically by intragenic cop mutations.

    Science.gov (United States)

    Haugan, K; Karunakaran, P; Blatny, J M; Valla, S

    1992-01-01

    The minimal replicon of the broad-host-range plasmid RK2 consists of the origin of vegetative replication (oriV) and a gene (trfA) encoding an essential replication protein that binds to short repeats in oriV. We report here the results of a DNA sequence analysis of seven unique mutants that are temperature sensitive for replication in Escherichia coli. The mutations (designated rts) were distributed throughout 40% of the downstream part of the trfA gene. Spontaneous revertants of the rts mutants were isolated, and further analysis of four such revertants demonstrated that the new phenotypes resulted from intragenic second-site copy up (cop) mutations. Subcloning experiments showed that all tested intragenic combinations of rts and cop mutations resulted in elimination or strong reduction of the temperature sensitivity of replication. This suppression was also observed under conditions where the mutant TrfA protein was provided in trans with respect to oriV, indicating that the reduction in temperature sensitivity could not be a TrfA protein dosage effect. The phenotypes of two of the cop mutants in Pseudomonas aeruginosa were analyzed; the results demonstrated that the mutants were either not functional or poorly functional in this host. The rts mutant plasmids were also reduced in their ability to replicate in P. aeruginosa, and the intragenic cop mutations did not improve the functionality of these mutants. The significance of the results is discussed in relation to current models of the mechanism of action of the TrfA protein. PMID:1400252

  7. A novel mutation at the JK locus causing Jknull phenotype in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    MENG; Yan

    2005-01-01

    [1]Olivès, B., Mattei, M. G., Huet, M. et al., Kidd blood group and urea transport of human erythrocytes are carried by the same pro-tein, J. Biol. Chem., 1995, 270(26): 15607―15610.[2]Sands, J. M., Timmer, R. T., Gunn, R. B., Urea transporters in kidney and erythrocytes, Am. J. Physiol.,1997, 273: F321―F339.[3]Heaton, D. C., McLoughlin, K., Jk(a-b-) red blood cells resist urea lysis, Transfusion, 1982, 22(1): 70―71.[4]Sands, J. M., Gargus, J. J., Frohlich, O. et al., Urinary concentrating ability in patients with Jk(a-b-) blood type who lack carrier-mediated urea transport, J. Am. Soc. Nephrol., 1992, 2(12): 1689―1696.[5]Nidal, M., Irshaid, N. I., Eicher, H. H. et al., Novel alleles at the JK blood group locus explain the absence of the erythrocyte urea transporter in European families, Br. J. Heaematol., 2002, 116(2): 445―453.[6]Okubo, Y., Yamaguchi, H., Nagao, N. et al., Heterogeneity of the pheno type JK(a-,b-) found in Japanese, Transfusion, 1986, 26(3): 237―239.[7]Olives, B., Merriman, M., Bailly, P. et al., The molecular basis of the Kidd blood group polymorphism and its lack of association with type 1 diabetes susceptibility, Hum. Mol. Genet., 1997, 6(7): 1017―1020.[8]Fr(o)hlich, O., Macey, R. I., Edwards-Moulds, J. et al., Urea transport deficiency in Jk(ab) erythrocytes, Am. J. Physiol., 1991, 260: C778―C783.[9]Irshaid, N. M., Hustinx, H., Olsson, M. L., A novel molecular basis of the JK(a-b-) phenotype in a Swiss family, Vox. Sanguinis, 2000, 78(suppl 1): O019.[10]Lucien, N., Chiaroni, J., Cartron, J. P. et al., Partial deletion in the JK locus causing a Jk(null ) phenotype, Blood, 2002, 99(3): 1079―1081.[11]Yang, B., Verkman, A. S., Analysis of double knockout mice lacking aquaporin-1 and urea transporter UT-B: Evidence for UT-B facilitated water transport in erythrocytes, J. Biol. Chem., 2002, 277(39): 36782―36786.[12]Van Hoek, A. N., Verkman, A. S., Functional reconstitution of the isolated erythrocyte water channel CHIP28, J

  8. Cyclic-AMP metabolism in synaptic growth, strength and precision: Neural and behavioral phenotype-specific counterbalancing effects between dnc PDE and rut AC mutations

    OpenAIRE

    Ueda, Atsushi; Wu, Chun-Fang

    2012-01-01

    Two classic learning mutants in Drosophila, rutabaga (rut) and dunce (dnc), are defective in cAMP synthesis and degradation, respectively, exhibiting a variety of neuronal and behavioral defects. We ask how the opposing effects of these mutations on cAMP levels modify subsets of phenotypes, and whether any specific phenotypes could be ameliorated by biochemical counter balancing effects in dnc rut double mutants. Our study at larval neuromuscular junctions (NMJs) demonstrate that dnc mutation...

  9. CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation

    Science.gov (United States)

    Mougou-Zerelli, Soumaya; Thomas, Sophie; Szenker, Emmanuelle; Audollent, Sophie; Elkhartoufi, Nadia; Babarit, Candice; Romano, Stéphane; Salomon, Rémi; Amiel, Jeanne; Esculpavit, Chantal; Gonzales, Marie; Escudier, Estelle; Leheup, Bruno; Loget, Philippe; Odent, Sylvie; Roume, Joëlle; Gérard, Marion; Delezoide, Anne-Lise; Khung, Suonavy; Patrier, Sophie; Cordier, Marie-Pierre; Bouvier, Raymonde; Martinovic, Jéléna; Gubler, Marie-Claire; Boddaert, Nathalie; Munnich, Arnold; Encha-Razavi, Férechté; Valente, Enza Maria; Saad, Ali; Saunier, Sophie; Vekemans, Michel; Attié-Bitach, Tania

    2009-01-01

    The Meckel syndrome (MKS) is a lethal fetal disorder characterized by diffuse renal cystic dysplasia, polydactyly, a brain malformation that is usually occipital encephalocele and/or vermian agenesis, with intrahepatic biliary duct proliferation. Joubert syndrome (JBS) is a viable neurological disorder with a characteristic “molar tooth sign” (MTS) on axial images reflecting cerebellar vermian hypoplasia/dysplasia. Both conditions are classified as ciliopathies with an autosomal recessive mode of inheritance. Allelism of MS and JBS has been reported for TMEM67/MKS3, CEP290/MKS4, and RPGRIP1L/MKS5. Recently, one homozygous splice mutation with a founder effect was reported in the CC2D2A gene in Finnish fetuses with MKS, defining the 6th locus for MKS. Shortly thereafter, CC2D2A mutations were reported in JBS also. The analysis of the CC2D2A gene in our series of MKS fetuses, identified 14 novel truncating mutations in 11 cases. These results confirm the involvement of CC2D2A in MKS and reveal a major contribution of CC2D2A to the disease. We also identified three missense CC2D2A mutations in two JBS cases. Therefore and in accordance with the data reported regarding RPGRIP1L, our results indicate phenotype-genotype correlations, as missense and presumably hypomorphic mutations lead to JBS while all null alleles lead to MKS. PMID:19777577

  10. Identification of a common mutation in mucopolysaccharidosis IVA: correlation among genotype, phenotype, and keratan sulfate.

    Science.gov (United States)

    Tomatsu, Shunji; Dieter, Tatiana; Schwartz, Ida V; Sarmient, Piedad; Giugliani, Roberto; Barrera, Luis A; Guelbert, Norberto; Kremer, Raquel; Repetto, Gabriela M; Gutierrez, Monica A; Nishioka, Tatsuo; Serrato, Olga Peña; Montaño, Adriana Maria; Yamaguchi, Seiji; Noguchi, Akihiko

    2004-01-01

    Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Mutation screening of the GALNS was performed by genomic PCR and direct sequence analyses in 20 MPS IVA patients from Latin America. In this study, 12 different gene mutations including nine unreported ones were identified in 16 severe and four attenuated patients and accounted for 90.0% of the unrelated mutant alleles. The gene alterations were missense mutations except one insertion. Six recurrent mutations, p.A75G, p.G116S, p.G139S, p.N164T, p.R380S, and p.R386C, accounted for 5.0, 10.0, 5.0, 7.5, 5.0, and 32.5% of the unrelated mutant alleles, respectively. The p.R386C mutation was identified in all Latin American populations studied. Eleven mutations correlated with a severe form, while one mutation, p.R380S, was associated with an attenuated form. MPS IVA patients had an elevation of urine and plasma keratan sulfate (KS) concentrations compared with those of the age-matched control. KS concentrations in severe patients were higher than those in attenuated patients. These data provide evidence for extensive allelic heterogeneity and presence of a common mutation in Latin American patients. Accumulation of mutations with clinical description and KS concentration will lead us to predict clinical severity of the patient more precisely.

  11. Mutation Analysis of 16 Mucolipidosis II and III Alpha/Beta Chinese Children Revealed Genotype-Phenotype Correlations

    Science.gov (United States)

    Liu, Shuang; Zhang, Weimin; Shi, Huiping; Yao, Fengxia; Wei, Min; Qiu, Zhengqing

    2016-01-01

    Mucolipidosis II and III alpha/beta are autosomal recessive diseases caused by mutations in the GNPTAB gene which encodes the α and β subunits of the N-acetylglucosamine-1-phosphotransferase. Clinically, mucolipidosis II (MLII) is characterized by severe developmental delay, coarse facial features, skeletal deformities, and other systemic involvement. In contrast, MLIII alpha/beta is a much milder disorder, the symptoms of which include progressive joint stiffness, short stature, and scoliosis. To study the relationship between the genotypes and phenotypes of the MLII and MLIII alpha/beta patients, we analyzed the GNPTAB gene in 16 Chinese MLII and MLIII alpha/beta patients. We collected and analyzed the patients’ available clinical data and all showed clinical features typical of MLII or MLIII alpha/beta. Moreover, the activity of several lysosomal enzymes was measured in the plasma and finally the GNPTAB gene was sequenced. We detected 30 mutant alleles out of 32 alleles in our patients. These include 10 new mutations (c.99delC, c.118-1G>A, c.523_524delAAinsG, c.1212C>G, c.2213C>A, c.2345C>T, c.2356C>T, c.2455G>T, c.2821dupA, and c.3136-2A>G) and 5 previously reported mutations (c.1071G>A, c.1090C>T, c.2715+1G>A, c.2550_2554delGAAA, and c.3613C>T). The most frequent mutation was the splicing mutation c.2715+1G>A, which accounted for 28% of the mutations. The majority of the mutations reported in the Chinese patients (57%) were located on exon 13 or in its intronic flanking regions. PMID:27662472

  12. Mutational analysis of ATP7B gene and the genotype-phenotype correlation in patients with Wilson's disease in Serbia

    Directory of Open Access Journals (Sweden)

    Tomić Aleksandra

    2013-01-01

    Full Text Available Background/Aim. Wilson’s disease (WD is an autosomal-recessive disorder which is characterized with a marked clinical heterogeneity. The gene responsible for WD is located in 13q14.3 chromosome, contains 21 exons and codes for copper specific transporting P-type adenosinetriphosphatase (ATPase (ATP7B. Mutations in ATP7B gene change biosynthetic and transporting role of ATPase in cell leading to damaged billiary excretion of copper and its accumulation in the liver, brain, cornea and other tissues. Until now, it has been described more than 400 mutations in ATP7B gene with characteristic geographic distribution. The aim of this study was to assess the spectrum of mutations of ATP7B gene on a large number of patients in Serbian population and to make a correlation between particular genotypes and specific phenotypes. Methods. Eighty-six consecutive patients with WD from WD Clinical Research programme were included in this study. Genetic analysis was performed by direct gene sequencing method. Results. Mutations in ATP7B gene were found in 93% analyzed patients (81.4% of all alleles analyzed. Thirteen mutations were identified, one of which (G998E was the novel one, so far undescribed in the literature. The most frequent mutation in our population was H1069Q, which was present in 38.4% patients, and the second most frequent mutation was 2304-2305insC (11.6%. Also, a great number of gene polymorphisms of DNA sequences, which do not disturb the ATP7B gene function, was identified. Although neurological form of the disease was more frequent in the group of homozygous for H1069Q and the group of non- H1069Q carriers, there was no statistically significant difference between the groups. Conclusion. Our research showed that genetic diagnosis of WD can be done in 80% of cases by analysis of 5 most common mutations in our population, which facilitate diagnosis significantly. There was no correlation between different genotypes and specific phenotypic

  13. Biochemical evidence for a mitochondrial genetic modifier in the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation.

    Science.gov (United States)

    Jiang, Pingping; Liang, Min; Zhang, Chaofan; Zhao, Xiaoxu; He, Qiufen; Cui, Limei; Liu, Xiaoling; Sun, Yan-Hong; Fu, Qun; Ji, Yanchun; Bai, Yidong; Huang, Taosheng; Guan, Min-Xin

    2016-08-15

    Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease. Mitochondrial modifiers are proposed to modify the phenotypic expression of primary LHON-associated mitochondrial DNA (mtDNA) mutations. In this study, we demonstrated that the LHON susceptibility allele (m.14502T > C, p. 58I > V) in the ND6 gene modulated the phenotypic expression of primary LHON-associated m.11778G > A mutation. Twenty-two Han Chinese pedigrees carrying m.14502T > C and m.11778G > A mutations exhibited significantly higher penetrance of optic neuropathy than those carrying only m.11778G > A mutation. We performed functional assays using the cybrid cell models, generated by fusing mtDNA-less ρ(o) cells with enucleated cells from LHON patients carrying both m.11778G > A and m.14502T > C mutations, only m.14502T > C or m.11778G > A mutation and a control belonging to the same mtDNA haplogroup. These cybrids cell lines bearing m.14502T > C mutation exhibited mild effects on mitochondrial functions compared with those carrying only m.11778G > A mutation. However, more severe mitochondrial dysfunctions were observed in cell lines bearing both m.14502T > C and m.11778G > A mutations than those carrying only m.11778G > A or m.14502T > C mutation. In particular, the m.14502T > C mutation altered assemble of complex I, thereby aggravating the respiratory phenotypes associated with m.11778G > A mutation, resulted in a more defective complex I. Furthermore, more reductions in the levels of mitochondrial ATP and increasing production of reactive oxygen species were also observed in mutant cells bearing both m.14502T > C and m.11778G > A mutation than those carrying only 11778G > A mutation. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between primary and secondary mtDNA mutations.

  14. Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene.

    Science.gov (United States)

    Marcon, Gabriella; Giaccone, Giorgio; Cupidi, Chiara; Balestrieri, Matteo; Beltrami, Carlo Alberto; Finato, Nicoletta; Bergonzi, Paolo; Sorbi, Sandro; Bugiani, Orso; Tagliavini, Fabrizio

    2004-03-01

    Presenilin 1 and 2 are 2 highly homologous genes involved in familial Alzheimer disease. While more than 100 mutations in presenilin 1 are known to segregate with the disease in familial Alzheimer disease, only 9 mutations of presenilin 2 have been identified to date. We report the clinical and neuropathological phenotype of FLO10, the large Italian Alzheimer kindred associated with methionine to valine substitution at residue 239 of presenilin 2. The patients showed a remarkable variability in age of onset of symptoms, disease duration, and clinical presentation. The neuropathological study of 2 patients revealed peculiar features in addition to neurofibrillary changes and A beta amyloid deposits in the neuropil and vessel wall. Ectopic neurons in the subcortical white matter, often containing neurofibrillary tangles, were found in both patients, one of whom presented with epilepsy. Furthermore, 1 patient showed an unusually high number of ghost tangles in the cerebral cortex. These observations indicate that the Alzheimer kindred FLO10 associated with M239V mutation of presenilin 2 is characterized by some peculiarities of the clinical and neuropathologic phenotype compared to sporadic Alzheimer disease.

  15. Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature.

    Science.gov (United States)

    Nachbauer, Wolfgang; Nocker, Michael; Karner, Elfriede; Stankovic, Iva; Unterberger, Iris; Eigentler, Andreas; Schneider, Rainer; Poewe, Werner; Delazer, Margarete; Boesch, Sylvia

    2014-05-01

    Episodic ataxia type 2 (EA2) is an autosomal dominant inherited neurological disorder that is characterized by paroxysmal episodes of ataxia. The causative gene for EA2 is CACNA1A which codes for the alpha 1A subunit of the voltage-gated P/Q-type calcium channel (Cav2.1). We detected a novel point mutation in the CACNA1A gene in a large Austrian family. All ten affected family members harbored a heterozygous c.3089+2T>C nucleotide exchange in intron 19. In silico modeling demonstrated a loss of the splice site of exon 19 by the mutation, which most likely results in exon skipping without frameshifting or use of an alternative splice site.Clinically, the family exhibited frequent ataxic episodes accompanied by headache in some individuals, which showed a good treatment response to acetazolamide or aminopyridine. Interictal phenotype variability was high ranging from an unremarkable clinical examination to a progressive cerebellar syndrome. Detailed cognitive testing with standardized neuropsychological tests revealed specific deficits in various domains including memory,executive functions and visual abilities. Moreover, a striking coincidence of socio-phobic behavior and anxiety disorders was detected within this family, which interfered with activities of daily living and has to be taken in consideration in EA2 patient management. We here characterize the phenotype of this novel CACNA1A mutation,review the respective literature and discuss implications on diagnosis and patient management.

  16. Saethre-Chotzen syndrome: notable intrafamilial phenotypic variability in a large family with Q28X TWIST mutation.

    Science.gov (United States)

    Dollfus, Hélène; Biswas, Partha; Kumaramanickavel, Govindsamy; Stoetzel, Corinne; Quillet, Renaud; Biswas, Jyotirmay; Lajeunie, Elisabeth; Renier, Dominique; Perrin-Schmitt, Fabienne

    2002-05-01

    Saethre-Chotzen syndrome is an autosomal dominant disease characterized by craniosynostosis, ptosis, and limb and external ear abnormalities. Variable expressivity is a well-known phenomenon in this disorder. A large Indian family has been recently identified as carrying a nonsense TWIST mutation (Q28 X) in 17 members, of whom 16 were examined in detail. Only 4 (25%) of the patients showed patent craniostenosis, namely, oxycephaly. The penetrance of craniosynostosis in this family is lower than previously reported in the literature. Fifteen patients (93%) had moderate to severe ptosis. Minor limb and external ear abnormalities were present in most patients. Eyelid features were the hallmark of the disease for 12 members of the family, suggesting that mutations in TWIST may lead to a phenotype with mainly palpebral features and no craniostenosis. The clinical analysis of this large family clearly illustrates the significant variable expressivity, probably related to haploinsufficiency because of the TWIST mutation. This phenotypic variability remains unclear but could be the result of modifier genes and/or genetic background effect, as noticed previously in the transgenic twist-null heterozygous mice.

  17. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes.

    Science.gov (United States)

    Waters, Michael F; Minassian, Natali A; Stevanin, Giovanni; Figueroa, Karla P; Bannister, John P A; Nolte, Dagmar; Mock, Allan F; Evidente, Virgilio Gerald H; Fee, Dominic B; Müller, Ulrich; Dürr, Alexandra; Brice, Alexis; Papazian, Diane M; Pulst, Stefan M

    2006-04-01

    Potassium channel mutations have been described in episodic neurological diseases. We report that K+ channel mutations cause disease phenotypes with neurodevelopmental and neurodegenerative features. In a Filipino adult-onset ataxia pedigree, the causative gene maps to 19q13, overlapping the SCA13 disease locus described in a French pedigree with childhood-onset ataxia and cognitive delay. This region contains KCNC3 (also known as Kv3.3), encoding a voltage-gated Shaw channel with enriched cerebellar expression. Sequencing revealed two missense mutations, both of which alter KCNC3 function in Xenopus laevis expression systems. KCNC3(R420H), located in the voltage-sensing domain, had no channel activity when expressed alone and had a dominant-negative effect when co-expressed with the wild-type channel. KCNC3(F448L) shifted the activation curve in the negative direction and slowed channel closing. Thus, KCNC3(R420H) and KCNC3(F448L) are expected to change the output characteristics of fast-spiking cerebellar neurons, in which KCNC channels confer capacity for high-frequency firing. Our results establish a role for KCNC3 in phenotypes ranging from developmental disorders to adult-onset neurodegeneration and suggest voltage-gated K+ channels as candidates for additional neurodegenerative diseases.

  18. Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort

    DEFF Research Database (Denmark)

    Lindquist, S G; Schwartz, M; Batbayli, M;

    2009-01-01

    Autosomal dominantly transmitted Alzheimer's disease (AD) and frontotemporal dementia (FTD) are genetically heterogeneous disorders. To date, three genes have been identified in which mutations cause early-onset autosomal dominant inherited AD: APP, PSEN1, and PSEN2. Mutations in two genes...

  19. Phenotype and clinical course in a family with a new de novo Twinkle gene mutation

    DEFF Research Database (Denmark)

    Jeppesen, Tina Dysgaard; Schwartz, M.; Colding-Jorgensen, E.;

    2008-01-01

    The Twinkle gene product is important for mtDNA replication. Only a few reports have investigated the clinically effect of mutations in this gene. We describe a new de novo mutation (1110C > A) in the PEO1 gene in a mother and her two sons. The mother had progressive ophthalmoplegia, limb weakness...

  20. REEP1 Mutation Spectrum and Genotype/Phenotype Correlation in Hereditary Spastic Paraplegia Type 31

    Science.gov (United States)

    Beetz, Christian; Schule, Rebecca; Deconinck, Tine; Tran-Viet, Khanh-Nhat; Zhu, Hui; Kremer, Berry P. H.; Frints, Suzanna G. M.; van Zelst-Stams, Wendy A. G.; Byrne, Paula; Otto, Susanne; Nygren, Anders O. H.; Baets, Jonathan; Smets, Katrien; Ceulemans, Berten; Dan, Bernard; Nagan, Narasimhan; Kassubek, Jan; Klimpe, Sven; Klopstock, Thomas; Stolze, Henning; Smeets, Hubert J. M.; Schrander-Stumpel, Constance T. R. M.; Hutchinson, Michael; van de Warrenburg, Bart P.; Braastad, Corey; Deufel, Thomas; Pericak-Vance, Margaret; Schols, Ludger; de Jonghe, Peter; Zuchner, Stephan

    2008-01-01

    Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for "REEP1" mutations and copy number variations. We identified 13 novel and 2 known "REEP1"…

  1. Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation.

    Science.gov (United States)

    De Braekeleer, M; Allard, C; Leblanc, J P; Simard, F; Aubin, G

    1997-12-01

    Cystic fibrosis (CF) has a high incidence in the French-Canadian population of Saguenay Lac-Saint-Jean (Quebec). The A455E mutation accounts for 8.3% of the CF chromosomes. This mutation was shown to be associated with a milder lung disease in the Dutch population. Twenty two CF patients distributed in 17 families and compound heterozygotes for the A455E mutation have been followed at the Clinique de Fibrose Kystique de Chicoutimi. Fourteen patients also carried the delta F508 mutation while the remaining eight patients had the 621 + 1G-->T mutation. Each patient was matched by sex and age to a patient homozygous for the delta F508 mutation. The pairs were analyzed for several clinical and laboratory variables. The A455E compound heterozygotes were diagnosed at a later age (P = 0.003) and had chloride concentrations at the sweat test lower than those homozygous for the delta F508 mutation (P = 0.007). More patients were pancreatic sufficient (P = 0.004). They had a higher Shwachman score (P = 0.001) and better pulmonary function tests (P < 0.02). CF patients compound heterozygous for the A455E mutation have a milder pancreatic and lung disease than the delta F508 homozygotes. Therefore, the A455E should be associated with a better prognosis.

  2. Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas

    NARCIS (Netherlands)

    S. Grover (Shilpa); F. Kastrinos (Fay); E.W. Steyerberg (Ewout); E.F. Cook (E. Francis); A. Dewanwala (Akriti); L.A. Burbidge; R.J. Wenstrup (Richard); S. Syngal (Sapna)

    2012-01-01

    textabstractContext: Patients with multiple colorectal adenomas may carry germline mutations in the APC or MUTYH genes. Objectives: To determine the prevalence of pathogenic APC and MUTYH mutations in patients with multiple colorectal adenomas who had undergone genetic testing and to compare the pre

  3. Genotype-phenotype relationship in patients with mutations in thyroid hormone transporter MCT8

    NARCIS (Netherlands)

    J.A. Jansen (John); E.C.H. Friesema (Edith); M.H.A. Kester (Monique); C.E. Schwartz; T.J. Visser (Theo)

    2008-01-01

    textabstractLoss-of-function mutations in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe X-linked psychomotor retardation and elevated serum T3levels. Most patients, for example those with mutations V235M, S448X, insI189, or delF230, cannot stand, walk, or speak. Pat

  4. Molecular genetic analysis of the calcium sensing receptor gene in patients clinically suspected to have familial hypocalciuric hypercalcemia: phenotypic variation and mutation spectrum in a Danish population

    DEFF Research Database (Denmark)

    Nissen, Peter H; Christensen, Signe E; Heickendorff, Lene

    2007-01-01

    hyperparathyroidism and is caused by inactivating mutations in the calcium sensing receptor (CASR) gene. OBJECTIVE: We sought to define the mutation spectrum of the CASR gene in a Danish FHH population and to establish genotype-phenotype relationships regarding the different mutations. DESIGN AND PARTICIPANTS...... calcium concentrations moderately above the upper reference limit, to calcium levels more than 20% above the upper reference limit. Furthermore, the mean plasma PTH concentration was within the normal range in eight of 11 studied mutations, but mild to moderately elevated in families with the mutations p...

  5. Identification of a Novel Mutation (867delA) in the Glucose-6-phosphatase Gene in Two Siblings with Glycogen Storage Disease Type Ia with Different Phenotypes

    NARCIS (Netherlands)

    Rake, Jan Peter; ten Berge, Annelies M.; Visser, Gepke; Verlind, Edwin; Niezen-Koning, Klary E.; Buys, Charles H. C. M.; Smit, G. Peter A.; Scheffer, Hans

    2000-01-01

    We identified a novel mutation (867delA) in the glucose-6-phosphatase gene of two siblings with glycogen storage disease type Ia. Although both siblings share the same mutations, their phenotype regarding adult height and hepatomegaly differs. In glycogen storage disease type Ia, substantial heterog

  6. 1031-1034delTAAC (Leu125Stop: a novel familial UBE3A mutation causing Angelman syndrome in two siblings showing distinct phenotypes

    Directory of Open Access Journals (Sweden)

    De Molfetta Greice Andreotti

    2012-12-01

    Full Text Available Abstract Background More than 50 mutations in the UBE3A gene (E6-AP ubiquitin protein ligase gene have been found in Angelman syndrome patients with no deletion, no uniparental disomy, and no imprinting defect. Case Presentation We here describe a novel UBE3A frameshift mutation in two siblings who have inherited it from their asymptomatic mother. Despite carrying the same UBE3A mutation, the proband shows a more severe phenotype whereas his sister shows a milder phenotype presenting the typical AS features. Conclusions We hypothesized that the mutation Leu125Stop causes both severe and milder phenotypes. Potential mechanisms include: i maybe the proband has an additional problem (genetic or environmental besides the UBE3A mutation; ii since the two siblings have different fathers, the UBE3A mutation is interacting with a different genetic variant in the proband that, by itself, does not cause problems but in combination with the UBE3A mutation causes the severe phenotype; iii this UBE3A mutation alone can cause either typical AS or the severe clinical picture seen in the proband.

  7. Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship

    DEFF Research Database (Denmark)

    Gregersen, N; Andresen, B S; Corydon, M J;

    2001-01-01

    Mutation analysis of metabolic disorders, such as the fatty acid oxidation defects, offers an additional, and often superior, tool for specific diagnosis compared to traditional enzymatic assays. With the advancement of the structural part of the Human Genome Project and the creation of mutation...... these practical uses emerges the possibility to study genotype-phenotype relationships and investigate the molecular pathogenesis resulting from specific mutations or groups of mutations. In the present review we summarize current knowledge regarding genotype-phenotype relationships in three disorders...... systems may help to assess the balance between genetic and environmental factors in the clinical expression of a given mutation. The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages...

  8. Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. Mutation in brief #960. Online.

    Science.gov (United States)

    Khaddour, Rana; Smith, Ursula; Baala, Lekbir; Martinovic, Jéléna; Clavering, Davina; Shaffiq, Rizwana; Ozilou, Catherine; Cullinane, Andrew; Kyttälä, Mira; Shalev, Stavit; Audollent, Sophie; d'Humières, Camille; Kadhom, Noman; Esculpavit, Chantal; Viot, Géraldine; Boone, Claire; Oien, Christine; Encha-Razavi, Férechté; Batman, Philip A; Bennett, Christopher P; Woods, C Geoffrey; Roume, Joelle; Lyonnet, Stanislas; Génin, Emmanuelle; Le Merrer, Martine; Munnich, Arnold; Gubler, Marie-Claire; Cox, Phillip; Macdonald, Fiona; Vekemans, Michel; Johnson, Colin A; Attié-Bitach, Tania

    2007-05-01

    Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations (typically occipital meningoencephalocele), postaxial polydactyly, multicystic kidney dysplasia, and ductal proliferation in the portal area of the liver. MKS is genetically heterogeneous and three loci have been mapped respectively on 17q23 (MKS1), 11q13 (MKS2), and 8q24 (MKS3). Very recently, two genes have been identified: MKS1/FLJ20345 on 17q in Finnish kindreds, carrying the same intronic deletion, c.1408-35_c.1408-7del29, and MKS3/TMEM67 on 8q in families from Pakistan and Oman. Here we report the genotyping of the MKS1 and MKS3 genes in a large, multiethnic cohort of 120 independent cases of MKS. Our first results indicate that the MKS1 and MKS3 genes are each responsible for about 7% of MKS cases with various mutations in different populations. A strong phenotype-genotype correlation, depending on the mutated gene, was observed regarding the type of central nervous system malformation, the frequency of polydactyly, bone dysplasia, and situs inversus. The MKS1 c.1408-35_1408-7del29 intronic mutation was identified in three cases from French or English origin and dated back to 162 generations (approx. 4050 years) ago. We also identified a common MKS3 splice-site mutation, c.1575+1G>A, in five Pakistani sibships of three unrelated families of Mirpuri origin, with an estimated age-of-mutation of 5 generations (125 years).

  9. Maternal genetic mutations as gestational and early life influences in producing psychiatric disease-like phenotypes in mice

    Directory of Open Access Journals (Sweden)

    Georgia eGleason

    2011-05-01

    Full Text Available Risk factors for psychiatric disorders have traditionally been classified as genetic or environmental. Risk (candidate genes, although typically possessing small effects, represent a clear starting point to elucidate downstream cellular/molecular pathways of disease. Environmental effects, especially during development, can also lead to altered behavior and increased risk for disease. An important environmental factor is the mother, demonstrated by the negative effects elicited by maternal gestational stress and altered maternal care. These maternal effects can also have a genetic basis (e.g. maternal genetic variability and mutations. The focus of this review is maternal genotype effects that influence the emotional development of the offspring resulting in life-long psychiatric disease-like phenotypes. We have recently found that genetic inactivation of the serotonin1A receptor (5-HT1AR and the fmr-1 gene (encoding the fragile X mental retardation protein in mouse dams results in psychiatric disease-like phenotypes in their genetically unaffected offspring. 5-HT1AR deficiency in dams results in anxiety and increased stress responsiveness in their offspring. Mice with 5-HT1AR deficient dams display altered development of the hippocampus, which could be linked to their anxiety-like phenotype. Maternal inactivation of fmr-1, like its inactivation in the offspring, results in a hyperactivity-like condition and is associated with receptor alterations in the striatum. These data indicate a high sensitivity of the offspring to maternal mutations and suggest that maternal genotype effects can increase the impact of genetic risk factors in a population by increasing the risk of the genetically normal offspring as well as by enhancing the effects of offspring mutations.

  10. Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome.

    Directory of Open Access Journals (Sweden)

    Nicholas L Rider

    2015-01-01

    Full Text Available Unbiased genetic diagnosis has increasingly associated seemingly unrelated somatic and immunological phenotypes. We report a male infant who presented within the first year of life with physical growth impairment, feeding difficulties, hyperemesis without diarrhea, and abnormal hair findings suggestive of trichorrhexis nodosa. With advancing age, moderate global developmental delay, susceptibility to frequent viral illnesses, otitis media and purulent conjunctivitis were identified. Because of the repeated infections an immunological evaluation was pursued and identified impaired antibody memory responses following pneumococcal vaccine administration. Immunoglobulin replacement therapy and nutritional support were employed as mainstays of therapy. The child is now aged 12 years and still without diarrhea. Whole exome sequencing identified compound heterozygous mutations in the TTC37 gene, a known cause of the Trichohepatoenteric Syndrome (THES. This case extends the known phenotype of THES and defines a potential subset for inclusion as an immune overlap syndrome.

  11. A study of familial MELAS: Evaluation of A3243G mutation, clinical phenotype, and magnetic resonance spectroscopy-monitored progression

    Directory of Open Access Journals (Sweden)

    Chunnuan Chen

    2012-01-01

    Full Text Available The clinical manifestations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS syndrome are nonspecific and can easily be misdiagnosed. Magnetic resonance spectroscopy (MRS-based detection of lactate in the brain has been found to be of diagnostic help in MELAS syndrome, however, the issue of whether MRS features vary by stage remains unresolved. We assessed the causative mutation and radiological features of a family of MELAS. Four of the family members harbored the A3243G mutation, probably of maternal inheritance. However, the clinical phenotypic expression was different in these patients. MRS showed a lactate peak, decreased N-acetylaspartate, choline, and creatine, which became more pronounced with progression of the disease, demonstrating that brain-MRS-based detection of lactate may be a suitable way to monitor the progression and treatment of MELAS.

  12. Trafficking defect and proteasomal degradation contribute to the phenotype of a novel KCNH2 long QT syndrome mutation.

    Directory of Open Access Journals (Sweden)

    Anton Mihic

    Full Text Available The Kv11.1 (hERG K+ channel plays a fundamental role in cardiac repolarization. Missense mutations in KCNH2, the gene encoding Kv11.1, cause long QT syndrome (LQTS and frequently cause channel trafficking-deficiencies. This study characterized the properties of a novel KCNH2 mutation discovered in a LQT2 patient resuscitated from a ventricular fibrillation arrest. Proband genotyping was performed by SSCP and DNA sequencing. The electrophysiological and biochemical properties of the mutant channel were investigated after expression in HEK293 cells. The proband manifested a QTc of 554 ms prior to electrolyte normalization. Mutation analysis revealed an autosomal dominant frameshift mutation at proline 1086 (P1086fs+32X; 3256InsG. Co-immunoprecipitation demonstrated that wild-type Kv11.1 and mutant channels coassemble. Western blot showed that the mutation did not produce mature complex-glycosylated Kv11.1 channels and coexpression resulted in reduced channel maturation. Electrophysiological recordings revealed mutant channel peak currents to be similar to untransfected cells. Co-expression of channels in a 1∶1 ratio demonstrated dominant negative suppression of peak Kv11.1 currents. Immunocytochemistry confirmed that mutant channels were not present at the plasma membrane. Mutant channel trafficking rescue was attempted by incubation at reduced temperature or with the pharmacological agents E-4031. These treatments did not significantly increase peak mutant currents or induce the formation of mature complex-glycosylated channels. The proteasomal inhibitor lactacystin increased the protein levels of the mutant channels demonstrating proteasomal degradation, but failed to induce mutant Kv11.1 protein trafficking. Our study demonstrates a novel dominant-negative Kv11.1 mutation, which results in degraded non-functional channels leading to a LQT2 phenotype.

  13. Dental phenotype in Jalili syndrome due to a c.1312 dupC homozygous mutation in the CNNM4 gene.

    Directory of Open Access Journals (Sweden)

    Hans U Luder

    Full Text Available Jalili syndrome denotes a recessively inherited combination of an eye disease (cone-rod dystrophy and a dental disorder (amelogenesis imperfecta, which is caused by mutations in the CNNM4 gene. Whereas the ophthalmic consequences of these mutations have been studied comprehensively, the dental phenotype has obtained less attention. A defective transport of magnesium ions by the photoreceptors of the retina is assumed to account for the progressive visual impairment. Since magnesium is also incorporated in the mineral of dental hard tissues, we hypothesized that magnesium concentrations in defective enamel resulting from mutations in CNNM4 would be abnormal, if a similar deficiency of magnesium transport also accounted for the amelogenesis imperfecta. Thus, a detailed analysis of the dental hard tissues was performed in two boys of Kosovan origin affected by Jalili syndrome. Retinal dystrophy of the patients was diagnosed by a comprehensive eye examination and full-field electroretinography. A mutational analysis revealed a c.1312 dupC homozygous mutation in CNNM4, a genetic defect which had already been identified in other Kosovan families and putatively results in loss-of-function of the protein. The evaluation of six primary teeth using light and scanning electron microscopy as well as energy-dispersive X-ray spectroscopy showed that dental enamel was thin and deficient in mineral, suggesting a hypoplastic/hypomineralized type of amelogenesis imperfecta. The reduced mineral density of enamel was accompanied by decreased amounts of calcium, but significantly elevated levels of magnesium. In dentin, however, a similar mineral deficiency was associated with reduced magnesium and normal calcium levels. It is concluded that the c.1312 dupC mutation of CNNM4 results in mineralization defects of both enamel and dentin, which are associated with significantly abnormal magnesium concentrations. Thus, we could not disprove the hypothesis that a

  14. The Zebrafish Model Organism Database: new support for human disease models, mutation details, gene expression phenotypes and searching

    Science.gov (United States)

    Howe, Douglas G.; Bradford, Yvonne M.; Eagle, Anne; Fashena, David; Frazer, Ken; Kalita, Patrick; Mani, Prita; Martin, Ryan; Moxon, Sierra Taylor; Paddock, Holly; Pich, Christian; Ramachandran, Sridhar; Ruzicka, Leyla; Schaper, Kevin; Shao, Xiang; Singer, Amy; Toro, Sabrina; Van Slyke, Ceri; Westerfield, Monte

    2017-01-01

    The Zebrafish Model Organism Database (ZFIN; http://zfin.org) is the central resource for zebrafish (Danio rerio) genetic, genomic, phenotypic and developmental data. ZFIN curators provide expert manual curation and integration of comprehensive data involving zebrafish genes, mutants, transgenic constructs and lines, phenotypes, genotypes, gene expressions, morpholinos, TALENs, CRISPRs, antibodies, anatomical structures, models of human disease and publications. We integrate curated, directly submitted, and collaboratively generated data, making these available to zebrafish research community. Among the vertebrate model organisms, zebrafish are superbly suited for rapid generation of sequence-targeted mutant lines, characterization of phenotypes including gene expression patterns, and generation of human disease models. The recent rapid adoption of zebrafish as human disease models is making management of these data particularly important to both the research and clinical communities. Here, we describe recent enhancements to ZFIN including use of the zebrafish experimental conditions ontology, ‘Fish’ records in the ZFIN database, support for gene expression phenotypes, models of human disease, mutation details at the DNA, RNA and protein levels, and updates to the ZFIN single box search. PMID:27899582

  15. Painful small fiber neuropathy with gastroparesis: A new phenotype with a novel mutation in the SCN10A gene.

    Science.gov (United States)

    Dabby, Ron; Sadeh, Menachem; Broitman, Yelena; Yosovich, Keren; Dickman, Ram; Leshinsky-Silver, Esther

    2016-04-01

    Gain-of-function mutations in the SCN10A gene (encoding the Nav1.8 voltage gated sodium channel) have been reported in a small number of patients. All presented with predominantly painful sensory neuropathy, congruent with the expression of Nav1.8 in nociceptive sensory neurons of the dorsal root ganglion. Only a few had mild autonomic symptoms, including dry eyes and mouth, orthostatic dizziness, palpitations, diarrhea and constipation. The underlying mechanism of the autonomic symptoms in these patients is unclear. We describe a 37-year-old woman with severe progressive gastroparesis and diffuse painful small fiber sensory neuropathy that started at age 32. Due to the severe dysphagia she could not ingest solid food, and lost eight kilograms. The gastroparesis was documented by esophageal manometry and gastric scintigraphy. The neuropathic pain started distally and then intensified and spread to most body areas. The patient harbored a novel heterozygous mutation: c.G4915A:p.D1639N in the SCN10A gene. To the best of our knowledge, this is the first description of such a phenotype due to a Nav1.8 mutation. Thus, our study expands the clinical spectrum of Nav1.8 associated disorders, and suggests that mutations in this sodium channel should be considered in patients with gastrointestinal motility dysfunction and painful neuropathy.

  16. RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma.

    Science.gov (United States)

    Krampitz, Geoffrey W; Norton, Jeffrey A

    2014-07-01

    The rapid technical advances in molecular biology and accelerating improvements in genomic and proteomic diagnostics have led to increasingly personalized strategies for cancer therapy. Such an approach integrates the genomic, proteomic, and molecular information unique to the individual to provide an accurate genetic diagnosis, molecular risk assessment, informed family counseling, therapeutic profiling, and early preventative management that best fits the particular needs of each patient. The discovery of mutations in the RET proto-oncogene resulting in variable onset and severity of multiple endocrine neoplasia type 2 (MEN2) was the first step in developing direct genetic testing for at-risk individuals. Patients with germline RET mutations may undergo risk assessment and appropriate intervention based on specific mutations. Moreover, family members of affected individuals receive counseling based on understanding of the genetic transmission of the disease. Increasingly, clinicians are able to make therapeutic choices guided by an informative biomarker code. Improvements in detection and management of patients with MEN2 resulting from understanding of the RET proto-oncogene are evidence of the benefits of personalized cancer medicine. This review describes the discovery of the RET proto-oncogene, the association between genotype and phenotype, and the role of mutation analysis on diagnosis and treatment of MEN2.

  17. Intermediate Phenotype between ADULT Syndrome and EEC Syndrome Caused by R243Q Mutation in TP63

    Science.gov (United States)

    Ueda, Koichi; Satoh, Chisei; Maekawa, Ryuta; Yoshiura, Koh-ichiro; Iseki, Sachiko

    2016-01-01

    Summary: A patient who had ectrodactyly, dry skin, exfoliative dermatitis, and hypodontia with peg-shaped teeth, but not cleft lip and palate, is described. Ectrodactyly with a tooth anomaly is recognized in both acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome and ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome. These 2 syndromes are caused by heterozygous mutations in the transcriptional factor gene p63. Mutation analysis of p63 gene showed a heterozygous mutation c.728G>A, p.Arg243Gln (previously referred to as R204Q) in the patient, but not in his parents. Therefore, this was a sporadic case of the p63 mutation–associated disorder. Although the mutation has been mostly reported in EEC syndrome patients, the present case did not have cleft lip and palate. Furthermore, the present case did not exhibit freckling or some of the other ectodermal dysplasia phenotypes typical of ADULT syndrome. The concept of ELA syndrome proposed by Prontera in 2011 resolves the problem confronted in diagnosing the present case. ELA syndrome is an acronym of EEC/limb–mammary syndrome/ADULT syndromes, and these 3 syndromes are united into a unique entity. This system can classify p63 mutation–associated disorders simply without interfering with treatment. PMID:28293528

  18. POLG1 p.R722H mutation associated with multiple mtDNA deletions and a neurological phenotype

    Directory of Open Access Journals (Sweden)

    Finnilä Saara

    2010-05-01

    Full Text Available Abstract Background The c.2447G>A (p.R722H mutation in the gene POLG1 of the catalytic subunit of human mitochondrial polymerase gamma has been previously found in a few occasions but its pathogenicity has remained uncertain. We set out to ascertain its contribution to neuromuscular disease. Methods Probands from two families with probable mitochondrial disease were examined clinically, muscle and buccal epithelial DNA were analyzed for mtDNA deletions, and the POLG1, POLG2, ANT1 and Twinkle genes were sequenced. Results An adult proband presented with progressive external ophthalmoplegia, sensorineural hearing impairment, diabetes mellitus, dysphagia, a limb myopathy and dementia. Brain MRI showed central and cortical atrophy, and 18F-deoxyglucose PET revealed reduced glucose uptake. Histochemical analysis of muscle disclosed ragged red fibers and cytochrome c oxidase-negative fibers. Electron microscopy showed subsarcolemmal aggregates of morphologically normal mitochondria. Multiple mtDNA deletions were found in the muscle, and sequencing of the POLG1 gene revealed a homozygous c.2447G>A (p.R722H mutation. His two siblings were also homozygous with respect to the p.R722H mutation and presented with dementia and sensorineural hearing impairment. In another family the p.R722H mutation was found as compound heterozygosity with the common p.W748S mutation in two siblings with mental retardation, ptosis, epilepsy and psychiatric symptoms. The estimated carrier frequency of the p.R722H mutation was 1:135 in the Finnish population. No mutations in POLG2, ANT1 and Twinkle genes were found. Analysis of the POLG1 sequence by homology modeling supported the notion that the p.R722H mutation is pathogenic. Conclusions The recessive c.2447G>A (p.R722H mutation in the linker region of the POLG1 gene is pathogenic for multiple mtDNA deletions in muscle and is associated with a late-onset neurological phenotype as a homozygous state. The onset of the disease

  19. Genotype-Phenotype Correlations Emerging from the Identification of Missense Mutations in MBTPS2

    NARCIS (Netherlands)

    Bornholdt, D.; Atkinson, T.P.; Bouadjar, B.; Catteau, B.; Cox, H.; Silva, D. De; Fischer, J.; Gunasekera, C.N.; Hadj-Rabia, S.; Happle, R.; Holder-Espinasse, M.; Kaminski, E.; Konig, A.; Megarbane, A.; Megarbane, H.; Neidel, U.; Oeffner, F.; Oji, V.; Theos, A.; Traupe, H.; Vahlquist, A.; Bon, B.W. van; Virtanen, M.; Grzeschik, K.H.

    2013-01-01

    Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This met

  20. Splicing factor gene mutations in the myelodysplastic syndromes: impact on disease phenotype and therapeutic applications.

    Science.gov (United States)

    Pellagatti, Andrea; Boultwood, Jacqueline

    2017-01-01

    Splicing factor gene mutations are the most frequent mutations found in patients with the myeloid malignancy myelodysplastic syndrome (MDS), suggesting that spliceosomal dysfunction plays a major role in disease pathogenesis. The aberrantly spliced target genes and deregulated cellular pathways associated with the commonly mutated splicing factor genes in MDS (SF3B1, SRSF2 and U2AF1) are being identified, illuminating the molecular mechanisms underlying MDS. Emerging data from mouse modeling studies indicate that the presence of splicing factor gene mutations can lead to bone marrow hematopoietic stem/myeloid progenitor cell expansion, impaired hematopoiesis and dysplastic differentiation that are hallmarks of MDS. Importantly, recent evidence suggests that spliceosome inhibitors and splicing modulators may have therapeutic value in the treatment of splicing factor mutant myeloid malignancies.

  1. TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections

    Science.gov (United States)

    Inamoto, Sakiko; Kwartler, Callie S.; Lafont, Andrea L.; Liang, Yao Yun; Fadulu, Van Tran; Duraisamy, Senthil; Willing, Marcia; Estrera, Anthony; Safi, Hazim; Hannibal, Mark C.; Carey, John; Wiktorowicz, John; Tan, Filemon K.; Feng, Xin-Hua; Pannu, Hariyadarshi; Milewicz, Dianna M.

    2010-01-01

    Aims Transforming growth factor-β (TGF-β) signaling is critical for the differentiation of smooth muscle cells (SMCs) into quiescent cells expressing a full repertoire of contractile proteins. Heterozygous mutations in TGF-β receptor type II (TGFBR2) disrupt TGF-β signaling and lead to genetic conditions that predispose to thoracic aortic aneurysms and dissections (TAADs). The aim of this study is to determine the molecular mechanism by which TGFBR2 mutations cause TAADs. Methods and results Using aortic SMCs explanted from patients with TGFBR2 mutations, we show decreased expression of SMC contractile proteins compared with controls. Exposure to TGF-β1 fails to increase expression of contractile genes in mutant SMCs, whereas control cells further increase expression of these genes. Analysis of fixed and frozen aortas from patients with TGFBR2 mutations confirms decreased in vivo expression of contractile proteins relative to unaffected aortas. Fibroblasts explanted from patients with TGFBR2 mutations fail to transform into mature myofibroblasts with TGF-β1 stimulation as assessed by expression of contractile proteins. Conclusions These data support the conclusion that heterozygous TGFBR2 mutations lead to decreased expression of SMC contractile protein in both SMCs and myofibroblasts. The failure of TGFBR2-mutant SMCs to fully express SMC contractile proteins predicts defective contractile function in these cells and aligns with a hypothesis that defective SMC contractile function contributes to the pathogenesis of TAAD. PMID:20628007

  2. GDAP1 mutations in Italian axonal Charcot-Marie-Tooth patients: Phenotypic features and clinical course.

    Science.gov (United States)

    Pezzini, I; Geroldi, A; Capponi, S; Gulli, R; Schenone, A; Grandis, M; Doria-Lamba, L; La Piana, C; Cremonte, M; Pisciotta, C; Nolano, M; Manganelli, F; Santoro, L; Mandich, P; Bellone, E

    2016-01-01

    Mutations in the ganglioside-induced differentiation associated-protein 1 (GDAP1) gene have been associated with both autosomal recessive (AR) and dominant (AD) Charcot-Marie-Tooth (CMT) axonal neuropathy. The relative frequency of heterozygous, dominant mutations in Italian CMT is unknown. We investigated the frequency of dominant mutations in GDAP1 in a cohort of 109 axonal Italian patients by sequencing genomic DNA and search for copy number variations. We also explored correlations with clinical features. All cases had already been tested for variants in common axonal AD genes. Eight patients (7.3%) harbored five already reported heterozygous mutations in GDAP1 (p.Arg120Gly, p.Arg120Trp, p.His123Arg, p.Gln218Glu, p.Arg226Ser). Mutations had different penetrances in the families; the onset of symptoms is in the first decade and progression is slower than usually seen in GDAP1-related AR-CMT. We show that the relative frequency of mutations in GDAP was slightly higher than those observed in MFN2 and MPZ (7.3% vs 6.3% and 5.0%). The relatively milder clinical features and the quite indolent course observed are relevant for prognostic assessment. On the basis of our experience and the data reported here, we suggest GDAP1 as the first gene that should be analysed in Italian patients affected by CMT2.

  3. Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations.

    LENUS (Irish Health Repository)

    Geranmayeh, Fatemeh

    2010-04-01

    Merosin deficient congenital muscular dystrophy 1A (MDC1A) results from mutations in the LAMA2 gene. We report 51 patients with MDC1A and examine the relationship between degree of merosin expression, genotype and clinical features. Thirty-three patients had absence of merosin and 13 showed some residual merosin. Compared to the residual merosin group, patients with absent merosin had an earlier presentation (<7days) (P=0.0073), were more likely to lack independent ambulation (P=0.0215), or require enteral feeding (P=0.0099) and ventilatory support (P=0.0354). We identified 33 novel LAMA2 mutations; these were distributed throughout the gene in patients with absent merosin, with minor clusters in exon 27, 14, 25 and 26 (55% of mutations). Patients with residual merosin often carried at least one splice site mutation and less frequently frameshift mutations. This large study identified novel LAMA2 mutations and highlights the role of immunohistochemical studies for merosin status in predicting clinical severity of MDC1A.

  4. Genome-Wide Association Studies Identify Two Novel BMP15 Mutations Responsible for an Atypical Hyperprolificacy Phenotype in Sheep

    Science.gov (United States)

    Demars, Julie; Fabre, Stéphane; Sarry, Julien; Rossetti, Raffaella; Gilbert, Hélène; Persani, Luca; Tosser-Klopp, Gwenola; Mulsant, Philippe; Nowak, Zuzanna; Drobik, Wioleta; Martyniuk, Elzbieta; Bodin, Loys

    2013-01-01

    Some sheep breeds are naturally prolific, and they are very informative for the studies of reproductive genetics and physiology. Major genes increasing litter size (LS) and ovulation rate (OR) were suspected in the French Grivette and the Polish Olkuska sheep populations, respectively. To identify genetic variants responsible for the highly prolific phenotype in these two breeds, genome-wide association studies (GWAS) followed by complementary genetic and functional analyses were performed. Highly prolific ewes (cases) and normal prolific ewes (controls) from each breed were genotyped using the Illumina OvineSNP50 Genotyping Beadchip. In both populations, an X chromosome region, close to the BMP15 gene, harbored clusters of markers with suggestive evidence of association at significance levels between 1E−05 and 1E−07. The BMP15 candidate gene was then sequenced, and two novel non-conservative mutations called FecXGr and FecXO were identified in the Grivette and Olkuska breeds, respectively. The two mutations were associated with the highly prolific phenotype (pFecXGr = 5.98E−06 and pFecXO = 2.55E−08). Homozygous ewes for the mutated allele showed a significantly increased prolificacy (FecXGr/FecXGr, LS = 2.50±0.65 versus FecX+/FecXGr, LS = 1.93±0.42, p<1E−03 and FecXO/FecXO, OR = 3.28±0.85 versus FecX+/FecXO, OR = 2.02±0.47, p<1E−03). Both mutations are located in very well conserved motifs of the protein and altered the BMP15 signaling activity in vitro using a BMP-responsive luciferase test in COV434 granulosa cells. Thus, we have identified two novel mutations in the BMP15 gene associated with increased LS and OR. Notably, homozygous FecXGr/FecXGr Grivette and homozygous FecXO/FecXO Olkuska ewes are hyperprolific in striking contrast with the sterility exhibited by all other known homozygous BMP15 mutations. Our results bring new insights into the key role played by the BMP15 protein in ovarian function and could

  5. Emergence of the P2 phenotype in Pseudomonas aeruginosa PAO1 strains involves various mutations in mexT or mexF.

    Science.gov (United States)

    Luong, Preston M; Shogan, Benjamin D; Zaborin, Alexander; Belogortseva, Natalia; Shrout, Joshua D; Zaborina, Olga; Alverdy, John C

    2014-01-01

    We recently demonstrated that Pseudomonas aeruginosa PAO1 undergoes a pronounced phenotypic change when introduced into the intestines of rats during surgical injury. Recovered strains displayed a specific phenotype (termed the P2 phenotype) characterized by altered pyocyanin production, high collagenase activity, high swarming motility, low resistance to chloramphenicol, and increased killing of Caenorhabditis elegans compared to the inoculating strain (termed the P1 phenotype). The aims of this study were to characterize the differences between the P. aeruginosa P1 and P2 phenotypes in quorum sensing and competitiveness. We then determined the presence of the P2 phenotype among PAO1 strains from various laboratories. Results demonstrated that P2 cells display accelerated growth during early exponential phase and early activation of quorum-sensing systems and overcome the growth of P1 cells in a mixed population. Among eight PAO1 strains obtained from different laboratories, four exhibited the P2 phenotype. Of 27 mutants analyzed from the P. aeruginosa MPAO1 transposon library, 25 displayed P2 phenotypes. The P2 phenotype in both cases correlated with a lack of expression of mexE or mexF due to mutations in mexT and mexF genes. In summary, strains possessing the P2 phenotype are distributed among PAO1 strains commonly used across a variety of research laboratories. Genetically, they are characterized by various mutations in mexT or mexF.

  6. Local amino acid sequence patterns dominate the heterogeneous phenotype for the collagen connective tissue disease Osteogenesis Imperfecta resulting from Gly mutations.

    Science.gov (United States)

    Xiao, Jianxi; Yang, Zhangfu; Sun, Xiuxia; Addabbo, Rayna; Baum, Jean

    2015-10-01

    Osteogenesis Imperfecta (OI), a hereditary connective tissue disease in collagen that arises from a single Gly → X mutation in the collagen chain, varies widely in phenotype from perinatal lethal to mild. It is unclear why there is such a large variation in the severity of the disease considering the repeating (Gly-X-Y)n sequence and the uniform rod-like structure of collagen. We systematically evaluate the effect of local (Gly-X-Y)n sequence around the mutation site on OI phenotype using integrated bio-statistical approaches, including odds ratio analysis and decision tree modeling. We show that different Gly → X mutations have different local sequence patterns that are correlated with lethal and nonlethal phenotypes providing a mechanism for understanding the sensitivity of local context in defining lethal and non-lethal OI. A number of important trends about which factors are related to OI phenotypes are revealed by the bio-statistical analyses; most striking is the complementary relationship between the placement of Pro residues and small residues and their correlation to OI phenotype. When Pro is present or small flexible residues are absent nearby a mutation site, the OI case tends to be lethal; when Pro is present or small flexible residues are absent further away from the mutation site, the OI case tends to be nonlethal. The analysis also reveals the dominant role of local sequence around mutation sites in the Major Ligand Binding Regions that are primarily responsible for collagen binding to its receptors and shows that non-lethal mutations are highly predicted by local sequence considerations alone whereas lethal mutations are not as easily predicted and may be a result of more complex interactions. Understanding the sequence determinants of OI mutations will enhance genetic counseling and help establish which steps in the collagen hierarchy to target for drug therapy.

  7. Unusual phenotype of congenital adrenal hyperplasia (CAH) with a novel mutation of the CYP21A2 gene.

    Science.gov (United States)

    Raisingani, Manish; Contreras, Maria F; Prasad, Kris; Pappas, John G; Kluge, Michelle L; Shah, Bina; David, Raphael

    2016-07-01

    Gonadotropin independent sexual precocity (SP) may be due to congenital adrenal hyperplasia (CAH), and its timing usually depends on the type of mutation in the CYP21A2 gene. Compound heterozygotes are common and express phenotypes of varying severity. The objective of this case report was to investigate the hormonal pattern and unusual genetic profile in a 7-year-old boy who presented with pubic hair, acne, an enlarged phallus, slightly increased testicular volume and advanced bone age. Clinical, hormonal and genetic studies were undertaken in the patient as well as his parents. We found elevated serum 17-hydroxyprogesterone (17-OHP) and androstenedione that were suppressed with dexamethasone, and elevated testosterone that actually rose after giving dexamethasone, indicating activity of the hypothalamic-pituitary-gonadal (HPG) axis. An initial search for common mutations was negative, but a more detailed genetic analysis of the CYP21A2 gene revealed two mutations including R341W, a non-classical mutation inherited from his mother, and g.823G>A, a novel not previously reported consensus donor splice site mutation inherited from his father, which is predicted to be salt wasting. However, the child had a normal plasma renin activity. He was effectively treated with low-dose dexamethasone and a GnRH agonist. His father was an unaffected carrier, but his mother had evidence of mild non-classical CAH. In a male child presenting with gonadotropin independent SP it is important to investigate adrenal function with respect to the androgen profile, and to carry out appropriate genetic studies.

  8. DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency

    Science.gov (United States)

    Volk, Timo; Pannicke, Ulrich; Reisli, Ismail; Bulashevska, Alla; Ritter, Julia; Björkman, Andrea; Schäffer, Alejandro A.; Fliegauf, Manfred; Sayar, Esra H.; Salzer, Ulrich; Fisch, Paul; Pfeifer, Dietmar; Di Virgilio, Michela; Cao, Hongzhi; Yang, Fang; Zimmermann, Karin; Keles, Sevgi; Caliskaner, Zafer; Güner, S¸ükrü; Schindler, Detlev; Hammarström, Lennart; Rizzi, Marta; Hummel, Michael; Pan-Hammarström, Qiang; Schwarz, Klaus; Grimbacher, Bodo

    2015-01-01

    Null mutations in genes involved in V(D)J recombination cause a block in B- and T-cell development, clinically presenting as severe combined immunodeficiency (SCID). Hypomorphic mutations in the non-homologous end-joining gene DCLRE1C (encoding ARTEMIS) have been described to cause atypical SCID, Omenn syndrome, Hyper IgM syndrome and inflammatory bowel disease—all with severely impaired T-cell immunity. By whole-exome sequencing, we investigated the molecular defect in a consanguineous family with three children clinically diagnosed with antibody deficiency. We identified perfectly segregating homozygous variants in DCLRE1C in three index patients with recurrent respiratory tract infections, very low B-cell numbers and serum IgA levels. In patients, decreased colony survival after irradiation, impaired proliferative response and reduced counts of naïve T cells were observed in addition to a restricted T-cell receptor repertoire, increased palindromic nucleotides in the complementarity determining regions 3 and long stretches of microhomology at switch junctions. Defective V(D)J recombination was complemented by wild-type ARTEMIS protein in vitro. Subsequently, homozygous or compound heterozygous DCLRE1C mutations were identified in nine patients from the same geographic region. We demonstrate that DCLRE1C mutations can cause a phenotype presenting as only antibody deficiency. This novel association broadens the clinical spectrum associated with ARTEMIS mutations. Clinicians should consider the possibility that an immunodeficiency with a clinically mild initial presentation could be a combined immunodeficiency, so as to provide appropriate care for affected patients. PMID:26476407

  9. DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency.

    Science.gov (United States)

    Volk, Timo; Pannicke, Ulrich; Reisli, Ismail; Bulashevska, Alla; Ritter, Julia; Björkman, Andrea; Schäffer, Alejandro A; Fliegauf, Manfred; Sayar, Esra H; Salzer, Ulrich; Fisch, Paul; Pfeifer, Dietmar; Di Virgilio, Michela; Cao, Hongzhi; Yang, Fang; Zimmermann, Karin; Keles, Sevgi; Caliskaner, Zafer; Güner, S Ükrü; Schindler, Detlev; Hammarström, Lennart; Rizzi, Marta; Hummel, Michael; Pan-Hammarström, Qiang; Schwarz, Klaus; Grimbacher, Bodo

    2015-12-20

    Null mutations in genes involved in V(D)J recombination cause a block in B- and T-cell development, clinically presenting as severe combined immunodeficiency (SCID). Hypomorphic mutations in the non-homologous end-joining gene DCLRE1C (encoding ARTEMIS) have been described to cause atypical SCID, Omenn syndrome, Hyper IgM syndrome and inflammatory bowel disease-all with severely impaired T-cell immunity. By whole-exome sequencing, we investigated the molecular defect in a consanguineous family with three children clinically diagnosed with antibody deficiency. We identified perfectly segregating homozygous variants in DCLRE1C in three index patients with recurrent respiratory tract infections, very low B-cell numbers and serum IgA levels. In patients, decreased colony survival after irradiation, impaired proliferative response and reduced counts of naïve T cells were observed in addition to a restricted T-cell receptor repertoire, increased palindromic nucleotides in the complementarity determining regions 3 and long stretches of microhomology at switch junctions. Defective V(D)J recombination was complemented by wild-type ARTEMIS protein in vitro. Subsequently, homozygous or compound heterozygous DCLRE1C mutations were identified in nine patients from the same geographic region. We demonstrate that DCLRE1C mutations can cause a phenotype presenting as only antibody deficiency. This novel association broadens the clinical spectrum associated with ARTEMIS mutations. Clinicians should consider the possibility that an immunodeficiency with a clinically mild initial presentation could be a combined immunodeficiency, so as to provide appropriate care for affected patients.

  10. A MITF Mutation Associated with a Dominant White Phenotype and Bilateral Deafness in German Fleckvieh Cattle

    Science.gov (United States)

    Philipp, Ute; Lupp, Bettina; Mömke, Stefanie; Stein, Veronika; Tipold, Andrea; Eule, Johanna Corinna; Rehage, Jürgen; Distl, Ottmar

    2011-01-01

    A dominantly inherited syndrome associated with hypopigmentation, heterochromia irides, colobomatous eyes and bilateral hearing loss has been ascertained in Fleckvieh cattle (German White Fleckvieh syndrome). This syndrome has been mapped to bovine chromosome (BTA) 22 using a genome-wide association study with the bovine high density single nucleotide polymorphism array. An R210I missense mutation has been identified within microphthalmia-associated transcription factor (MITF) as responsible for this syndrome. The mutation is located in the highly conserved basic region of the protein and causes a negative-dominant effect. SOX10 and PAX3 promoter binding site mutations in MITF could be ruled out as causative for the German White Fleckvieh syndrome. Molecular characterization of this newly detected bovine syndrome means a large animal model is now available for the Tietz syndrome in humans. PMID:22174915

  11. A MITF mutation associated with a dominant white phenotype and bilateral deafness in German Fleckvieh cattle.

    Directory of Open Access Journals (Sweden)

    Ute Philipp

    Full Text Available A dominantly inherited syndrome associated with hypopigmentation, heterochromia irides, colobomatous eyes and bilateral hearing loss has been ascertained in Fleckvieh cattle (German White Fleckvieh syndrome. This syndrome has been mapped to bovine chromosome (BTA 22 using a genome-wide association study with the bovine high density single nucleotide polymorphism array. An R210I missense mutation has been identified within microphthalmia-associated transcription factor (MITF as responsible for this syndrome. The mutation is located in the highly conserved basic region of the protein and causes a negative-dominant effect. SOX10 and PAX3 promoter binding site mutations in MITF could be ruled out as causative for the German White Fleckvieh syndrome. Molecular characterization of this newly detected bovine syndrome means a large animal model is now available for the Tietz syndrome in humans.

  12. Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism and related phenotypes

    Directory of Open Access Journals (Sweden)

    Simpson Elizabeth M

    2007-07-01

    Full Text Available Abstract Background A disruption of sorting nexin 3 (SNX3 on 6q21 was previously reported in a patient with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism and t(6;13(q21;q12 but no SNX3 mutations were identified in another sporadic case of MMEP, suggesting involvement of another gene. In this work, SNX3 was sequenced in three patients not previously studied for this gene. In addition, we test the hypothesis that mutations in the neighbouring gene NR2E1 may underlie MMEP and related phenotypes. Methods Mutation screening was performed in five patients: the t(6;13(q21;q12 MMEP patient, three additional patients with possible MMEP or a related phenotype, and one patient with oligodactyly, ulnar aplasia, and a t(6;7(q21;q31.2 translocation. We used sequencing to exclude SNX3 coding mutations in three patients not previously studied for this gene. To test the hypothesis that mutations in NR2E1 may contribute to MMEP or related phenotypes, we sequenced the entire coding region, complete 5' and 3' untranslated regions, consensus splice-sites, and evolutionarily conserved regions including core and proximal promoter in all five patients. Two-hundred and fifty control subjects were genotyped for any candidate mutation. Results We did not detect any synonymous nor nonsynonymous coding mutations of NR2E1 or SNX3. In one patient with possible MMEP, we identified a candidate regulatory mutation that has been reported previously in a patient with microcephaly but was not found in 250 control subjects examined here. Conclusion Our results do not support involvement of coding mutations in NR2E1 or SNX3 in MMEP or related phenotypes; however, we cannot exclude the possibility that regulatory NR2E1 or SNX3 mutations or deletions at this locus may underlie abnormal human cortical development in some patients.

  13. The congenital "ant-egg" cataract phenotype is caused by a missense mutation in connexin46

    DEFF Research Database (Denmark)

    Hansen, Lars; Yao, Wenliang; Eiberg, Hans;

    2006-01-01

    "Ant-egg" cataract is a rare, distinct variety of congenital/infantile cataract that was reported in a large Danish family in 1967. This cataract phenotype is characterized by ant-egg-like bodies embedded in the lens in a laminar configuration and is inherited as an autosomal dominant trait. We...

  14. Epistatic Mutations And Unpredictable Phenotypes In Pseudomonas Aeruginosa

    DEFF Research Database (Denmark)

    Andresen, Eva Kammer; Abou Hachem, Maher; Jelsbak, Lars

    2015-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen, able to adapt to stressful environments such as the cystic fibrosis (CF) airways. Adaptation of P. aeruginosa to the CF environment is associated with phenotypic changes, such as switch in mucoidy, antibiotic resistance and loss of virulence fa...

  15. Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration

    NARCIS (Netherlands)

    Nishiguchi, K.M.; Avila-Fernandez, A.; Huet, R.A.C. van; Corton, M.; Perez-Carro, R.; Martin-Garrido, E.; Lopez-Molina, M.I.; Blanco-Kelly, F.; Hoefsloot, L.H.; Zelst-Stams, W.A.G. van; Garcia-Ruiz, P.J.; Val, J. Del; Gioia, S.A. Di; Klevering, B.J.; Warrenburg, B.P.C. van de; Vazquez, C.; Cremers, F.P.M.; Garcia-Sandoval, B.; Hoyng, C.B.; Collin, R.W.J.; Rivolta, C.; Ayuso, C.

    2014-01-01

    OBJECTIVE: To identify the genetic causes underlying autosomal recessive retinitis pigmentosa (arRP) and to describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: Three hundred forty-seven unrelated families affected by arRP and 33 unrelated families affected by retinitis pigmentosa (

  16. Mutations in Two Genes Encoding Different Subunits of a Receptor Signaling Complex Result in an Identical Disease Phenotype

    Science.gov (United States)

    Paloneva, Juha; Manninen, Tuula; Christman, Grant; Hovanes, Karine; Mandelin, Jami; Adolfsson, Rolf; Bianchin, Marino; Bird, Thomas; Miranda, Roxana; Salmaggi, Andrea; Tranebjærg, Lisbeth; Konttinen, Yrjö; Peltonen, Leena

    2002-01-01

    Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as “Nasu-Hakola disease,” is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified PLOSL mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in PLOSL, with some patients carrying no mutations in TYROBP. Here we complete the molecular pathology of PLOSL by identifying TREM2 as the second PLOSL gene. TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Patients with PLOSL have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype. PMID:12080485

  17. Two novel distinct COL1A2 mutations highlight the complexity of genotype-phenotype correlations in osteogenesis imperfecta and related connective tissue disorders.

    Science.gov (United States)

    Reuter, Miriam S; Schwabe, Georg C; Ehlers, Christian; Marschall, Christoph; Reis, André; Thiel, Christian; Graul-Neumann, Luitgard

    2013-12-01

    Osteogenesis imperfecta is a heritable connective tissue disorder characterized by variable symptoms including predisposition to fractures. Despite the identification of numerous mutations, a reliable genotype-phenotype correlation has remained notoriously difficult. We now describe two patients with osteogenesis imperfecta and novel, so far undescribed mutations in the COL1A2 gene, further highlighting this complexity. A 3-year-old patient presented with features reminiscent of a connective tissue disorder, with joint hypermobility, Wormian bones, streaky lucencies in the long bones and relative macrocephaly. The patient carried a heterozygous c.1316G > A (p.Gly439Asp) mutation in the COL1A2 gene located in a triple-helix region, in which glycine substitutions have been assumed to cause perinatal lethal OI (Sillence type II). A second family with type I osteogenesis imperfecta carried a heterozygous nonsense mutation c.4060C > T (p.Gln1354X) within the last exon of COL1A2. Whereas other heterozygous nonsense mutations in COL1A2 do not lead to a phenotype, in this case the mRNA is presumed to escape nonsense-mediated decay. Therefore the predicted COL1A2 propeptide lacks the last 13 C-terminal amino acids, suggesting that the OI phenotype results from decelerated assembly and overmodification of the collagen triple helix. The presented COL1A2 mutations exemplify the complexity of COL1A2 genotype-phenotype correlation in genetic counselling in OI.

  18. Prion protein amyloidosis with divergent phenotype associated with two novel nonsense mutations in PRNP

    NARCIS (Netherlands)

    C. Jansen (Casper); P. Parchi (Piero); S. Capellari (Sabina); A.J. Vermeij (Ad); P. Corrado (Patrizia); F. Baas (Frank); R. Strammiello (Rosario); W.A. van Gool (Willem); J.C. van Swieten; A.J.M. Rozemuller (Annemieke)

    2010-01-01

    textabstractStop codon mutations in the gene encoding the prion protein (PRNP) are very rare and have thus far only been described in two patients with prion protein cerebral amyloid angiopathy (PrP-CAA). In this report, we describe the clinical, histopathological and pathological prion protein (PrP

  19. Postlingual hearing loss as a mitochondrial 3243A>G mutation phenotype.

    Directory of Open Access Journals (Sweden)

    Katarzyna Iwanicka-Pronicka

    Full Text Available BACKGROUND: The prevalence of isolated hearing loss (HL associated with the m.3243A>G mutation is unknown. The aim of this study was to assess the frequency and heteroplasmy level of the m.3243A>G mutation in a large group of Polish patients with postlingual bilateral sensorineural HL of unidentified cause. METHODOLOGY/PRINCIPAL FINDINGS: A molecular search was undertaken in the archival blood DNA of 1482 unrelated patients with isolated HL that had begun at ages between 5 and 40 years. Maternal relatives of the probands were subsequently investigated and all carriers underwent audiological tests. The m.3243A>G mutation was found in 16 of 1482 probands (an incidence of 1.08% and 18 family members. Of these 34 individuals, hearing impairment was detected in 29 patients and the mean onset of HL was at 26 years. Some 42% of the identified m.3243A>G carriers did not develop multisystem symptomatology over the following 10 years. Mean heteroplasmy level of m.3243A>G was lowest in blood at a level of 14% and highest in urine at 58%. These values were independent of the manifested clinical severity of the disease. CONCLUSIONS: A single m.3243A>G carrier can usually be found among each 100 individuals who have postlingual hearing loss of unknown cause. Urine samples are best for detecting the m.3243A>G mutation and diagnosing mitochondrially inherited hearing loss.

  20. Phenotypical Characteristics of Idiopathic Infantile Nystagmus with and without Mutations in "FRMD7"

    Science.gov (United States)

    Thomas, Shery; Proudlock, Frank A.; Sarvananthan, Nagini; Roberts, Eryl O.; Awan, Musarat; McLean, Rebecca; Surendran, Mylvaganam; Kumar, A. S. Anil; Farooq, Shegufta J.; Degg, Chris; Gale, Richard P.; Reinecke, Robert D.; Woodruff, Geoffrey; Langmann, Andrea; Lindner, Susanne; Jain, Sunila; Tarpey, Patrick; Raymond, F. Lucy; Gottlob, Irene

    2008-01-01

    Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene "FRMD7" (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye…

  1. Mutational spectrum and phenotypes in Danish families with hereditary angioedema because of C1 inhibitor deficiency

    DEFF Research Database (Denmark)

    Bygum, A; Fagerberg, C R; Ponard, D

    2011-01-01

    Hereditary angioedema (HAE), type I and II, is an autosomal dominant disease with deficiency of functional C1 inhibitor protein causing episodic swellings of skin, mucosa and viscera. HAE is a genetically heterogeneous disease with more than 200 different mutations in the SERPING1 gene. A genotype...

  2. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy

    NARCIS (Netherlands)

    K.G. Claeys; S. Züchner; M. Kennerson; J. Berciano; A. Garcia; K. Verhoeven; E. Storey; J.R. Merory; H.M.E. Bienfait; M. Lammens; E. Nelis; J. Baets; E. de Vriendt; Z.N. Berneman; I. de Veuster; J.M. Vance; G. Nicholson; V. Timmerman; P. de Jonghe

    2009-01-01

    Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B familie

  3. Mutations in Thyroid Hormone Transporter MCT8: genotype, function and phenotype

    NARCIS (Netherlands)

    J. Jansen (Jurgen)

    2008-01-01

    textabstractThe studies presented in this thesis demonstrate that MCT8 is a transmembrane protein that facilitates both in- and efflux of thyroid hormone. MCT8 function is crucial for normal neurological development, as loss-of-function mutations are associated with severe psychomotor retardation. I

  4. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy.

    NARCIS (Netherlands)

    Claeys, K.G.; Zuchner, S.; Kennerson, M.; Berciano, J.; Garcia, A.; Verhoeven, K.; Storey, E.; Merory, J.R.; Bienfait, H.M.; Lammens, M.M.Y.; Nelis, E.; Baets, J.; Vriendt, E. De; Berneman, Z.N.; Veuster, I. De; Vance, J.M.; Nicholson, G.; Timmerman, V.; Jonghe, P. de

    2009-01-01

    Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B familie

  5. A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype.

    Science.gov (United States)

    Albiger, N M; Regazzo, D; Rubin, B; Ferrara, A M; Rizzati, S; Taschin, E; Ceccato, F; Arnaldi, G; Pecori Giraldi, F; Stigliano, A; Cerquetti, L; Grimaldi, F; De Menis, E; Boscaro, M; Iacobone, M; Occhi, G; Scaroni, C

    2017-03-01

    ARMC5 mutations have recently been identified as a common genetic cause of primary bilateral macronodular adrenal hyperplasia (PBMAH). We aimed to assess the prevalence of ARMC5 germline mutations and correlate genotype with phenotype in a large cohort of PBMAH patients. A multicenter study was performed, collecting patients from different endocrinology units in Italy. Seventy-one PBMAH patients were screened for small mutations and large rearrangements in the ARMC5 gene: 53 were cortisol-secreting (two with a family history of adrenal hyperplasia) and 18 were non-secreting cases of PBMAH. Non-mutated and mutated patients' clinical phenotypes were compared and related to the type of mutation. A likely causative germline ARMC5 mutation was only identified in cortisol-secreting PBMAH patients (one with a family history of adrenal hyperplasia and ten apparently sporadic cases). Screening in eight first-degree relatives of three index cases revealed four carriers of an ARMC5 mutation. Evidence of a second hit at somatic level was identified in five nodules. Mutated patients had higher cortisol levels (p = 0.062), and more severe hypertension and diabetes (p < 0.05). Adrenal glands were significantly larger, with a multinodular phenotype, in the mutant group (p < 0.01). No correlation emerged between type of mutation and clinical parameters. ARMC5 mutations are frequent in cortisol-secreting PBMAH and seem to be associated with a particular pattern of the adrenal masses. Their identification may have implications for the clinical care of PBMAH cases and their relatives.

  6. Ocular Phenotype Analysis of a Family With Biallelic Mutations in the BEST1 Gene

    DEFF Research Database (Denmark)

    Sharon, Dror; Al-Hamdani, Sermed; Engelsberg, Karl

    2014-01-01

    -segregation analysis. Clinical investigations included electro-oculography, full-field electroretinography, multifocal electroretinography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. Immunohistochemical analysis was performed. main outcome measures: BEST1 mutations, imaging......PURPOSE: To investigate the genetic cause and perform a comprehensive clinical analysis of a Danish family with autosomal recessive bestrophinopathy; to investigate whether Bestrophin may be expressed in normal human retina. DESIGN: Retrospective clinical and molecular genetic analysis...... and immunohistochemical observational study. METHODS: setting: National referral center. participants: A family with 5 individuals and biallelic BEST1 mutations, and enucleated eyes from 2 individuals with nonaffected retinas. observation procedures: Molecular genetic analysis included sequencing of BEST1 and co...

  7. Arrhythmogenic Biophysical Phenotype for SCN5A Mutation S1787N Depends upon Splice Variant Background and Intracellular Acidosis.

    Directory of Open Access Journals (Sweden)

    Rou-Mu Hu

    Full Text Available SCN5A is a susceptibility gene for type 3 long QT syndrome, Brugada syndrome, and sudden infant death syndrome. INa dysfunction from mutated SCN5A can depend upon the splice variant background in which it is expressed and also upon environmental factors such as acidosis. S1787N was reported previously as a LQT3-associated mutation and has also been observed in 1 of 295 healthy white controls. Here, we determined the in vitro biophysical phenotype of SCN5A-S1787N in an effort to further assess its possible pathogenicity.We engineered S1787N in the two most common alternatively spliced SCN5A isoforms, the major isoform lacking a glutamine at position 1077 (Q1077del and the minor isoform containing Q1077, and expressed these two engineered constructs in HEK293 cells for electrophysiological study. Macroscopic voltage-gated INa was measured 24 hours after transfection with standard whole-cell patch clamp techniques. We applied intracellular solutions with pH7.4 or pH6.7. S1787N in the Q1077 background had WT-like INa including peak INa density, activation and inactivation parameters, and late INa amplitude in both pH 7.4 and pH 6.7. However, with S1787N in the Q1077del background, the percentages of INa late/peak were increased by 2.1 fold in pH 7.4 and by 2.9 fold in pH 6.7 when compared to WT.The LQT3-like biophysical phenotype for S1787N depends on both the SCN5A splice variant and on the intracellular pH. These findings provide further evidence that the splice variant and environmental factors affect the molecular phenotype of cardiac SCN5A-encoded sodium channel (Nav1.5, has implications for the clinical phenotype, and may provide insight into acidosis-induced arrhythmia mechanisms.

  8. NOD2/CARD15 mutations in Polish and Bosnian populations with and without Crohn’s disease: prevalence and genotype-phenotype analysis

    Science.gov (United States)

    Salkic, Nermin N.; Adler, Grazyna; Zawada, Iwona; Alibegovic, Ervin; Karakiewicz, Beata; Kozlowska-Wiechowska, Anna; Wasilewicz, Michał; Sulzyc-Bielicka, Violetta; Bielicki, Dariusz

    2015-01-01

    Data on prevalence and phenotypic consequences of nucleotide-binding oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) variants in Crohn’s disease (CD) population in Poland and Bosnia and Herzegovina (B&H) are nonexistent. We aimed to determine the prevalence of NOD2/CARD15 mutations and their association with disease phenotype in Polish and Bosnian patients with CD and in healthy controls. We prospectively recruited 86 CD patients and 83 controls in Poland and 30 CD patients and 30 controls in B&H, 229 in total. We determined the prevalence of NOD2/CARD15 mutations and their association with the disease phenotype according to Montreal classification. Participants were genotyped for Leu1007fsinsC and Gly908Arg mutations. At least one CD-associated allele was found in 29/86 (33.7%) of Polish CD patients and in 9/83 (10.8%) of healthy controls (p<0.001). In both CD patients and controls in Bosnian sample, at least one NOD2 mutation was found in equal number of patients (3/30; 10%) with all of the NOD2 mutation positive CD patients being homozygous, while controls being heterozygous. In Polish sample, perianal disease was less frequent in CD patients with any NOD2 mutation (1/21; 4.8%) compared to those without (11/41; 26.8%; p=0.046). Higher percentage of patients with NOD2 mutations had history of CD related surgery when compared with those without mutations (66.7% vs. 43.3%; p=0.05). The risk for CD is increased in patients with NOD2 mutations (Poland) and especially in the presence of homozygous NOD2 mutations (Poland and Bosnia). The presence of variant NOD2 alleles is associated with increased need for surgery and reduced occurrence of perianal disease. PMID:26042516

  9. NOD2/CARD15 mutations in Polish and Bosnian populations with and without Crohn's disease: prevalence and genotype-phenotype analysis

    Directory of Open Access Journals (Sweden)

    Nermin N Salkic

    2015-05-01

    Full Text Available Data on prevalence and phenotypic consequences of nucleotide-binding oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15 variants in Crohn's disease (CD population in Poland and Bosnia and Herzegovina (B&H are nonexistent. We aimed to determine the prevalence of NOD2/CARD15 mutations and their association with disease phenotype in Polish and Bosnian patients with CD and in healthy controls. We prospectively recruited 86 CD patients and 83 controls in Poland and 30 CD patients and 30 controls in B&H, 229 in total. We determined the prevalence of NOD2/CARD15 mutations and their association with the disease phenotype according to Montreal classification. Participants were genotyped for Leu1007fsinsC and Gly908Arg mutations. At least one CD-associated allele was found in 29/86 (33.7% of Polish CD patients and in 9/83 (10.8% of healthy controls (p<0.001. In both CD patients and controls in Bosnian sample, at least one NOD2 mutation was found in equal number of patients (3/30; 10% with all of the NOD2 mutation positive CD patients being homozygous, while controls being heterozygous. In Polish sample, perianal disease was less frequent in CD patients with any NOD2 mutation (1/21; 4.8% compared to those without (11/41; 26.8%; p=0.046. Higher percentage of patients with NOD2 mutations had history of CD related surgery when compared with those without mutations (66.7% vs. 43.3%; p=0.05. The risk for CD is increased in patients with NOD2 mutations (Poland and especially in the presence of homozygous NOD2 mutations (Poland and Bosnia. The presence of variant NOD2 alleles is associated with increased need for surgery and reduced occurrence of perianal disease.

  10. Phenotypical characteristics of idiopathic infantile nystagmus with and without mutations in FRMD7.

    Science.gov (United States)

    Thomas, Shery; Proudlock, Frank A; Sarvananthan, Nagini; Roberts, Eryl O; Awan, Musarat; McLean, Rebecca; Surendran, Mylvaganam; Kumar, A S Anil; Farooq, Shegufta J; Degg, Chris; Gale, Richard P; Reinecke, Robert D; Woodruff, Geoffrey; Langmann, Andrea; Lindner, Susanne; Jain, Sunila; Tarpey, Patrick; Raymond, F Lucy; Gottlob, Irene

    2008-05-01

    Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene FRMD7 (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye movement recordings of 90 subjects with mutation in the gene (FRMD7 group) to 48 subjects without mutations but with clinical IIN (non-FRMD7 group). Fifty-eight female obligate carriers of the mutation were also investigated. The median visual acuity (VA) was 0.2 logMAR (Snellen equivalent 6/9) in both groups and most patients had good stereopsis. The prevalence of strabismus was also similar (FRMD7: 7.8%, non-FRMD7: 10%). The presence of anomalous head posture (AHP) was significantly higher in the non-FRMD7 group (P < 0.0001). The amplitude of nystagmus was more strongly dependent on the direction of gaze in the FRMD7 group being lower at primary position (P < 0.0001), compared to non-FRMD7 group (P = 0.83). Pendular nystagmus waveforms were also more frequent in the FRMD7 group (P = 0.003). Fifty-three percent of the obligate female carriers of an FRMD7 mutation were clinically affected. The VA's in affected females were slightly better compared to affected males (P = 0.014). Subnormal optokinetic responses were found in a subgroup of obligate unaffected carriers, which may be interpreted as a sub-clinical manifestation. FRMD7 is a major cause of X-linked IIN. Most clinical and eye movement characteristics were similar in the FRMD7 group and non-FRMD7 group with most patients having good VA and stereopsis and low incidence of strabismus. Fewer patients in the FRMD7 group had AHPs, their amplitude of nystagmus being lower in primary position. Our findings are helpful in the clinical identification of IIN and genetic counselling of nystagmus patients.

  11. High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.

    Science.gov (United States)

    Rojnueangnit, Kitiwan; Xie, Jing; Gomes, Alicia; Sharp, Angela; Callens, Tom; Chen, Yunjia; Liu, Ying; Cochran, Meagan; Abbott, Mary-Alice; Atkin, Joan; Babovic-Vuksanovic, Dusica; Barnett, Christopher P; Crenshaw, Melissa; Bartholomew, Dennis W; Basel, Lina; Bellus, Gary; Ben-Shachar, Shay; Bialer, Martin G; Bick, David; Blumberg, Bruce; Cortes, Fanny; David, Karen L; Destree, Anne; Duat-Rodriguez, Anna; Earl, Dawn; Escobar, Luis; Eswara, Marthanda; Ezquieta, Begona; Frayling, Ian M; Frydman, Moshe; Gardner, Kathy; Gripp, Karen W; Hernández-Chico, Concepcion; Heyrman, Kurt; Ibrahim, Jennifer; Janssens, Sandra; Keena, Beth A; Llano-Rivas, Isabel; Leppig, Kathy; McDonald, Marie; Misra, Vinod K; Mulbury, Jennifer; Narayanan, Vinodh; Orenstein, Naama; Galvin-Parton, Patricia; Pedro, Helio; Pivnick, Eniko K; Powell, Cynthia M; Randolph, Linda; Raskin, Salmo; Rosell, Jordi; Rubin, Karol; Seashore, Margretta; Schaaf, Christian P; Scheuerle, Angela; Schultz, Meredith; Schorry, Elizabeth; Schnur, Rhonda; Siqveland, Elizabeth; Tkachuk, Amanda; Tonsgard, James; Upadhyaya, Meena; Verma, Ishwar C; Wallace, Stephanie; Williams, Charles; Zackai, Elaine; Zonana, Jonathan; Lazaro, Conxi; Claes, Kathleen; Korf, Bruce; Martin, Yolanda; Legius, Eric; Messiaen, Ludwine

    2015-11-01

    Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.

  12. Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient

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    Burglen Lydie

    2012-03-01

    Full Text Available Abstract Background Pontocerebellar hypoplasia (PCH is a heterogeneous group of diseases characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. According to clinical features, seven subtypes of PCH have been described, PCH type 2 related to TSEN54 mutations being the most frequent. PCH is most often autosomal recessive though de novo anomalies in the X-linked gene CASK have recently been identified in patients, mostly females, presenting with intellectual disability, microcephaly and PCH (MICPCH. Methods Fourteen patients (12 females and two males; aged 16 months-14 years presenting with PCH at neuroimaging and with clinical characteristics unsuggestive of PCH1 or PCH2 were included. The CASK gene screening was performed using Array-CGH and sequencing. Clinical and neuroradiological features were collected. Results We observed a high frequency of patients with a CASK mutation (13/14. Ten patients (8 girls and 2 boys had intragenic mutations and three female patients had a Xp11.4 submicroscopic deletion including the CASK gene. All were de novo mutations. Phenotype was variable in severity but highly similar among the 11 girls and was characterized by psychomotor retardation, severe intellectual disability, progressive microcephaly, dystonia, mild dysmorphism, and scoliosis. Other signs were frequently associated, such as growth retardation, ophthalmologic anomalies (glaucoma, megalocornea and optic atrophy, deafness and epilepsy. As expected in an X-linked disease manifesting mainly in females, the boy hemizygous for a splice mutation had a very severe phenotype with nearly no development and refractory epilepsy. We described a mild phenotype in a boy with a mosaic truncating mutation. We found some degree of correlation between severity of the vermis hypoplasia and clinical phenotype. Conclusion This study describes a new series of PCH female patients with CASK inactivating mutations and confirms that

  13. CRB2 mutations produce a phenotype resembling congenital nephrosis, Finnish type, with cerebral ventriculomegaly and raised alpha-fetoprotein.

    Science.gov (United States)

    Slavotinek, Anne; Kaylor, Julie; Pierce, Heather; Cahr, Michelle; DeWard, Stephanie J; Schneidman-Duhovny, Dina; Alsadah, Adnan; Salem, Fadi; Schmajuk, Gabriela; Mehta, Lakshmi

    2015-01-01

    We report five fetuses and a child from three families who shared a phenotype comprising cerebral ventriculomegaly and echogenic kidneys with histopathological findings of congenital nephrosis. The presenting features were greatly elevated maternal serum alpha-fetoprotein (MSAFP) or amniotic fluid alpha-fetoprotein (AFAFP) levels or abnormalities visualized on ultrasound scan during the second trimester of pregnancy. Exome sequencing revealed deleterious sequence variants in Crumbs, Drosophila, Homolog of, 2 (CRB2) consistent with autosomal-recessive inheritance. Two fetuses with cerebral ventriculomegaly and renal microcysts were compound heterozygotes for p.Asn800Lys and p.Trp759Ter, one fetus with renal microcysts was a compound heterozygote for p.Glu643Ala and p.Asn800Lys, and one child with cerebral ventriculomegaly, periventricular heterotopias, echogenic kidneys, and renal failure was homozygous for p.Arg633Trp in CRB2. Examination of the kidneys in one fetus showed tubular cysts at the corticomedullary junction and diffuse effacement of the epithelial foot processes and microvillous transformation of the renal podocytes, findings that were similar to those reported in congenital nephrotic syndrome, Finnish type, that is caused by mutations in nephrin (NPHS1). Loss of function for crb2b and nphs1 in Danio rerio were previously shown to result in loss of the slit diaphragms of the podocytes, leading to the hypothesis that nephrosis develops from an inability to develop a functional glomerular barrier. We conclude that the phenotype associated with CRB2 mutations is pleiotropic and that the condition is an important consideration in the evaluation of high MSAFP/AFAFP where a renal cause is suspected.

  14. An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3).

    Science.gov (United States)

    Dimitri, Paul; De Franco, Elisa; Habeb, Abdelhadi M; Gurbuz, Fatih; Moussa, Khairya; Taha, Doris; Wales, Jerry K H; Hogue, Jacob; Slavotinek, Anne; Shetty, Ambika; Balasubramanian, Meena

    2016-07-01

    Neonatal diabetes and hypothyroidism (NDH) syndrome was first described in 2003 in a consanguineous Saudi Arabian family where two out of four siblings were reported to have presented with proportionate IUGR, neonatal non-autoimmune diabetes mellitus, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by enlarged kidneys and multiple small cysts with deficient cortico-medullary junction differentiation and normal kidney function. There was minor facial dysmorphism (depressed nasal bridge, large anterior fontanelle, long philtrum) reported but no facial photographs were published. Mutations in the transcription factor GLI-similar 3 (GLIS3) gene in the original family and two other families were subsequently reported in 2006. All affected individuals had neonatal diabetes, congenital hypothyroidism but glaucoma and liver and kidney involvement were less consistent features. Detailed descriptions of the facial dysmorphism have not been reported previously. In this report, we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognizable facial gestalt in this group which evolves with age. © 2016 Wiley Periodicals, Inc.

  15. Biochemical and molecular characterization of a mutation that confers a decreased raffinosaccharide and phytic acid phenotype on soybean seeds.

    Science.gov (United States)

    Hitz, William D; Carlson, Thomas J; Kerr, Phil S; Sebastian, Scott A

    2002-02-01

    A single, recessive mutation in soybean (Glycine max L. Merr.), which confers a seed phenotype of increased inorganic phosphate, decreased phytic acid, and a decrease in total raffinosaccharides, has been previously disclosed (S.A. Sebastian, P.S. Kerr, R.W. Pearlstein, W.D. Hitz [2000] Soy in Animal Nutrition, pp 56-74). The genetic lesion causing the multiple changes in seed phenotype is a single base change in the third base of the codon for what is amino acid residue 396 of the mature peptide encoding a seed-expressed myo-inositol 1-phospate synthase gene. The base change causes residue 396 to change from lysine to asparagine. That amino acid change decreases the specific activity of the seed-expressed myo-inositol 1-phosphate synthase by about 90%. Radio tracer experiments indicate that the supply of myo-inositol to the reaction, which converts UDP-galactose and myo-inositol to galactinol is a controlling factor in the conversion of total carbohydrate into the raffinosaccharides in both wild-type and mutant lines. That same decrease in myo-inositol 1-phosphate synthetic capacity leads to a decreased capacity for the synthesis of myo-inositol hexaphosphate (phytic acid) and a concomitant increase in inorganic phosphate.

  16. The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation.

    Science.gov (United States)

    Jiang, Pingping; Jin, Xiaofen; Peng, Yanyan; Wang, Meng; Liu, Hao; Liu, Xiaoling; Zhang, Zengjun; Ji, Yanchun; Zhang, Juanjuan; Liang, Min; Zhao, Fuxin; Sun, Yan-Hong; Zhang, Minglian; Zhou, Xiangtian; Chen, Ye; Mo, Jun Qin; Huang, Taosheng; Qu, Jia; Guan, Min-Xin

    2016-02-01

    Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. Nuclear modifier genes are proposed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations. By using an exome sequencing approach, we identified a LHON susceptibility allele (c.572G>T, p.191Gly>Val) in YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase, which interacts with m.11778G>A mutation to cause visual failure. We performed functional assays by using lymphoblastoid cell lines derived from members of Chinese families (asymptomatic individuals carrying m.11778G>A mutation, or both m.11778G>A and heterozygous p.191Gly>Val mutations and symptomatic subjects harboring m.11778G>A and homozygous p.191Gly>Val mutations) and controls lacking these mutations. The 191Gly>Val mutation reduced the YARS2 protein level in the mutant cells. The aminoacylated efficiency and steady-state level of tRNA(Tyr) were markedly decreased in the cell lines derived from patients both carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The failure in tRNA(Tyr) metabolism impaired mitochondrial translation, especially for polypeptides with high content of tyrosine codon such as ND4, ND5, ND6 and COX2 in cells lines carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The YARS2 p.191Gly>Val mutation worsened the respiratory phenotypes associated with m.11778G>A mutation, especially reducing activities of complexes I and IV. The respiratory deficiency altered the efficiency of mitochondrial ATP synthesis and increased the production of reactive oxygen species. Thus, mutated YARS2 aggravates mitochondrial dysfunctions associated with the m.11778G>A mutation, exceeding the threshold for the expression of blindness phenotype. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutation and mutated nuclear-modifier YARS2.

  17. A new mutation in MC1R explains a coat color phenotype in 2 "old" breeds: Saluki and Afghan hound.

    Science.gov (United States)

    Dreger, Dayna L; Schmutz, Sheila M

    2010-01-01

    Melanocortin 1 Receptor (MC1R) has been studied in a wide variety of domestic animals (Klungland et al. 1995; Marklund et al. 1996; Våge et al. 1997; Kijas et al. 1998; Newton et al. 2000; Våge et al. 2003), and also several wild animals (Robbins et al. 1993; Ritland et al. 2001; Eizirik et al. 2003; Nachman et al. 2003; McRobie et al. 2009) in relation to coat color variation. A variety of phenotypic changes have been reported including coat colors from pure black to pure red, as well as some phenotypes with hairs with red and black bands. One phenotype, called grizzle in Salukis and domino in Afghan Hounds, appears to be unique to these 2 old dog breeds. This pattern is characterized by a pale face with a widow's peak above the eyes. The body hairs on the dorsal surface of Salukis and Afghan Hounds have both phaeomelanin and eumelanin portions, even though they had an a(t)/a(t) genotype at ASIP. In addition, all had at least one copy of a newly identified mutation in MC1R, g.233G>T, resulting in p.Gly78Val. This new allele, that we suggest be designated as E(G), is dominant to the E and e (p.Arg306ter) alleles at MC1R but recessive to the E(M) (p.Met264Val) allele. The K(B) allele (p.Gly23del) at DEFB103 and the a(y) allele (p.Ala82Ser and p.Arg83His) of ASIP are epistatic to grizzle and domino.

  18. Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.

    Science.gov (United States)

    Ghorbanoghli, Z; Nieuwenhuis, M H; Houwing-Duistermaat, J J; Jagmohan-Changur, S; Hes, F J; Tops, C M; Wagner, A; Aalfs, C M; Verhoef, S; Gómez García, E B; Sijmons, R H; Menko, F H; Letteboer, T G; Hoogerbrugge, N; van Wezel, T; Vasen, H F A; Wijnen, J T

    2016-10-01

    Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.

  19. Mutations in fibroblast growth factor receptors: Phenotypic consequences during eukaryotic development

    Energy Technology Data Exchange (ETDEWEB)

    Park, W.J.; Bellus, G.A.; Jabs, E.W. [Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)

    1995-10-01

    Recently, a tremendous amount of excitement and interest has been generated by the rapid succession of discoveries in the human fibroblast growth factor receptor (FGFR) field. In less than a year, mutations in three FGFRs (FGFR1-FGFR3) have been associated with three skeletal dysplasias and four craniosynostotic syndromes. FGFRs are members of the receptor tyrosine kinase family that bind fibroblast growth factors (FGFs). The FGF family consists of structurally related polypeptides that play a key role in numerous aspects of embryogenesis, growth, and homeostasis. FGFs have a potent growth stimulatory and/or differentiation-inducing effect on cells such as those derived from the early-embryonic mesoderm or ectoderm. In addition to mitogenesis and differentiation, FGFs also stimulate chemotaxis, cell survival, and angiogenesis. FGFs mediate cellular responses on binding to and activation of FGFRs. 45 refs., 2 figs., 1 tab.

  20. FGFR2 mutation in a patient without typical features of Pfeiffer syndrome--The emerging role of combined NGS and phenotype based strategies.

    Science.gov (United States)

    Flöttmann, Ricarda; Knaus, Alexej; Zemojtel, Tomasz; Robinson, Peter N; Mundlos, Stefan; Horn, Denise; Spielmann, Malte

    2015-08-01

    Pfeiffer syndrome (MIM: #101600) is a rare autosomal dominant disorder classically characterized by limb and craniofacial anomalies. It is caused by heterozygous mutations in the fibroblast growth factor receptors types 1 and 2 (FGFR1 and FGFR2). We applied a next generation sequencing (NGS) panel approach comprising all 2877 genes currently known to be causative for one or more Mendelian diseases combined with the phenotype based computational tool PhenIX (Phenotypic Interpretation of eXomes). We report on a patient presenting with multiple anomalies of hands and feet including brachydactyly and symphalangism. No clinical diagnosis could be established based on the clinical findings and testing of several genes associated with brachydactyly and symphalangism failed to identify mutations. Via next generation sequencing (NGS) panel approach we then identified a novel de novo missense FGFR2 mutation affecting an amino acid reported to be mutated in Pfeiffer syndrome. Since our patient shows typical radiological findings of Pfeiffer syndrome in hands and feet but at the same time lacks several characteristic features such as clinical signs of craniosynostosis and prominent eyes we suggest introducing the term "FGFR2 associated phenotypes" for similar cases. Our results highlight the emerging role of combined NGS and phenotype based bioinformatics strategies to establish clinical diagnoses.

  1. Mitochondrial ND6 T14502C variant may modulate the phenotypic expression of LHON-associated G11778A mutation in four Chinese families.

    Science.gov (United States)

    Zhang, Juanjuan; Zhou, Xiangtian; Zhou, Jian; Li, Chengwu; Zhao, Fuxin; Wang, Yan; Meng, Yanzi; Wang, Jiying; Yuan, Meixia; Cai, Wanshi; Tong, Yi; Sun, Yan-Hong; Yang, Li; Qu, Jia; Guan, Min-Xin

    2010-09-01

    We report here the clinical, genetic, and molecular evaluations of four Han Chinese families with Leber's hereditary optic neuropathy. Thirty-one (20 males/11 females) of 83 matrilineal relatives in these families exhibited the variable severity and age-at-onset in visual impairment. The average age-of-onset of vision loss was 22years old. Strikingly, these penetrances of visual impairment in these Chinese families were higher than those in other 11 Chinese pedigrees carrying the only ND4 G11778A mutation. Molecular analysis identified the known G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M10a and M7c2. Of these, the T14502C mutation caused the substitution of a highly conserved isoleucine for valine at position 58 in ND6. This mutation has been associated with LHON in other Chinese families with very low penetrance of LHON. Thus, the deficient activities of complex I, caused by G11778A mutation, would be worsened by the T14502C mutation in these four Chinese families. As a result, mitochondrial dysfunctions would lead to the high penetrance and expressivity of visual loss in these Chinese families carrying both G11778A and T14502C mutations than other 11 Chinese families carrying only G11778A mutation. These data suggested that the T14502C variant may modulate the phenotypic manifestation of the G11778A mutation in these Chinese pedigrees.

  2. Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a Danish five-generation family with a novel FAM83H nonsense mutation.

    Science.gov (United States)

    Haubek, Dorte; Gjørup, Hans; Jensen, Lillian G; Juncker, Inger; Nyegaard, Mette; Børglum, Anders D; Poulsen, Sven; Hertz, Jens M

    2011-11-01

    BACKGROUND.  Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI) is a disease with severe dental manifestations. OBJECTIVES.  The aims were by means of a genome-wide linkage scan to search for the gene underlying the ADHCAI phenotype in a Danish five-generation family and to study the phenotypic variation of the enamel in affected family members. RESULTS.  Significant linkage was found to a locus at chromosome 8q24.3 comprising the gene FAM83H identified to be responsible for ADHCAI in other families. Subsequent sequencing of FAM83H in affected family members revealed a novel nonsense mutation, p.Y302X. Limited phenotypic variation was found among affected family members with loss of translucency and discoloration of the enamel. Extensive posteruptive loss of enamel was found in all teeth of affected subjects. The tip of the cusps on the premolars and molars and a zone along the gingival margin seemed resistant to posteruptive loss of enamel. We have screened FAM83H in another five unrelated Danish patients with a phenotype of ADHCAI similar to that in the five-generation family, and identified a de novo FAM83H nonsense mutation, p.Q452X in one of these patients. CONCLUSION.  We have identified a FAM83H mutation in two of six unrelated families with ADHCAI and found limited phenotypic variation of the enamel in these patients.

  3. The rem Mutations in the ATP-Binding Groove of the Rad3/XPD Helicase Lead to Xeroderma pigmentosum-Cockayne Syndrome-Like Phenotypes

    Science.gov (United States)

    Montelone, Beth A.; Aguilera, Andrés

    2014-01-01

    The eukaryotic TFIIH complex is involved in Nucleotide Excision Repair and transcription initiation. We analyzed three yeast mutations of the Rad3/XPD helicase of TFIIH known as rem (recombination and mutation phenotypes). We found that, in these mutants, incomplete NER reactions lead to replication fork breaking and the subsequent engagement of the homologous recombination machinery to restore them. Nevertheless, the penetrance varies among mutants, giving rise to a phenotype gradient. Interestingly, the mutations analyzed reside at the ATP-binding groove of Rad3 and in vivo experiments reveal a gain of DNA affinity upon damage of the mutant Rad3 proteins. Since mutations at the ATP-binding groove of XPD in humans are present in the Xeroderma pigmentosum-Cockayne Syndrome (XP-CS), we recreated rem mutations in human cells, and found that these are XP-CS-like. We propose that the balance between the loss of helicase activity and the gain of DNA affinity controls the capacity of TFIIH to open DNA during NER, and its persistence at both DNA lesions and promoters. This conditions NER efficiency and transcription resumption after damage, which in human cells would explain the XP-CS phenotype, opening new perspectives to understand the molecular basis of the role of XPD in human disease. PMID:25500814

  4. Novel compound heterozygous mutations in DYNC2H1 in a patient with severe short-rib polydactyly syndrome type III phenotype.

    Science.gov (United States)

    Okamoto, Toshio; Nagaya, Ken; Kawata, Yumi; Asai, Hiroko; Tsuchida, Etsushi; Nohara, Fumikatsu; Okajima, Kazuki; Azuma, Hiroshi

    2015-08-01

    Short-rib polydactyly syndrome type III is an autosomal recessive lethal skeletal ciliopathy, which is phenotypically similar to nonlethal asphyxiating thoracic dystrophy. Mutations in DYNC2H1 have been identified in both of these disorders, indicating that they are variants of a single disorder. However, short-rib polydactyly syndrome type III is the more severe variant. Here, we report novel compound heterozygous mutations in DYNC2H1 (p.E1894fsX10 and p.R3004C) in a patient with typical short-rib polydactyly syndrome type III phenotype. R3004 is located within the microtubule-binding domain of DYNC2H1, and its substitution is predicted to disrupt the interaction with microtubules. Considering the severe phenotype of our patient, our findings suggest that R3004 may be a key residue for the microtubule-binding affinity of dynein.

  5. The expanding phenotype of MELAS caused by the m.3291T > C mutation in the MT-TL1 gene.

    Science.gov (United States)

    Keilland, E; Rupar, C A; Prasad, Asuri N; Tay, K Y; Downie, A; Prasad, C

    2016-03-01

    m.3291T > C mutation in the MT-TL1 gene has been infrequently encountered in association with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), however remains poorly characterized from a clinical perspective. In the following report we describe in detail the phenotypic features, long term follow up (> 7 years) and management in a Caucasian family with MELAS due to the m.3291T > C mutation and review the literature on m.3291T > C mutation. The clinical phenotype in the proposita included overlapping features of MELAS, MERRF (Myoclonic epilepsy and ragged-red fiber syndrome), MNGIE (Mitochondrial neurogastrointestinal encephalopathy), KSS (Kearns-Sayre Syndrome) and CPEO (Chronic progressive external ophthalmoplegia).

  6. The expanding phenotype of MELAS caused by the m.3291T>C mutation in the MT-TL1 gene

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    E. Keilland

    2016-03-01

    Full Text Available m.3291T>C mutation in the MT-TL1 gene has been infrequently encountered in association with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS, however remains poorly characterized from a clinical perspective. In the following report we describe in detail the phenotypic features, long term follow up (>7 years and management in a Caucasian family with MELAS due to the m.3291T>C mutation and review the literature on m.3291T>C mutation. The clinical phenotype in the proposita included overlapping features of MELAS, MERRF (Myoclonic epilepsy and ragged-red fiber syndrome, MNGIE (Mitochondrial neurogastrointestinal encephalopathy, KSS (Kearns-Sayre Syndrome and CPEO (Chronic progressive external ophthalmoplegia.

  7. Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4 phenotype

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    Fernandez Bridget A

    2012-11-01

    Full Text Available Abstract Background Severe congenital neutropenia type 4 (SCN4 is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3. Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4 is caused by autosomal recessive mutations in SLC45A2. Methods We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature. Results The siblings’ phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with “partial OCA” in childhood. Conclusions This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.

  8. Tracing the pathway between mutation and phenotype in osteogenesis imperfecta: Isolation of mineralization-specific genes

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    Culbert, A.A.; Wallis, G.A.; Kadler, K.E. [Univ. of Manchester (United Kingdom)

    1996-05-03

    The brittleness of bone in people with lethal (type II) osteogenesis imperfecta, a heritable disorder caused by mutations in the type I collagen genes, arises from the deposition of abnormal collagen in the bone matrix. The inability of the abnormal collagen to participate in mineralization may be caused by its failure to interact with other bone proteins. Here, we have designed a strategy to isolate the genes important for mineralization of collagen during bone formation. Cells isolated from 16-day embryonic chick calvaria and seeded post-confluence in culture deposited a mineralized matrix over a period of 2 weeks. Chick skin fibroblasts seeded and cultured under the same conditions did not mineralize. Using RT-PCR, we prepared short cDNAs ({approximately}300 bp) corresponding to the 3{prime} ends of mRNA from fibroblasts and separately from the mineralizing calvarial cells. Subtractive cDNA hybridization generated a pool of cDNAs that were specific to mineralizing calvarial cells but not to fibroblasts. Screening of 100,000 plaques of a chick bone ZAP Express cDNA library with this pool of mineralizing-specific cDNAs identified ten clones which comprised full-length cDNAs for the bone proteins osteopontin (eight of the ten positives), bone sialoprotein II (one of the ten positives), and cystatin (one of the ten positives). cDNAs for type I collagen, fibronectin, alkaline phosphatase, house-keeping genes, and other genes expressed in fibroblasts were not identified in this preliminary screen. The pool of short cDNAs is likely to comprise cDNAs for further bone-specific genes and will be used to screen the entire bone cDNA library of 4.2 million clones. 30 refs., 4 figs.

  9. Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation.

    Science.gov (United States)

    Ben-Shachar, Shay; Constantini, Shlomi; Hallevi, Hen; Sach, Emma K; Upadhyaya, Meena; Evans, Gareth D; Huson, Susan M

    2013-05-01

    Neurofibromatosis type 1 (NF1) and its related disorders (NF1-Noonan syndrome (NFNS) and Watson syndrome (WS)) are caused by heterozygous mutations in the NF1 gene. Pulmonary stenosis (PS) occurs more commonly in NF1 and its related disorders than in the general population. This study investigated whether PS is associated with specific types of NF1 gene mutations in NF1, NFNS and WS. The frequency of different NF1 mutation types in a cohort of published and unpublished cases with NF1/NFNS/WS and PS was examined. Compared with NF1 in general, NFNS patients had higher rates of PS (9/35=26% vs 25/2322=1.1%, P valueNF1 in general (PNF1 and PS, were found to have non-truncating mutations, a much higher frequency than the 19% reported in NF1 cohorts (PNF1 and its related disorders is clearly associated with non-truncating mutations in the NF1 gene providing a new genotype-phenotype correlation. The data indicate a specific role of non-truncating mutations on the NF1 cardiac phenotype.

  10. Uniparental disomy as a cause of spinal muscular atrophy and progressive myoclonic epilepsy: phenotypic homogeneity due to the homozygous c.125C>T mutation in ASAH1.

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    Giráldez, Beatriz G; Guerrero-López, Rosa; Ortega-Moreno, Laura; Verdú, Alfonso; Carrascosa-Romero, M Carmen; García-Campos, Óscar; García-Muñozguren, Susana; Pardal-Fernández, José Manuel; Serratosa, José M

    2015-03-01

    Spinal muscular atrophy and progressive myoclonic epilepsy (SMAPME, OMIM#159950) is a rare autosomal recessive disorder characterized by the combination of progressive myoclonic epilepsy and muscular weakness due to lower motor neuron disease. Mutations in ASAH1, previously associated only to Farber disease, have been recently described in seven patients with SMAPME. A homozygous c.125C>T mutation was initially found in six patients with a clinical homogeneous phenotype. A heterozygous compound mutation found in an additional patient has broadened the clinical and genetic spectrum of clinical SMAPME. We report a new case of a 13-year-old girl with SMAPME with the homozygous ASAH1 c.125C>T mutation, unique in that it is due to paternal uniparental disomy. She experienced muscle weakness from the age of three due to lower motor neuron involvement that lead to severe handicap and onset in late childhood of a progressive myoclonic epilepsy. This clinical picture fully overlaps with that of previously reported patients with this mutation and supports our view that the clinical phenotype associated with the homozygous c.125C>T mutation constitutes a clinically homogenous and recognizable disease.

  11. Clinical phenotypes, ALK1 gene mutation and level of related plasma proteins in Chinese hereditary hemorrhagic telangiectasia

    Institute of Scientific and Technical Information of China (English)

    张广森; 易彦; 彭宏凌; 申建凯; 谢鼎华; 贺湘波

    2004-01-01

    Background We determined the diagnosis of hereditary hemorrhagic telangiectasis (HHT) in a suspected HHT family, identified ALK1 gene mutation and established a gene diagnosis method of HHT. The level of related plasma proteins (transforming growth factor β and thrombomodulin) were also analyzed.Methods Bleeding history and family history were collected; Dilatant nasal mucosal capillaries in proband were observed under nasal cavity endoscope; exons 3, 7, 8 of ALK1 gene in proband and her family members were amplified with polymerase chain reaction (PCR), and the PCR products were analyzed. Using enzyme-linked immunosorbent assay (ELISA), plasma TGF-β1 and TGF-β2 concentrations were measured. Plasma thrombomodulin (TM) level was detected by Western blotting.Results Of all family members, four had epstaxis, two had evident telangiectases on skin or mucosa. Gene screening results showed that C to T substitution at position 1231 in exon 8 of ALK1 gene (CGG→TGG) existed in proband,her affected brother and their father. The mutation did not exist in proband's sister-in-law and nephew. Plasma TGF-β1 concentrations in the affected HHT was 20538, 17194, 13131 pg/ml, while that of normal control and unaffected family members was 15950, 20297, 12836 pg/ml, respectively. Plasma TGF-β2 in HHT patients was 14502, 9550, 10592 and that of normal controls 8579, 20297, 7680 pg/ml respectively. Level of plasma TM was in HHT subjects significantly lower than in normal subjects.Conclusions Chinese HHT individuals have mutant ALK1 gene, a C1231T variation on exon 8 of ALK1 is responsible for HHT clinical phenotypes in this family. ALK1 gene analysis, together with special clinical phenotypes and family history, provides a reliable method in diagnosing HHT. In affected HHT subjects, plasma TGFβ levels were not obviously different from those of normal subject; while plasma TM concentration was significantly lower than that in normal subjects. The significance and mechanism remain

  12. On the traces of XPD: cell cycle matters - untangling the genotype-phenotype relationship of XPD mutations

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    Cameroni Elisabetta

    2010-09-01

    Full Text Available Abstract Mutations in the human gene coding for XPD lead to segmental progeria - the premature appearance of some of the phenotypes normally associated with aging - which may or may not be accompanied by increased cancer incidence. XPD is required for at least three different critical cellular functions: in addition to participating in the process of nucleotide excision repair (NER, which removes bulky DNA lesions, XPD also regulates transcription as part of the general transcription factor IIH (TFIIH and controls cell cycle progression through its interaction with CAK, a pivotal activator of cyclin dependent kinases (CDKs. The study of inherited XPD disorders offers the opportunity to gain insights into the coordination of important cellular events and may shed light on the mechanisms that regulate the delicate equilibrium between cell proliferation and functional senescence, which is notably altered during physiological aging and in cancer. The phenotypic manifestations in the different XPD disorders are the sum of disturbances in the vital processes carried out by TFIIH and CAK. In addition, further TFIIH- and CAK-independent cellular activities of XPD may also play a role. This, added to the complex feedback networks that are in place to guarantee the coordination between cell cycle, DNA repair and transcription, complicates the interpretation of clinical observations. While results obtained from patient cell isolates as well as from murine models have been elementary in revealing such complexity, the Drosophila embryo has proven useful to analyze the role of XPD as a cell cycle regulator independently from its other cellular functions. Together with data from the biochemical and structural analysis of XPD and of the TFIIH complex these results combine into a new picture of the XPD activities that provides ground for a better understanding of the patophysiology of XPD diseases and for future development of diagnostic and therapeutic tools.

  13. A mutation in the cytosolic O-acetylserine (thiol lyase induces a genome-dependent early leaf death phenotype in Arabidopsis

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    Schippers Jos HM

    2010-04-01

    Full Text Available Abstract Background Cysteine is a component in organic compounds including glutathione that have been implicated in the adaptation of plants to stresses. O-acetylserine (thiol lyase (OAS-TL catalyses the final step of cysteine biosynthesis. OAS-TL enzyme isoforms are localised in the cytoplasm, the plastids and mitochondria but the contribution of individual OAS-TL isoforms to plant sulphur metabolism has not yet been fully clarified. Results The seedling lethal phenotype of the Arabidopsis onset of leaf death3-1 (old3-1 mutant is due to a point mutation in the OAS-A1 gene, encoding the cytosolic OAS-TL. The mutation causes a single amino acid substitution from Gly162 to Glu162, abolishing old3-1 OAS-TL activity in vitro. The old3-1 mutation segregates as a monogenic semi-dominant trait when backcrossed to its wild type accession Landsberg erecta (Ler-0 and the Di-2 accession. Consistent with its semi-dominant behaviour, wild type Ler-0 plants transformed with the mutated old3-1 gene, displayed the early leaf death phenotype. However, the old3-1 mutation segregates in an 11:4:1 (wild type: semi-dominant: mutant ratio when backcrossed to the Colombia-0 and Wassilewskija accessions. Thus, the early leaf death phenotype depends on two semi-dominant loci. The second locus that determines the old3-1 early leaf death phenotype is referred to as odd-ler (for old3 determinant in the Ler accession and is located on chromosome 3. The early leaf death phenotype is temperature dependent and is associated with increased expression of defence-response and oxidative-stress marker genes. Independent of the presence of the odd-ler gene, OAS-A1 is involved in maintaining sulphur and thiol levels and is required for resistance against cadmium stress. Conclusions The cytosolic OAS-TL is involved in maintaining organic sulphur levels. The old3-1 mutation causes genome-dependent and independent phenotypes and uncovers a novel function for the mutated OAS-TL in cell

  14. Isocitrate dehydrogenase 1 R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype.

    Science.gov (United States)

    Whitehall, V L J; Dumenil, T D; McKeone, D M; Bond, C E; Bettington, M L; Buttenshaw, R L; Bowdler, L; Montgomery, G W; Wockner, L F; Leggett, B A

    2014-11-01

    The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause of CIMP in colorectal cancer. The IDH1 mutational hotspot was screened in 86 CIMP-positive and 80 CIMP-negative cancers. The entire coding sequence was examined in 81 CIMP-positive colorectal cancers. Forty-seven cancers varying by CIMP-status and IDH1 mutation status were examined using Illumina 450K DNA methylation microarrays. The R132C IDH1 mutation was detected in 4/166 cancers. All IDH1 mutations were in CIMP cancers that were BRAF mutant and microsatellite stable (4/45, 8.9%). Unsupervised hierarchical cluster analysis identified an IDH1 mutation-like methylation signature in approximately half of the CIMP-positive cancers. IDH1 mutation appears to cause CIMP in a small proportion of BRAF mutant, microsatellite stable colorectal cancers. This study provides a precedent that a single gene mutation may cause CIMP in colorectal cancer, and that this will be associated with a specific epigenetic signature and clinicopathological features.

  15. Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation.

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    Takehiko Naito

    Full Text Available The present study of KCNQ4 mutations was carried out to 1 determine the prevalence by unbiased population-based genetic screening, 2 clarify the mutation spectrum and genotype/phenotype correlations, and 3 summarize clinical characteristics. In addition, a review of the reported mutations was performed for better understanding of this deafness gene. The screening using 287 probands from unbiased Japanese autosomal dominant nonsyndromic hearing loss (ADNSHL families identified 19 families with 7 different disease causing mutations, indicating that the frequency is 6.62% (19/287. While the majority were private mutations, one particular recurrent mutation, c.211delC, was observed in 13 unrelated families. Haplotype analysis in the vicinity of c.211delC suggests existence of a common ancestor. The majority of the patients showed all frequency, but high-frequency predominant, sensorineural hearing loss. The present study adds a new typical audiogram configuration characterized by mid-frequency predominant hearing loss caused by the p.V230E mutation. A variant at the N-terminal site (c. 211delC showed typical ski-slope type audiogram configuration. Concerning clinical features, onset age was from 3 to 40 years old, and mostly in the teens, and hearing loss was gradually progressive. Progressive nature is a common feature of patients with KCNQ4 mutations regardless of the mutation type. In conclusion, KCNQ4 mutations are frequent among ADNSHL patients, and therefore screening of the gene and molecular confirmation of these mutations have become important in the diagnosis of these conditions.

  16. Severe craniosynostosis with Noonan syndrome phenotype associated with SHOC2 mutation: clinical evidence of crosslink between FGFR and RAS signaling pathways.

    Science.gov (United States)

    Takenouchi, Toshiki; Sakamoto, Yoshiaki; Miwa, Tomoru; Torii, Chiharu; Kosaki, Rika; Kishi, Kazuo; Takahashi, Takao; Kosaki, Kenjiro

    2014-11-01

    Dysregulation in the RAS signaling cascade results in a family of malformation syndromes called RASopathies. Meanwhile, alterations in FGFR signaling cascade are responsible for various syndromic forms of craniosynostosis. In general, the phenotypic spectra of RASopathies and craniosynostosis syndromes do not overlap. Recently, however, mutations in ERF, a downstream molecule of the RAS signaling cascade, have been identified as a cause of complex craniosynostosis, suggesting that the RAS and FGFR signaling pathways can interact in the pathogenesis of malformation syndromes. Here, we document a boy with short stature, developmental delay, and severe craniosynostosis involving right coronal, bilateral lambdoid, and sagittal sutures with a de novo mutation in exon1 of SHOC2 (c.4A>G p.Ser2Gly). This observation further supports the existence of a crosslink between the RAS signaling cascade and craniosynostosis. In retrospect, the propositus had physical features suggestive of a dysregulated RAS signaling cascade, such as fetal pleural effusion, fetal hydrops, and atrial tachycardia. In addition to an abnormal cranial shape, which has been reported for this specific mutation, craniosynostosis might be a novel associated phenotype. In conclusion, the phenotypic combination of severe craniosynostosis and RASopathy features observed in the propositus suggests an interaction between the RAS and FGFR signaling cascades. Patients with craniosynostosis in combination with any RASopathy feature may require mutation screening for molecules in the FGFR-RAS signaling cascade.

  17. Structural and dynamic characterization of the C313Y mutation in Myostatin dimeric protein, responsible for the double muscle phenotype in Piedmontese cattle

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    Silvia eBongiorno

    2016-02-01

    Full Text Available The knowledge of the molecular effects of the C313Y mutation, responsible for the double muscle phenotype in Piedmontese cattle, can help understanding the actual mechanism of phenotype determination and paves the route for a better modulation of the positive effects of this economic important phenotype in the beef industry, while minimizing the negative side effects, now inevitably intersected.The structure and dynamic behaviour of the active dimeric form of Myostatin in cattle was analyzed by means of three state-of-the-art Molecular Dynamics simulations, 200-ns long, of wild-type and C313Y mutants. Our results highlight a role for the conserved Arg333 in establishing a network of short and long range interactions between the two monomers in the wild-type protein that is destroyed upon the C313Y mutation even in a single monomer. Furthermore, the native protein shows an asymmetry in residue fluctuation that is absent in the double monomer mutant. Time window analysis on further 200-ns of simulation demonstrates that this is a characteristic behaviour of the protein, likely depended from the long range communications between monomers. The same behaviour, in fact, has already been observed in other mutated dimers. Finally, the mutation does not produce alterations in the secondary structure elements that compose the characteristic TGF-β cystine-knot motif.

  18. Two novel heterozygous mutations of EVC2 cause a mild phenotype of Ellis-van Creveld syndrome in a Chinese family.

    Science.gov (United States)

    Shen, Wenjing; Han, Dong; Zhang, Jin; Zhao, Hongshan; Feng, Hailan

    2011-09-01

    Ellis-van Creveld syndrome (EvC, chondroectodermal dysplasia; OMIM 225500) is an autosomal recessive skeletal dysplasia with associated multisystem involvement. The syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, and abnormal teeth. Congenital heart defects occur in 50-60% of cases. In this study, we report EvC in a 6-year-old Chinese girl with hypodontia and polydactyly, mild short stature, and abnormalities of the knee joints. No signs of short ribs, narrow thorax, or congenital heart defects were found in this patient. The EvC phenotype shares some similarity with Weyers acrofacial dysostosis (Weyer; OMIM 193530), an autosomal dominant disorder clinically characterized by mild short stature, postaxial polydactyly, nail dystrophy, and dysplastic teeth. Mutations in EVC or EVC2 are associated with both EvC syndrome and Weyers acrodental dysostosis, but the two conditions differ in the severity of the phenotype and their pattern of inheritance. In this study, two novel heterozygous EVC2 mutations, IVS5-2A > G and c.2653C > T (Arg885X), were identified in the patient. The IVS5-2A > G mutation was inherited from the patient's mother and the c.2653C > T from her father. Her parents have no phenotypic symptoms similar to those of the patient. These findings extend the mutation spectrum of this malformation syndrome and provide the possibility of prenatal diagnosis for future offspring in this family.

  19. N-acetylglutamate synthase deficiency: Novel mutation associated with neonatal presentation and literature review of molecular and phenotypic spectra

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    Eiman H. Al Kaabi

    2016-09-01

    Full Text Available The urea cycle is the main pathway for the disposal of excess nitrogen. Carbamoylphosphate synthetase 1 (CPS1, the first and rate-limiting enzyme of urea cycle, is activated by N-acetylglutamate (NAG, and thus N-acetylglutamate synthase (NAGS is an essential part of the urea cycle. Although NAGS deficiency is the rarest urea cycle disorder, it is the only one that can be specifically and effectively treated by a drug, N-carbamylglutamate, a stable structural analogous of NAG that activates CPS1. Here we report an infant with NAGS deficiency who presented with neonatal hyperammonemia. She was found to have a novel homozygous splice-site mutation, c.1097-2A>T, in the NAGS gene. We describe the clinical course of this infant, who had rapid response to N-carbamylglutamate treatment. In addition, we reviewed the clinical and molecular spectra of previously reported individuals with NAGS deficiency, which presents in most cases with neonatal hyperammonemia, and in some cases the presentation is later, with a broad spectrum of ages and manifestations. With this broad later-onset phenotypic spectrum, maintaining a high index of suspicion is needed for the early diagnosis of this treatable disease.

  20. N-acetylglutamate synthase deficiency: Novel mutation associated with neonatal presentation and literature review of molecular and phenotypic spectra.

    Science.gov (United States)

    Al Kaabi, Eiman H; El-Hattab, Ayman W

    2016-09-01

    The urea cycle is the main pathway for the disposal of excess nitrogen. Carbamoylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of urea cycle, is activated by N-acetylglutamate (NAG), and thus N-acetylglutamate synthase (NAGS) is an essential part of the urea cycle. Although NAGS deficiency is the rarest urea cycle disorder, it is the only one that can be specifically and effectively treated by a drug, N-carbamylglutamate, a stable structural analogous of NAG that activates CPS1. Here we report an infant with NAGS deficiency who presented with neonatal hyperammonemia. She was found to have a novel homozygous splice-site mutation, c.1097-2A>T, in the NAGS gene. We describe the clinical course of this infant, who had rapid response to N-carbamylglutamate treatment. In addition, we reviewed the clinical and molecular spectra of previously reported individuals with NAGS deficiency, which presents in most cases with neonatal hyperammonemia, and in some cases the presentation is later, with a broad spectrum of ages and manifestations. With this broad later-onset phenotypic spectrum, maintaining a high index of suspicion is needed for the early diagnosis of this treatable disease.

  1. Cyclic adenosine monophosphate metabolism in synaptic growth, strength, and precision: neural and behavioral phenotype-specific counterbalancing effects between dnc phosphodiesterase and rut adenylyl cyclase mutations.

    Science.gov (United States)

    Ueda, Atsushi; Wu, Chun-Fang

    2012-03-01

    Two classic learning mutants in Drosophila, rutabaga (rut) and dunce (dnc), are defective in cyclic adenosine monophosphate (cAMP) synthesis and degradation, respectively, exhibiting a variety of neuronal and behavioral defects. We ask how the opposing effects of these mutations on cAMP levels modify subsets of phenotypes, and whether any specific phenotypes could be ameliorated by biochemical counter balancing effects in dnc rut double mutants. Our study at larval neuromuscular junctions (NMJs) demonstrates that dnc mutations caused severe defects in nerve terminal morphology, characterized by unusually large synaptic boutons and aberrant innervation patterns. Interestingly, a counterbalancing effect led to rescue of the aberrant innervation patterns but the enlarged boutons in dnc rut double mutant remained as extreme as those in dnc. In contrast to dnc, rut mutations strongly affect synaptic transmission. Focal loose-patch recording data accumulated over 4 years suggest that synaptic currents in rut boutons were characterized by unusually large temporal dispersion and a seasonal variation in the amount of transmitter release, with diminished synaptic currents in summer months. Experiments with different rearing temperatures revealed that high temperature (29-30°C) decreased synaptic transmission in rut, but did not alter dnc and wild-type (WT). Importantly, the large temporal dispersion and abnormal temperature dependence of synaptic transmission, characteristic of rut, still persisted in dnc rut double mutants. To interpret these results in a proper perspective, we reviewed previously documented differential effects of dnc and rut mutations and their genetic interactions in double mutants on a variety of physiological and behavioral phenotypes. The cases of rescue in double mutants are associated with gradual developmental and maintenance processes whereas many behavioral and physiological manifestations on faster time scales could not be rescued. We discuss

  2. Homozygosity for the V377I mutation in mevalonate kinase causes distinct clinical phenotypes in two sibs with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS)

    Science.gov (United States)

    Messer, Laurent; Alsaleh, Ghada; Georgel, Philippe; Carapito, Raphael; Waterham, Hans R; Dali-Youcef, Nassim; Bahram, Siamak; Sibilia, Jean

    2016-01-01

    Objective Mevalonate kinase (MVK) deficiency is a rare autosomal recessive auto-inflammatory disorder characterised by recurring episodes of fever associated with multiple non-specific inflammatory symptoms and caused by mutations in the MVK gene. The phenotypic spectrum is wide and depends mostly on the nature of the mutations. Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a relatively mild presentation and predominantly associated with a c.1129G>A (p.V377I) mutation in the MVK gene. We report cases of two sisters homozygous for this mutation but exhibiting distinct (symptomatic vs asymptomatic) phenotypes. Methods Patient history was obtained; physical and clinical examination and laboratory tests were performed; lipopolysaccharide (LPS) response of peripheral blood mononuclear cells was quantified. Results Low MVK enzymatic activity is not necessarily associated with inflammatory symptoms. Increased inflammatory cytokine secretion in response to LPS is associated with symptomatic MVK deficiency. Conclusions Individuals who are homozygous for the common p.V377I mutation in the MVK gene may not display the characteristic inflammatory episodes diagnostic of MKD and thus may be lost for correct and timely diagnosis. PMID:26977311

  3. A novel mutation in NF1 is associated with diverse intra-familial phenotypic variation and astrocytoma in a Chinese family.

    Science.gov (United States)

    Banerjee, Santasree; Dai, Yi; Liang, Shengran; Chen, Huishuang; Wang, Yanyan; Tang, Lihui; Wu, Jing; Huang, Hui

    2016-09-01

    Neurofibromatosis type 1 (NF1) is a dysregulated neurocutaneous disorder, characterized by neurofibromas and café-au-lait spots. NF1 is caused by mutations in the NF1 gene, encoding neurofibromin. Here, we present a clinical molecular study of a three-generation Chinese family with NF1. The proband was a male patient who showed café-au-lait spots and multiple subcutaneous neurofibromas over the whole body, but his siblings only had regional lesions. The man's daughter presented with severe headache and vomiting. Neurological examination revealed an intracranial space occupying lesion. Surgery was undertaken and the histopathological examination showed a grade I-II astrocytoma. Next-Generation sequencing (Illumina HiSeq2500 Analyzers; Illumina, San Diego, CA, USA) and Sanger sequencing (ABI PRISM 3730 automated sequencer; Applied Biosystems, Foster City, CA, USA) identified the c.227delA mutation in the NF1 gene in the man. The mutation is co-segregated with the disease phenotypes among the affected members of this family and was absent in 100 healthy controls. This novel mutation results in a frameshift (p.Asn78IlefsX7) as well as truncation of neurofibromin by formation of a premature stop codon. Our results not only extended the mutational and phenotypic spectra of the gene and the disease, but also highlight the importance of the other genetic or environmental factors in the development and severity of the disease.

  4. Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: Different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation

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    Hanna, M.G.; Nelson, I.; Sweeney, M.G.; Cooper, J.M.; Watkins, P.J.; Morgan-Hughes, J.A.; Harding, A.E. [Kings College Hospital, London (United Kingdom)

    1995-05-01

    We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus. 43 refs., 4 figs., 1 tab.

  5. Biochemical and computational analyses of two phenotypically related GALT mutations (S222N and S135L that lead to atypical galactosemia

    Directory of Open Access Journals (Sweden)

    Benjamin Cocanougher

    2015-06-01

    Full Text Available Galactosemia is a metabolic disorder caused by mutations in the GALT gene [1,2]. We encountered a patient heterozygous for a known pathogenic H132Q mutation and a novel S222N variant of unknown significance [3]. Reminiscent of patients with the S135L mutation, our patient had loss of GALT enzyme activity in erythrocytes but a very mild clinical phenotype [3–8]. We performed splicing experiments and computational structural analyses to investigate the role of the novel S222N variant. Alamut software data predicted loss of splicing enhancers for the S222N and S135L mutations [9,10]. A cDNA library was generated from our patient׳s RNA to investigate for splicing errors, but no change in transcript length was seen [3]. In silico structural analysis was performed to investigate enzyme stability and attempt to understand the mechanism of the atypical galactosemia phenotype. Stability results are publicly available in the GALT Protein Database 2.0 [11–14]. Animations were created to give the reader a dynamic view of the enzyme structure and mutation locations. Protein database files and python scripts are included for further investigation.

  6. Autosomal dominant precocious osteoarthropathy due to a mutation of the cartilage oligomeric matrix protein (COMP) gene: further expansion of the phenotypic variations of COMP defects

    Energy Technology Data Exchange (ETDEWEB)

    Kawaji, Hiroyuki [Department of Orthopaedic Surgery, Sanyudo Hospital, 6-1-219 Chuou, Yonezawa, Yamagata 992-0045 (Japan); Nishimura, Gen [Department of Radiology, Nasu Chuou Hospital, Tochigi (Japan); Watanabe, Sobei; Sasaki, Akira; Sano, Tokuhisa [Department of Orthopaedic Surgery, Tohoku Kohsei-Nenkin Hospital, Miyagi (Japan); Mabuchi, Akihiko; Ikeda, Toshiyuki; Ikegawa, Shiro [Laboratory for Bone and Joint Diseases, SNP Research Center, Tokyo (Japan); Ohashi, Hirofumi [Division of Medical Genetics, Saitama Children' s Medical Center, Saitama (Japan)

    2002-12-01

    We report on a Japanese family of four generations with an autosomal dominant precocious osteoarthropathy. The cardinal clinical manifestations of affected individuals were painful weight-bearing large joints, which started in late childhood or adolescence. The radiological hallmarks included coxa plana, mild epiphyseal dysplasia of the knee, and round talar domes with tibiotalar slant in childhood, which evolved into degenerative joint diseases in adulthood. The disease phenotype was cosegregated with a mutation of the cartilage oligomeric matrix protein (COMP) gene in the family members, who underwent molecular evaluation. COMP mutations have been reported in a mild form of multiple epiphyseal dysplasia (MED), Ribbing type, as well as allied disorders with more severe manifestations, such as MED Fairbank type and pseudoachondroplasia. Unlike previously reported cases with the Ribbing type, the present patients did not have short stature or brachydactyly. This report expands further the phenotypic variations of COMP defects. (orig.)

  7. Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype.

    Science.gov (United States)

    Krause, Amanda; Mitchell, Claire; Essop, Fahmida; Tager, Susan; Temlett, James; Stevanin, Giovanni; Ross, Christopher; Rudnicki, Dobrila; Margolis, Russell

    2015-10-01

    Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline, and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations.

  8. Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations | Office of Cancer Genomics

    Science.gov (United States)

    Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are composed of causal "driver" mutations that promote tumor progression along with many more pathologically neutral "passenger" events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers.

  9. Mutation in a gene for type I procollagen (COL1A2) in a woman with postmenopausal osteoporosis: Evidence for phenotypic and genotypic overlap with mild osteogenesis imperfecta

    Energy Technology Data Exchange (ETDEWEB)

    Spotila, L.D.; Constantinou, C.D.; Sereda, L.; Ganguly, A.; Prockop, D.J. (Jefferson Medical College, Philadelphia, PA (United States)); Riggs, B.L. (Mayo Clinic, Rochester, MN (United States))

    1991-06-15

    Mutations in the two genes for type I collagen (COL1A1 or COL1A2) cause osteogenesis imperfecta (OI), a heritable disease characterized by moderate to extreme brittleness of bone early in life. Here, the authors show that a 52-year-old post menopausal woman with severe osteopenia and a compression fracture of a thoracic vertebra had a mutation in the gene for the {alpha}2(I) chain of type I collagen (COL1A2) similar to mutations that cause OI. cDNA was prepared from the woman's skin fibroblast RNA and assayed for the presence of a mutation by treating DNA heteroduplexes with carbodiimide. The results indicated a sequence variation in the region encoding amino acid residues 660-667 of the {alpha}2(I) chain. Further analysis demonstrated a single-base mutation that caused a serine-for-glycine substitution at position 661 of the {alpha}2(I) triple-helical domain. The substitution produced posttranslational overmodification of the collagen triple helix, as is seen with most glycine substitutions that cause OI. The patient had a history of five previous fractures, slightly blue sclerae, and slight hearing loss. Therefore, the results suggest that there may be phenotypic and genotypic overlap between mild osteogenesis imperfecta and postmenopausal osteoporosis, and that a subset of women with postmenopausal osteoporosis may have mutations in the genes for type I procollagen.

  10. Cleft palate and ADULT phenotype in a patient with a novel TP63 mutation suggests lumping of EEC/LM/ADULT syndromes into a unique entity: ELA syndrome.

    Science.gov (United States)

    Prontera, Paolo; Garelli, Emanuela; Isidori, Ilenia; Mencarelli, Amedea; Carando, Adriana; Silengo, Margherita Cirillo; Donti, Emilio

    2011-11-01

    Acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome is a rare condition belonging to the group of ectodermal dysplasias caused by TP63 mutations. Its clinical phenotype is similar to ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) and limb-mammary syndrome (LMS), and differs from these disorders mainly by the absence of cleft lip and/or palate. We report on a 39-year-old patient who was found to be heterozygous for a c.401G > T (p.Gly134Val) de novo mutation of TP63. This patient had the ADULT phenotype associated with cleft palate. Our findings, rather than extend the clinical spectrum of ADULT syndrome, suggest that cleft palate can no longer be considered an element for differential diagnosis for ADULT, EEC, and LMS. Our data, added to other reports on overlapping phenotypes, support the combining of these three phenotypes into a unique entity that we propose to call "ELA syndrome," which is an acronym of ectrodactyly-ectodermal dysplasia-cleft lip and palate, limb-mammary, and ADULT syndromes.

  11. Rapid Mutation of Spirulina platensis by a New Mutagenesis System of Atmospheric and Room Temperature Plasmas (ARTP) and Generation of a Mutant Library with Diverse Phenotypes

    Science.gov (United States)

    Zhang, Chong; Tan, Yinyee; Jiang, Peixia; Ge, Nan; Heping Li; Xing, Xinhui

    2013-01-01

    In this paper, we aimed to improve the carbohydrate productivity of Spirulina platensis by generating mutants with increased carbohydrate content and growth rate. ARTP was used as a new mutagenesis tool to generate a mutant library of S. platensis with diverse phenotypes. Protocol for rapid mutation of S. platensis by 60 s treatment with helium driven ARTP and high throughput screening method of the mutants using the 96-well microplate and microplate reader was established. A mutant library of 62 mutants was then constructed and ideal mutants were selected out. The characteristics of the mutants after the mutagenesis inclined to be stable after around 9th subculture, where the total mutation frequency and positive mutation frequency in terms of specific growth rate reached 45% and 25%, respectively. The mutants in mutant library showed diverse phenotypes in terms of cell growth rate, carbohydrate content and flocculation intensity. The positive mutation frequency in terms of cellular carbohydrate content with the increase by more than 20% percent than the wild strain was 32.3%. Compared with the wild strain, the representative mutants 3-A10 and 3-B2 showed 40.3% and 78.0% increase in carbohydrate content, respectively, while the mutant 4-B3 showed 10.5% increase in specific growth rate. The carbohydrate contents of the representative mutants were stable during different subcultures, indicating high genetic stability. ARTP was demonstrated to be an effective and non-GMO mutagenesis tool to generate the mutant library for multicellular microalgae. PMID:24319517

  12. Rapid mutation of Spirulina platensis by a new mutagenesis system of atmospheric and room temperature plasmas (ARTP and generation of a mutant library with diverse phenotypes.

    Directory of Open Access Journals (Sweden)

    Mingyue Fang

    Full Text Available In this paper, we aimed to improve the carbohydrate productivity of Spirulina platensis by generating mutants with increased carbohydrate content and growth rate. ARTP was used as a new mutagenesis tool to generate a mutant library of S. platensis with diverse phenotypes. Protocol for rapid mutation of S. platensis by 60 s treatment with helium driven ARTP and high throughput screening method of the mutants using the 96-well microplate and microplate reader was established. A mutant library of 62 mutants was then constructed and ideal mutants were selected out. The characteristics of the mutants after the mutagenesis inclined to be stable after around 9(th subculture, where the total mutation frequency and positive mutation frequency in terms of specific growth rate reached 45% and 25%, respectively. The mutants in mutant library showed diverse phenotypes in terms of cell growth rate, carbohydrate content and flocculation intensity. The positive mutation frequency in terms of cellular carbohydrate content with the increase by more than 20% percent than the wild strain was 32.3%. Compared with the wild strain, the representative mutants 3-A10 and 3-B2 showed 40.3% and 78.0% increase in carbohydrate content, respectively, while the mutant 4-B3 showed 10.5% increase in specific growth rate. The carbohydrate contents of the representative mutants were stable during different subcultures, indicating high genetic stability. ARTP was demonstrated to be an effective and non-GMO mutagenesis tool to generate the mutant library for multicellular microalgae.

  13. Effect of GBA Mutations on Phenotype of Parkinson’s Disease: A Study on Chinese Population and a Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Yuan Zhang

    2015-01-01

    Full Text Available GBA has been identified as a genetic risk factor for PD. Whether the clinical manifestations of PD patients with or without GBA mutations are different has still not reached a consensus. We firstly detected the GBA mutation L444P in 1147 Chinese PD patients and simultaneously evaluated their corresponding clinical data. Then we compared the phenotypes between 646 PD patients with GBA mutations and 10344 PD patients without GBA mutations worldwide through meta-analysis. Through the method of meta-analysis, there was significant difference in age at onset (MD = −3.10 [95% CI: −4.88, −1.32], bradykinesia as an initial symptom (OR = 1.49 [95% CI: 1.15, 1.94], having family history (OR = 1.50 [95% CI: 1.18, 1.91], and dementia (OR = 3.21 [95% CI: 1.97, 5.24] during the comparison between PD patients with and without GBA mutations. While, in the aspect of tremor as an initial symptom (OR = 0.81 [95% CI: 0.64, 1.03], the severity of motor symptoms such as H-Y (MD = 0.06 [95% CI: −0.06, 0.17] and UPDRS-III (MD = 1.61 [95% CI: −0.65, 3.87] and having dyskinesia (OR = 1.60 [95% CI: 0.90, 2.84] during the comparison between the two groups revealed no statistical differences. Our results suggested that the phenotypes of PD patients with GBA mutations are different from GBA noncarriers.

  14. Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated m.14484T>C (MT-ND6) mutation in Chinese families.

    Science.gov (United States)

    Zhang, Juanjuan; Zhao, Fuxin; Fu, Qun; Liang, Min; Tong, Yi; Liu, Xiaoling; Lin, Bei; Mi, Hui; Zhang, Minglian; Wei, Qi-Ping; Xue, Ling; Jiang, Pingping; Zhou, Xiangtian; Mo, Jun Qin; Huang, Taosheng; Qu, Jia; Guan, Min-Xin

    2013-11-01

    Mitochondrial m.14484T>C (MT-ND6) mutation has been associated with Leber's hereditary optic neuropathy. Previous investigations revealed that the m.14484T>C mutation is a primary factor underlying the development of optic neuropathy but is not sufficient to produce a clinical phenotype. However, mitochondrial haplogroups have been proposed to modulate the phenotypic manifestation of the m.14484T>C mutation. Here, we performed the clinical, genetic evaluation and complete mitochondrial genome sequence analysis of 41 Han Chinese pedigrees carrying the m.14484T>C mutation. These families exhibited a wide range of penetrances and expressivities of optic neuropathy. The average ratio between affected male/female matrilineal relatives from 41 families was 2:1. The penetrance of optic neuropathy in these Chinese pedigrees ranged from 5.6% to 100%, with the average of 23.8%. Furthermore, the age-of-onset for optic neuropathy varied from 4 to 44 years, with the average of 19.3 years. Sequence analysis of their mitochondrial genomes identified distinct sets of polymorphisms belonging to ten Eastern Asian haplogroups, indicating that the m.14484T>C mutation occurred through recurrent origins and founder events. We showed that mitochondrial haplogroups M9, M10 and N9 increased the penetrance of optic neuropathy in these Chinese families. In particular, these mitochondrial haplogroup specific variants: m.3394T>C (MT-ND1), m.14502T>C (MT-ND4) and m.14693A>G (MT-TE) enhanced the penetrance of visual loss in these Chinese families. These data provided the direct evidence that mitochondrial modifiers modulate the variable penetrance and expressivity of optic neuropathy among Chinese pedigrees carrying the m.14484T>C mutation.

  15. Two variants in the KIT gene as candidate causative mutations for a dominant white and a white spotting phenotype in the donkey.

    Science.gov (United States)

    Haase, B; Rieder, S; Leeb, T

    2015-06-01

    White spotting phenotypes have been intensively studied in horses, and although similar phenotypes occur in the donkey, little is known about the molecular genetics underlying these patterns in donkeys. White spotting in donkeys can range from only a few white areas to almost complete depigmentation and is characterised by a loss of pigmentation usually progressing from a white spot in the hip area. Completely white-born donkeys are rare, and the phenotype is characterised by the complete absence of pigment resulting in pink skin and a white coat. A dominant mode of inheritance has been demonstrated for spotting in donkeys. Although the mode of inheritance for the completely white phenotype in donkeys is not clear, the phenotype shows similarities to dominant white in horses. As variants in the KIT gene are known to cause a range of white phenotypes in the horse, we investigated the KIT gene as a potential candidate gene for two phenotypes in the donkey, white spotting and white. A mutation analysis of all 21 KIT exons identified a missense variant in exon 4 (c.662A>C; p.Tyr221Ser) present only in a white-born donkey. A second variant affecting a splice donor site (c.1978+2T>A) was found exclusively in donkeys with white spotting. Both variants were absent in 24 solid-coloured controls. To the authors' knowledge, this is the first study investigating genetic mechanisms underlying white phenotypes in donkeys. Our results suggest that two independent KIT alleles are probably responsible for white spotting and white in donkeys.

  16. NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype.

    Science.gov (United States)

    Berciano, José; Peeters, Kristien; García, Antonio; López-Alburquerque, Tomás; Gallardo, Elena; Hernández-Fabián, Arantxa; Pelayo-Negro, Ana L; De Vriendt, Els; Infante, Jon; Jordanova, Albena

    2016-02-01

    The purpose of this study was to describe a pedigree with NEFL N98S mutation associated with a dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) and heterogeneous early-onset phenotype. The pedigree comprised two patients, the proband and her son, aged 38 and 5 years. The proband, evaluated at age 31, showed delayed motor milestones that, as of the second decade, evolved into severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound. By then, a working diagnosis of sporadic early onset cerebellar ataxia with peripheral neuropathy was established. Screening of mutations associated with SCA and autosomal recessive cerebellar ataxias was negative. Her son showed a mild phenotype characterized by delayed motor milestones, and lower-limb hypotonia and areflexia. Electrophysiology in both patients showed nerve conduction slowing in the intermediate range, both in proximal and distal nerve segments, but where compound muscle action potentials exhibited severe attenuation there was conduction slowing down to the demyelinating range. In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy; furthermore, on water sensitive MRI sequences there was edema of calf muscles. We conclude that the NEFL N98S mutation is associated with a DI-CMT phenotype characterized by early-onset sensorimotor neuropathy delaying motor milestones, which may evolve into a severe and complex clinical picture including cerebellar ataxia.

  17. Polymorphisms in interleukin-10 gene according to mutations of NOD2/CARD15 gene and relation to phenotype in Spanish patients with Crohn's disease

    Institute of Scientific and Technical Information of China (English)

    Juan L Mendoza; Elena Urcelay; Raquel Lana; Alfonso Martinez; Carlos Taxonera; Emilio G de la Concha; Manuel Díaz-Rubio

    2006-01-01

    AIM: To examine the contribution of interleukin-10(IL-10) gene polymorphisms to Crohn's disease (CD)phenotype, and the possible genetic epistasis between IL-10 gene polymorphisms and CARD15/NOD2 gene mutations.METHODS: A cohort of 205 Spanish unrelated patients with Crohn's disease recruited from a single center was studied. All patients were rigorously phenotyped and followed-up for at least 3 years (mean time, 12.5years). The clinical phenotype was established prior to genotyping.RESULTS: The correlation of genotype-Vienna classification groups showed that the ileocolonic location was significantly associated with the -1082G allele in the NOD2/CARD15 mutation-positive patients (RR= 1.52,95%CI, 1.21 to 1.91,P= 0.008). The multivariate analysis demonstrated that the IL-10 G14 microsatellite allele in the NOD2/CARD15 mutation positive patients was associated with two risk factors, history of appendectomy(RR=2.15, 95%CI=1.1-4.30, P=0.001) and smoking habit at diagnosis (RR = 1.29, 95%CI= 1.04-4.3,P= 0.04).CONCLUSION: In Spanish population from Madrid, in CD patients carrying at least one NOD2/CARD15 mutation,the -1082G allele is associated with ileocolonic disease and the IL-10G14 microsatellite allele is associated with previous history of appendectomy and smoking habit at diagnosis. These data provide further molecular evidence for a genetic basis of the clinical heterogeneity of CD.

  18. Genotype-phenotype relationship in patients with arrhythmogenic right ventricular cardiomyopathy caused by desmosomal gene mutations: A systematic review and meta-analysis

    Science.gov (United States)

    Xu, Zhenyan; Zhu, Wengen; Wang, Cen; Huang, Lin; Zhou, Qiongqiong; Hu, Jinzhu; Cheng, Xiaoshu; Hong, Kui

    2017-01-01

    The relationship between clinical phenotypes and desmosomal gene mutations in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is poorly characterized. Therefore, we performed a meta-analysis to explore the genotype-phenotype relationship in patients with ARVC. Any studies reporting this genotype-phenotype relationship were included. In total, 11 studies involving 1,113 patients were included. The presence of desmosomal gene mutations was associated with a younger onset age of ARVC (32.7 ± 15.2 versus 43.2 ± 13.3 years; P = 0.001), a higher incidence of T wave inversion in V1–3 leads (78.5% versus 51.6%; P = 0.0002) or a family history of ARVC (39.5% versus 27.1%; P = 0.03). There was no difference in the proportion of males between desmosomal-positive and desmosomal-negative patients (68.3% versus 68.9%; P = 0.60). The presence of desmosomal gene mutations was not associated with global or regional structural and functional alterations (63.5% versus 60.5%; P = 0.37), epsilon wave (29.4% versus 26.2%; P = 0.51) or ventricular tachycardia of left bundle-branch morphology (62.6% versus 57.2%; P = 0.30). Overall, patients with desmosomal gene mutations are characterized by an earlier onset age, a higher incidence of T wave inversion in V1–3 leads and a strong family history of ARVC. PMID:28120905

  19. Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients

    DEFF Research Database (Denmark)

    Hoornaert, Kristien P; Vereecke, Inge; Dewinter, Chantal;

    2010-01-01

    in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation......-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were...... found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients...

  20. The mutation p.E113K in the Schiff base counterion of rhodopsin is associated with two distinct retinal phenotypes within the same family

    Science.gov (United States)

    Reiff, Charlotte; Owczarek-Lipska, Marta; Spital, Georg; Röger, Carsten; Hinz, Hebke; Jüschke, Christoph; Thiele, Holger; Altmüller, Janine; Nürnberg, Peter; Da Costa, Romain; Neidhardt, John

    2016-01-01

    The diagnoses of retinitis pigmentosa (RP) and stationary night blindness (CSNB) are two distinct clinical entities belonging to a group of clinically and genetically heterogeneous retinal diseases. The current study focused on the identification of causative mutations in the RP-affected index patient and in several members of the same family that reported a phenotype resembling CSNB. Ophthalmological examinations of the index patient confirmed a typical form of RP. In contrast, clinical characterizations and ERGs of another affected family member showed the Riggs-type CSNB lacking signs of RP. Applying whole exome sequencing we detected the non-synonymous substitution c.337G > A, p.E113 K in the rhodopsin (RHO) gene. The mutation co-segregated with the diseases. The identification of the pathogenic variant p.E113 K is the first description of a naturally-occurring mutation in the Schiff base counterion of RHO in human patients. The heterozygous mutation c.337G > A in exon 1 was confirmed in the index patient as well as in five CSNB-affected relatives. This pathogenic sequence change was excluded in a healthy family member and in 199 ethnically matched controls. Our findings suggest that a mutation in the biochemically well-characterized counterion p.E113 in RHO can be associated with RP or Riggs-type CSNB, even within the same family. PMID:27812022

  1. Expanding phenotype of p.Ala140Val mutation in MECP2 in a 4 generation family with X-linked intellectual disability and spasticity.

    Science.gov (United States)

    Lambert, Sophie; Maystadt, Isabelle; Boulanger, Sébastien; Vrielynck, Pascal; Destrée, Anne; Lederer, Damien; Moortgat, Stéphanie

    2016-10-01

    Mutations in MECP2 (MIM #312750), located on Xq28 and encoding a methyl CpG binding protein, are classically associated with Rett syndrome in female patients, with a lethal effect in hemizygous males. However, MECP2 mutations have already been reported in surviving males with severe neonatal-onset encephalopathy, or with X-linked intellectual disability associated with psychosis, pyramidal signs, parkinsonian features and macro-orchidism (PPM-X syndrome; MIM3 #300055). Here we report on the identification of the p.Ala140Val mutation in the MECP2 gene in 4 males and 3 females of a large Caucasian family affected with X-linked intellectual disability. Females present with mild cognitive impairment and speech difficulties. Males have moderate intellectual disability, impaired language development, friendly behavior, slowly progressive spastic paraparesis and dystonic movements of the hands. Two of them show microcephaly. The p.Ala140Val mutation is recurrent, as it was already described in 4 families with X-linked mental retardation and in three sporadic male patients with intellectual disability. We further delineate the phenotype associated with the p.Ala140Val mutation, illustrating a variable expressivity even within a given family, and we compare our patients with previous reported cases in the literature.

  2. Constructional apraxia in frontotemporal dementia associated with the C9orf72 mutation: broadening the clinical and neuropsychological phenotype.

    Science.gov (United States)

    Floris, Gianluca; Borghero, Giuseppe; Cannas, Antonino; Di Stefano, Francesca; Ruiu, Elisa; Murru, Maria R; Corongiu, Daniela; Cuccu, Stefania; Tranquilli, Stefania; Sardu, Claudia; Marrosu, Maria G; Chiò, Adriano; Marrosu, Francesco

    2015-03-01

    In our study we analysed clinical and neuropsychological data in a cohort of 57 Sardinian patients with FTD (55 apparently unrelated and two belonging to the same family), who underwent genetic screening for the C9orf72 mutation. Eight out of 56 patients were found positive for the C9orf72 mutation representing 14% of the entire cohort and 31.6% of the familial cases (6/19). C9orf72 mutated patients differed from the other FTD cases of the cohort for a younger age of onset, higher frequency of familial history for FTD and higher prevalence of delusional psychotic symptoms and hallucinations. In the neuropsychological assessment, C9orf72 mutated patients differed from non-mutated for the high frequency of visuospatial dysfunction regarding constructional apraxia (p = 0.02). In conclusion, our study confirms that Sardinian FTD patients have peculiar genetic characteristics and that C9orf72 mutated patients have a distinctive clinical and neuropsychological profile that could help differentiate them from other FTD patients. In our cohort we found that constructional apraxia, rarely reported in FTD, can properly discriminate between C9orf72 mutated and non-mutated patients and contribute to broaden the neuropsychological profile in frontotemporal dementia associated with this mutation.

  3. PSEN1 and PRNP gene mutations: co-occurrence makes onset very early in a family with FTD phenotype.

    Science.gov (United States)

    Bernardi, Livia; Anfossi, Maria; Gallo, Maura; Geracitano, Silvana; Cola, Rosanna; Puccio, Gianfranco; Curcio, Sabrina A M; Frangipane, Francesca; Mirabelli, Maria; Clodomiro, Alessandra; Di Lorenzo, Raffaele; Smirne, Nicoletta; Maletta, Raffaele; Iapaolo, David; Bruni, Amalia C

    2011-01-01

    Prion protein (PRNP) gene mutations have recently been associated with clinical pictures resembling Frontotemporal dementia (FTD). We describe a novel seven extra-repeat insertional mutation in the PRNP gene in a family affected by early-onset autosomal dominant FTD previously reported as caused by a PSEN1 mutation in which there was inconsistency between clinical picture and genotype. Both mutations were pathogenic and showed a variable penetrance when present separately; when occurring together, the onset was very early, within the third decade of life. Genetic screening of the PRNP gene becomes of major importance in early onset autosomal dominant dementia.

  4. Missense and nonsense mutations in melanocortin 1 receptor (MC1R gene of different goat breeds: association with red and black coat colour phenotypes but with unexpected evidences

    Directory of Open Access Journals (Sweden)

    Davoli Roberta

    2009-08-01

    phenotypes. However, they are probably not the only factors. In particular, the surprising not complete association of the nonsense mutation (p.Q225X with red coat colour raises a few hypotheses on the determination of pheomelanic phenotypes in goats that should be further investigated.

  5. Molecular basis of the pleiotropic phenotype of mice carrying the hypervariable yellow (A{sup hvy}) mutation at the agouti locus

    Energy Technology Data Exchange (ETDEWEB)

    Argeson, A.C.; Nelson, K.K.; Siracusa, L.D. [Jefferson Cancer Center, Philadelphia, PA (United States)

    1996-02-01

    The murine agouti locus regulates a switch in pigment synthesis between eumelanin (black/brown pigment) and phaeomelanin (yellow/red pigment) by hair bulb melanocytes. We recently described a spontaneous mutation, hypervariable yellow (A{sup hvy}) and demonstrated that A{sup hvy} is responsible for the largest range of phenotypes yet identified at the agouti locus, producing mice that are obese with yellow coats to mice that are of normal weight with black coats. Here, we show that agouti expression is altered both temporally and spatially in A{sup hvy} mutants. Agouti expression levels are positively correlated with the degree of yellow pigmentation in individual A{sup hvy} mice, consistent with results from other dominant yellow agouti mutations. Sequencing of 5{prime} RACE and genomic PCR products revealed that A{sup hvy} resulted from the integration of an intracisternal A particle (IAP) in an antisense orientation within the 5{prime} untranslated agouti exon 1C. This retrovirus-like element is responsible for deregulating agouti expression in A{sup hvy} mice; agouti expression is correlated with the methylation state of CpG residues in the IAP long terminal repeat as well as in host genomic DNA. In addition, the data suggest that the variable phenotype of A{sup hvy} offspring is influenced in part by the phenotype of their A{sup hvy} female parent. 42 refs., 7 figs., 1 tab.

  6. Genetic and Epigenetic Tumor Suppressor Gene Silencing Are Distinct Molecular Phenotypes Driven by Growth Promoting Mutations in Nonsmall Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Carmen J. Marsit

    2008-01-01

    Full Text Available Both genetic and epigenetic alterations characterize human nonsmall cell lung cancer (NSCLC, but the biological processes that create or select these alterations remain incompletely investigated. Our hypothesis posits that a roughly reciprocal relationship between the propensity for promoter hypermethylation and a propensity for genetic deletion leads to distinct molecular phenotypes of lung cancer. To test this hypothesis, we examined promoter hypermethylation of 17 tumor suppressor genes, as a marker of epigenetic alteration propensity, and deletion events at the 3p21 region, as a marker of genetic alteration. To model the complex biology between these somatic alterations, we utilized an item response theory model. We demonstrated that tumors exhibiting LOH at greater than 30% of informative alleles in the 3p21 region have a significantly reduced propensity for hypermethylation. At the same time, tumors with activating KRAS mutations showed a significantly increased propensity for hypermethylation of the loci examined, a result similar to what has been observed in colon cancer. These data suggest that NSCLCs have distinct epigenetic or genetic alteration phenotypes acting upon tumor suppressor genes and that mutation of oncogenic growth promoting genes, such as KRAS, is associated with the epigenetic phenotype.

  7. Missense mutation of FUT1 and deletion of FUT2 are responsible for Indian Bombay phenotype of ABO blood group system.

    Science.gov (United States)

    Koda, Y; Soejima, M; Johnson, P H; Smart, E; Kimura, H

    1997-09-01

    The Bombay phenotype fails to express the ABH antigens of ABO blood group system on red blood cells and in secretions because of a lack in activities of the H gene (FUT1)- and Secretor gene (FUT2)-encoded alpha (1,2)fucosyltransferases. In this study, we have examined the FUT1 and the FUT2 from three unrelated Indian individuals with the Bombay phenotype. These three individuals were found to be homozygous for a T725G mutation in the coding region of the FUT1, which inactivated the enzyme activity. In addition, we did not detect any hybridized band corresponding to the FUT2 by Southern blot analysis using the catalytic domain of the FUT2 as a probe, indicating that the three individuals were homozygous for a gene deletion in the FUT2. These results suggest that the T725G mutation of FUT1 and the gene deletion of FUT2 are responsible for the classical Indian Bombay phenotype.

  8. SM2PH-db: an interactive system for the integrated analysis of phenotypic consequences of missense mutations in proteins involved in human genetic diseases.

    Science.gov (United States)

    Friedrich, Anne; Garnier, Nicolas; Gagnière, Nicolas; Nguyen, Hoan; Albou, Laurent-Philippe; Biancalana, Valérie; Bettler, Emmanuel; Deléage, Gilbert; Lecompte, Odile; Muller, Jean; Moras, Dino; Mandel, Jean-Louis; Toursel, Thierry; Moulinier, Luc; Poch, Olivier

    2010-02-01

    Understanding how genetic alterations affect gene products at the molecular level represents a first step in the elucidation of the complex relationships between genotypic and phenotypic variations, and is thus a major challenge in the postgenomic era. Here, we present SM2PH-db (http://decrypthon.igbmc.fr/sm2ph), a new database designed to investigate structural and functional impacts of missense mutations and their phenotypic effects in the context of human genetic diseases. A wealth of up-to-date interconnected information is provided for each of the 2,249 disease-related entry proteins (August 2009), including data retrieved from biological databases and data generated from a Sequence-Structure-Evolution Inference in Systems-based approach, such as multiple alignments, three-dimensional structural models, and multidimensional (physicochemical, functional, structural, and evolutionary) characterizations of mutations. SM2PH-db provides a robust infrastructure associated with interactive analysis tools supporting in-depth study and interpretation of the molecular consequences of mutations, with the more long-term goal of elucidating the chain of events leading from a molecular defect to its pathology. The entire content of SM2PH-db is regularly and automatically updated thanks to a computational grid data federation facilities provided in the context of the Decrypthon program.

  9. Genetic Inhibition of the Ubiquitin Ligase Rnf5 Attenuates Phenotypes Associated to F508del Cystic Fibrosis Mutation

    NARCIS (Netherlands)

    V. Tomati (Valeria); E. Sondo (Elvira); A. Armirotti (Andrea); E. Caci (Emanuela); E. Pesce (Emanuela); M. Marini (Monica); A. Gianotti (Ambra); Y. Ju Jeon (Young); M. Cilli (Michele); A. Pistorio (Angela); L. Mastracci (Luca); R. Ravazzolo (Roberto); B.J. Scholte (Bob); Z. Ronai (Ze'ev); L.J.V. Galietta (Luis J. V.); N. Pedemonte (Nicoletta)

    2015-01-01

    textabstractCystic fibrosis (CF) is caused by mutations in the CFTR chloride channel. Deletion of phenylalanine 508 (F508del), the most frequent CF mutation, impairs CFTR trafficking and gating. F508del-CFTR mistrafficking may be corrected by acting directly on mutant CFTR itself or by modulating ex

  10. Induction of a mutant phenotype in human repair proficient cells after overexpression of a mutated human DNA repair gene.

    NARCIS (Netherlands)

    P.B.G.M. Belt; M.F. van Oostenrijk; H. Odijk (Hanny); J.H.J. Hoeijmakers (Jan); C.M.P. Backendorf (Claude)

    1991-01-01

    textabstractAntisense and mutated cDNA of the human excision repair gene ERCC-1 were overexpressed in repair efficient HeLa cells by means of an Epstein-Barr-virus derived CDNA expression vector. Whereas antisense RNA did not influence the survival of the transfected cells, a mutated cDNA generating

  11. A nonsymbiotic root hair tip growth phenotype in NORK-mutated legumes: implications for nodulation factor-induced signaling and formation of a multifaceted root hair pocket for bacteria

    NARCIS (Netherlands)

    Esseling, J.J.; Lhuissier, F.G.P.; Emons, A.M.C.

    2004-01-01

    The Medicago truncatula Does not Make Infections (DMI2) mutant is mutated in the nodulation receptor-like kinase, NORK. Here, we report that NORK-mutated legumes of three species show an enhanced touch response to experimental handling, which results in a nonsymbiotic root hair phenotype. When care

  12. Wilson's disease in Southern Brazil: genotype-phenotype correlation and description of two novel mutations in ATP7B gene

    Directory of Open Access Journals (Sweden)

    Ricardo Schmitt de Bem

    2013-08-01

    Full Text Available OBJECTIVE: Wilson's disease (WD is an inborn error of metabolism caused by abnormalities of the copper-transporting protein encoding gene ATP7B. In this study, we examined ATP7B for mutations in a group of patients living in southern Brazil. METHODS: 36 WD subjects were studied and classified according to their clinical and epidemiological data. In 23 subjects the ATP7B gene was analyzed. RESULTS: Fourteen distinct mutations were detected in at least one of the alleles. The c.3207C>A substitution at exon 14 was the most common mutation (allelic frequency=37.1% followed by the c.3402delC at exon 15 (allelic frequency=11.4%. The mutations c.2018-2030del13 at exon 7 and c.4093InsT at exon 20 are being reported for the first time. CONCLUSION: The c.3207C>A substitution at exon 14, was the most common mutation, with an allelic frequency of 37.1%. This mutation is the most common mutation described in Europe.

  13. Observation of c.260A > G mutation in superoxide dismutase 1 that causes p.Asn86Ser in Iranian amyotrophic lateral sclerosis patient and absence of genotype/phenotype correlation

    Directory of Open Access Journals (Sweden)

    Marzieh Khani

    2015-10-01

    Full Text Available Background: Amyotrophic lateral sclerosis (ALS is the most common motor neuron disorder in European populations. ALS can be sporadic ALS (SALS or familial ALS (FALS. Among 20 known ALS genes, mutations in C9orf72 and superoxide dismutase 1 (SOD1 are the most common genetic causes of the disease. Whereas C9orf72 mutations are more common in Western populations, the contribution of SOD1 to ALS in Iran is more than C9orf72. At present, a clear genotype/phenotype correlation for ALS has not been identified. We aimed to perform mutation screening of SOD1 in a newly identified Iranian FALS patient and to assess whether a genotype/phenotype correlation for the identified mutation exists.Methods: The five exons of SOD1 and flanking intronic sequences of a FALS proband were screened for mutations by direct sequencing. The clinical features of the proband were assessed by a neuromuscular specialist (SN. The phenotypic presentations were compared to previously reported patients with the same mutation.Results: Heterozygous c.260A > G mutation in SOD1 that causes Asn86Ser was identified in the proband. Age at onset was 34 years and site of the first presentation was in the lower extremities. Comparisons of clinical features of different ALS patients with the same mutation evidenced variable presentations.Conclusion: The c.260A > G mutation in SOD1 that causes Asn86Ser appears to cause ALS with variable clinical presentations.

  14. Classical phenotype of Laron syndrome in a girl with a heterozygous mutation and heterozygous polymorphism of the growth hormone receptor gene.

    Science.gov (United States)

    Shevah, Orit; Galli-Tsinopoulou, Assimina; Rubinstein, Menachem; Nousia-Arvanitakis, Sanda; Laron, Zvi

    2004-03-01

    We describe here a 19 month-old girl with classical Laron syndrome (LS). Molecular analysis of the GH receptor gene in the patient and her parents was performed. The patient was found to be heterozygous for a mutation in exon 4 (R43X) and heterozygous for a polymorphism in exon 6 (Gly168Gly). Her mother was also heterozygous for R43X but homozygous for the polymorphism. In the father, a heterozygous polymorphism was found. Contrary to previous assumptions that only homozygous patients express the typical phenotype, this patient shows all the classical features of LS, despite being a heterozygote for a pathological defect.

  15. Identification of a New Lamin A/C Mutation in a Chinese Family Affected with Atrioventricular Block as the Prominent Phenotype

    Institute of Scientific and Technical Information of China (English)

    吴小艳; 王擎; 桂乐; 刘木根; 张贤钦; 金润铭; 李伟; 闫露; 杜戎; 王秋芬; 祝建芳; 杨钧国

    2010-01-01

    Even though mutations in LMNA have been reported in patients with typical dilated cardio-myopathy(DCM)and atrioventricular block(AVB)previously,the purpose of this study was to disclose this novel genetic abnormality in one Chinese family with the atypical phenotype of progressive AVB followed by DCM with normal QRS interval.Genome-wide linkage analysis mapped the AVB gene in this family to a marker at chromosome 1q21.2,where the LMNA gene was located.Direct DNA sequence analysis revealed a heterozygous G t...

  16. Transfection with extracellularly UV-damaged DNA induces human and rat cells to express a mutator phenotype towards parvovirus H-1

    Energy Technology Data Exchange (ETDEWEB)

    Dinsart, C.; Cornelis, J.J.; Klein, B.; van der Eb, A.J.; Rommelaere, J.

    1984-02-01

    Human and rat cells transfected with UV-irradiated linear double-stranded DNA from calf thymus displayed a mutator activity. This phenotype was identified by growing a lytic thermosensitive single-stranded DNA virus (parvovirus H-1) in those cells and determining viral reversion frequencies. Likewise, exogenous UV-irradiated closed circular DNAs, either double-stranded (simian virus 40) or single-stranded (phi X174), enhanced the ability of recipient cells to mutate parvovirus H-1. The magnitude of mutator activity expression increased along with the number of UV lesions present in the inoculated DNA up to a saturation level. Unirradiated DNA displayed little inducing capacity, irrespective of whether it was single or double stranded. Deprivation of a functional replication origin did not impede UV-irradiated simian virus 40 DNA from providing rat and human cells with a mutator function. Our data suggest that in mammalian cells a trans-acting mutagenic signal might be generated from UV-irradiated DNA without the necessity for damaged DNA to replicate.

  17. The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations

    Directory of Open Access Journals (Sweden)

    Valentina Citro

    2016-12-01

    Full Text Available Fabry disease is caused by mutations in the GLA gene and is characterized by a large genotypic and phenotypic spectrum. Missense mutations pose a special problem for graduating diagnosis and choosing a cost-effective therapy. Some mutants retain enzymatic activity, but are less stable than the wild type protein. These mutants can be stabilized by small molecules which are defined as pharmacological chaperones. The first chaperone to reach clinical trial is 1-deoxygalactonojirimycin, but others have been tested in vitro. Residual activity of GLA mutants has been measured in the presence or absence of pharmacological chaperones by several authors. Data obtained from transfected cells correlate with those obtained in cells derived from patients, regardless of whether 1-deoxygalactonojirimycin was present or not. The extent to which missense mutations respond to 1-deoxygalactonojirimycin is variable and a reference table of the results obtained by independent groups that is provided with this paper can facilitate the choice of eligible patients. A review of other pharmacological chaperones is provided as well. Frequent mutations can have residual activity as low as one-fourth of normal enzyme in vitro. The reference table with residual activity of the mutants facilitates the identification of non-pathological variants.

  18. The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations

    Science.gov (United States)

    Citro, Valentina; Cammisa, Marco; Liguori, Ludovica; Cimmaruta, Chiara; Lukas, Jan; Cubellis, Maria Vittoria; Andreotti, Giuseppina

    2016-01-01

    Fabry disease is caused by mutations in the GLA gene and is characterized by a large genotypic and phenotypic spectrum. Missense mutations pose a special problem for graduating diagnosis and choosing a cost-effective therapy. Some mutants retain enzymatic activity, but are less stable than the wild type protein. These mutants can be stabilized by small molecules which are defined as pharmacological chaperones. The first chaperone to reach clinical trial is 1-deoxygalactonojirimycin, but others have been tested in vitro. Residual activity of GLA mutants has been measured in the presence or absence of pharmacological chaperones by several authors. Data obtained from transfected cells correlate with those obtained in cells derived from patients, regardless of whether 1-deoxygalactonojirimycin was present or not. The extent to which missense mutations respond to 1-deoxygalactonojirimycin is variable and a reference table of the results obtained by independent groups that is provided with this paper can facilitate the choice of eligible patients. A review of other pharmacological chaperones is provided as well. Frequent mutations can have residual activity as low as one-fourth of normal enzyme in vitro. The reference table with residual activity of the mutants facilitates the identification of non-pathological variants. PMID:27916943

  19. A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome.

    Science.gov (United States)

    Kelly, A D; Kroeger, H; Yamazaki, J; Taby, R; Neumann, F; Yu, S; Lee, J T; Patel, B; Li, Y; He, R; Liang, S; Lu, Y; Cesaroni, M; Pierce, S A; Kornblau, S M; Bueso-Ramos, C E; Ravandi, F; Kantarjian, H M; Jelinek, J; Issa, J-Pj

    2017-01-31

    Genetic changes are infrequent in acute myeloid leukemia (AML) compared with other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation data revealed a CGI methylator phenotype independent of IDH1/2 mutations we term AML-CGI methylator phenotype (CIMP) (A-CIMP(+)). A-CIMP was associated with longer overall survival (OS) in this data set (median OS, years: A-CIMP(+)=not reached, CIMP(-)=1.17; P=0.08). For validation we used 194 samples from The Cancer Genome Atlas interrogated with Illumina 450k methylation arrays where we confirmed longer OS in A-CIMP (median OS, years: A-CIMP(+)=2.34, A-CIMP(-)=1.00; P=0.01). Hypermethylation in A-CIMP(+) favored CGIs (OR: CGI/non-CGI=5.21), and while A-CIMP(+) was enriched in CEBPA (P=0.002) and WT1 mutations (P=0.02), 70% of cases lacked either mutation. Hypermethylated genes in A-CIMP(+) function in pluripotency maintenance, and a gene expression signature of A-CIMP was associated with outcomes in multiple data sets. We conclude that CIMP in AML cannot be explained solely by gene mutations (for example, IDH1/2, TET2), and that curability in A-CIMP(+) AML should be validated prospectively.Leukemia advance online publication, 31 January 2017; doi:10.1038/leu.2017.12.

  20. Detection of mutations in the CYP21A2 gene: genotype-phenotype correlation in Slovenian couples with conceiving problems

    Directory of Open Access Journals (Sweden)

    Stangler Herodež Š

    2015-12-01

    Full Text Available The objective of this study was to compare the CYP 21A2 genetic profiles of couples with unexplained fertility problems (UFP with genetic profiles of healthy controls (HCs. Furthermore, we analyzed associations between mutations in the CYP21A2 gene and various clinical and laboratory parameters. Allele-specific polymerase chain reaction (PCR was used in 638 probands with UFP and 200 HCs. Statistic analysis with χ2 was used to study the association of mutations with infertility. The effect of mutations on particular clinical and laboratory parameters was assessed with the analysis of variance (ANOVA test. With regard to the CYP21A2 gene, 0.6% of probands with UFP and 0.5% of HCs were positive for the c.290-13A/C>G mutation; 0.6% of probands with UFP and 1.5% of HCs were positive for the p.I172N mutation; there were no probands with UFP positive for the p.P30L mutation, whereas 0.5% of HCs were; and 0.2% of probands with UFP and 0.5% of HCs were found to have the p.V281L mutation. We found a significant association between c.290-13A/C>G mutation and the frequency of significant hormone deviations (χ2 = 6.997, p = 0.008. Similar association was also observed between the c.29013A/C>G mutation and the frequency of polycystic ovary syndrome (PCOS (χ2 = 16.775, p = 0.000. Our findings indicate that no significant difference in the prevalence of CYP 21A2 mutations can be found in probands with UFP when compared with HCs without infertility history. The results also imply the significant association of the c.290-13A/ C>G mutation in the CYP21A2 gene, not only with the frequency of PCOS, but also with the frequency of significant hormone deviations.

  1. Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype–Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy

    OpenAIRE

    Böhm, Johann; Biancalana, Valérie; DeChene, Elizabeth T; Bitoun, Marc; Pierson, Christopher R.; Schaefer, Elise; Karasoy, Hatice; Dempsey, Melissa A.; Klein, Fabrice; Dondaine, Nicolas; Kretz, Christine; Haumesser, Nicolas; Poirson, Claire; Toussaint, Anne; Greenleaf, Rebecca S.

    2012-01-01

    Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad ge...

  2. Phenotype of Usher syndrome type Ⅱ assosiated with compound missense mutations of c.721 C>T and c.1969 C>T in MYO7A in a Chinese Usher syndrome family

    Institute of Scientific and Technical Information of China (English)

    Wei; Zhai; Xin; Jin; Yan; Gong; Ling-Hui; Qu; Chen; Zhao; Zhao-Hui; Li

    2015-01-01

    ·AIM: To identify the pathogenic mutations in a Chinese pedigree affected with Usher syndrome type II(USH2).· METHODS: The ophthalmic examinations and audiometric tests were performed to ascertain the phenotype of the family. To detect the genetic defect,exons of 103 known RDs-associated genes including 12 Usher syndrome(USH) genes of the proband were captured and sequencing analysis was performed to exclude known genetic defects and find potential pathogenic mutations. Subsequently, candidate mutations were validated in his pedigree and 100 normal controls using polymerase chain reaction(PCR) and Sanger sequencing.·RESULTS: The patient in the family occurred hearing loss(HL) and retinitis pigmentosa(RP) without vestibular dysfunction, which were consistent with standards of classification for USH2. He carried the compound heterozygous mutations, c.721 C >T and c.1969 C >T, in the MYO7 A gene and the unaffected members carried only one of the two mutations. The mutations were not present in the 100 normal controls.· CONCLUSION: We suggested that the compound heterozygous mutations of the MYO7 A could lead to USH2, which had revealed distinguished clinical phenotypes associated with MYO7 A and expanded the spectrum of clinical phenotypes of the MYO7 A mutations.

  3. Delineation of the KIAA2022 mutation phenotype: two patients with X-linked intellectual disability and distinctive features.

    Science.gov (United States)

    Kuroda, Yukiko; Ohashi, Ikuko; Naruto, Takuya; Ida, Kazumi; Enomoto, Yumi; Saito, Toshiyuki; Nagai, Jun-Ichi; Wada, Takahito; Kurosawa, Kenji

    2015-06-01

    Next-generation sequencing has enabled the screening for a causative mutation in X-linked intellectual disability (XLID). We identified KIAA2022 mutations in two unrelated male patients by targeted sequencing. We selected 13 Japanese male patients with severe intellectual disability (ID), including four sibling patients and nine sporadic patients. Two of thirteen had a KIAA2022 mutation. Patient 1 was a 3-year-old boy. He had severe ID with autistic behavior and hypotonia. Patient 2 was a 5-year-old boy. He also had severe ID with autistic behavior, hypotonia, central hypothyroidism, and steroid-dependent nephrotic syndrome. Both patients revealed consistent distinctive features, including upswept hair, narrow forehead, downslanting eyebrows, wide palpebral fissures, long nose, hypoplastic alae nasi, open mouth, and large ears. De novo KIAA2022 mutations (p.Q705X in Patient 1, p.R322X in Patient 2) were detected by targeted sequencing and confirmed by Sanger sequencing. KIAA2022 mutations and alterations have been reported in only four families with nonsyndromic ID and epilepsy. KIAA2022 is highly expressed in the fetal and adult brain and plays a crucial role in neuronal development. These additional patients support the evidence that KIAA2022 is a causative gene for XLID.

  4. Mitochondrial variants may influence the phenotypic manifestation of Leber's hereditary optic neuropathy-associated ND4 G11778A mutation

    Institute of Scientific and Technical Information of China (English)

    Wanshi Cai; Qun Fu; Xiangtian Zhou; Jia Qu; Yi Tong; Min-Xin Guan

    2008-01-01

    We report here the characterization of a five-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON). Strik-ingly, this Chinese family displayed high penetrance and expressivity of visual loss. The average age-of-onset of vision loss was 18 years in this family. Nineteen (11 males/8 females) of 29 matrilineal relatives in this family developed visual loss with a wide range of severity,ranging from blindness to normal vision. Sequence analysis of mitochondrial genome in this pedigree revealed the presence of the ND4 G11778A mutation and 44 other variants belonging to Asian haplogroup M7b. The G11778A mutation is present at homoplasmy in matri-lineal relatives of this Chinese family. Of other variants, the CO1 G6480A, ND5 T12811C and Cytb A15395G located at highly conserved residues of corresponding polypeptides. In fact, these variants were implicated to be involved in other clinical abnormalities. Here, these variants may act in synergy with the primary LHON-associated Gl1778A mutation. Thus, the mitochondrial dysfunction caused by the primary ND4 G11778A mutation may be worsened by these mitochondrial variants. The results imply that the G6480A, T12811C and A15395G variants might have a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in this Chinese family.

  5. Somatic-cell selection is a major determinant of the blood-cell phenotype in heterozygotes for glucose-6-phosphate dehydrogenase mutations causing severe enzyme deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Filosa, S.; Giacometti, N.; Wangwei, C.; Martini, G. [Istituto Internazionale di Genetica e Biofisica, Naples (Italy)] [and others

    1996-10-01

    X-chromosome inactivation in mammals is regarded as an essentially random process, but the resulting somatic-cell mosaicism creates the opportunity for cell selection. In most people with red-blood-cell glucose-6-phosphate dehydrogenase (G6PD) deficiency, the enzyme-deficient phenotype is only moderately expressed in nucleated cells. However, in a small subset of hemizygous males who suffer from chronic nonspherocytic hemolytic anemia, the underlying mutations (designated class I) cause more-severe G6PD deficiency, and this might provide an opportunity for selection in heterozygous females during development. In order to test this possibility we have analyzed four heterozygotes for class I G6PD mutations: two with G6PD Portici (1178G{r_arrow}A) and two with G6PD Bari (1187C{r_arrow}T). We found that in fractionated blood cell types (including erythroid, myeloid, and lymphoid cell lineages) there was a significant excess of G6PD-normal cells. The significant concordance that we have observed in the degree of imbalance in the different blood-cell lineages indicates that a selective mechanism is likely to operate at the level of pluripotent blood stem cells. Thus, it appears that severe G6PD deficiency affects adversely the proliferation or the survival of nucleated blood cells and that this phenotypic characteristic is critical during hematopoiesis. 65 refs., 6 figs., 3 tabs.

  6. Novel homozygous mutation in DSP causing skin fragility-woolly hair syndrome: report of a large family and review of the desmoplakin-related phenotypes.

    Science.gov (United States)

    Al-Owain, M; Wakil, S; Shareef, F; Al-Fatani, A; Hamadah, E; Haider, M; Al-Hindi, H; Awaji, A; Khalifa, O; Baz, B; Ramadhan, R; Meyer, B

    2011-07-01

    Desmoplakin is an important cytoskeletal linker for the function of the desmosomes. Linking desmoplakin to certain types of cardiocutaneous syndromes has been a hot topic recently. Skin fragility-woolly hair syndrome is a rare autosomal recessive disorder involving the desmosomes and is caused by mutation in the desmoplakin gene (DSP). We report five members from a large family with skin fragility-woolly hair syndrome. The index is a 14-year-old girl with palmoplantar keratoderma, woolly hair, variable alopecia, dystrophic nails, and excessive blistering to trivial mechanical trauma. No cardiac symptoms were reported. Although formal cardiac examination was not feasible, the echocardiographic evaluation of the other two affected younger siblings was normal. Homozygosity mapping and linkage analysis revealed a high LOD score region in the short arm of chromosome 6 that harbors the DSP. Full sequencing of the DSP showed a novel homozygous c.7097 G>A (p.R2366H) mutation in all affected members, and the parents were heterozygous. This is the report of the third case/family of the skin fragility-woolly hair syndrome in the literature. We also present a clinical and molecular review of various desmoplakin-related phenotypes, with emphasis on onset of cardiomyopathy. The complexity of the desmoplakin and its variable presentations warrant introducing the term 'desmoplakinopathies' to describe all the phenotypes related to defects in the desmoplakin.

  7. Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke.

    Science.gov (United States)

    Murray, Lydia S; Lu, Yinhui; Taggart, Aislynn; Van Regemorter, Nicole; Vilain, Catheline; Abramowicz, Marc; Kadler, Karl E; Van Agtmael, Tom

    2014-01-15

    Haemorrhagic stroke accounts for ∼20% of stroke cases and porencephaly is a clinical consequence of perinatal cerebral haemorrhaging. Here, we report the identification of a novel dominant G702D mutation in the collagen domain of COL4A2 (collagen IV alpha chain 2) in a family displaying porencephaly with reduced penetrance. COL4A2 is the obligatory protein partner of COL4A1 but in contrast to most COL4A1 mutations, the COL4A2 mutation does not lead to eye or kidney disease. Analysis of dermal biopsies from a patient and his unaffected father, who also carries the mutation, revealed that both display basement membrane (BM) defects. Intriguingly, defective collagen IV incorporation into the dermal BM was observed in the patient only and was associated with endoplasmic reticulum (ER) retention of COL4A2 in primary dermal fibroblasts. This intracellular accumulation led to ER stress, unfolded protein response activation, reduced cell proliferation and increased apoptosis. Interestingly, the absence of ER retention of COL4A2 and ER stress in cells from the unaffected father indicate that accumulation and/or clearance of mutant COL4A2 from the ER may be a critical modifier for disease development. Our analysis also revealed that mutant collagen IV is degraded via the proteasome. Importantly, treatment of patient cells with a chemical chaperone decreased intracellular COL4A2 levels, ER stress and apoptosis, demonstrating that reducing intracellular collagen accumulation can ameliorate the cellular phenotype of COL4A2 mutations. Importantly, these data highlight that manipulation of chaperone levels, intracellular collagen accumulation and ER stress are potential therapeutic options for collagen IV diseases including haemorrhagic stroke.

  8. Brain calcification process and phenotypes according to age and sex: Lessons from SLC20A2, PDGFB, and PDGFRB mutation carriers.

    Science.gov (United States)

    Nicolas, Gaël; Charbonnier, Camille; de Lemos, Roberta Rodrigues; Richard, Anne-Claire; Guillin, Olivier; Wallon, David; Legati, Andrea; Geschwind, Daniel; Coppola, Giovanni; Frebourg, Thierry; Campion, Dominique; de Oliveira, João Ricardo Mendes; Hannequin, Didier

    2015-10-01

    Primary Familial Brain Calcification (PFBC) is a dominantly inherited cerebral microvascular calcifying disorder with diverse neuropsychiatric expression. Three causative genes have been identified: SLC20A2, PDGFRB and, recently, PDGFB, whose associated phenotype has not yet been extensively studied. We included in the largest published case series of genetically confirmed PFBC, 19 PDGFB (including three new mutations), 24 SLC20A2 (including 4 new mutations), and 14 PDGFRB mutation carriers, from two countries (France and Brazil). We studied clinical features and applied our visual rating scale on all 49 available CT scans. Among the symptomatic mutation carriers (33/57, 58%), the three most frequently observed categories of clinical features were psychiatric signs (72.7%, 76.5%, and 80% for PDGFB, SLC20A2, and PDGFRB, respectively), movement disorders (45.5%, 76.5%, and 40%), and cognitive impairment (54.6%, 64.7%, and 40%). The median age of clinical onset was 31 years, 25% had an early onset (before 18) and 25% a later onset (after 53). Patients with an early clinical onset exhibited mostly isolated psychiatric or cognitive signs, while patients with a later onset exhibited mostly movement disorders, especially in association with other clinical features. CT scans rating allowed identifying four patterns of calcification. The total calcification score was best predicted by the combined effects of gene (SLC20A2 > PDGFB > PDGFRB mutations), sex (male), and (increasing) age, defining three risk classes, which correlated with the four patterns of calcification. These calcification patterns could reflect the natural history of the calcifying process, with distinct risk classes characterized by different age at onset or rate of progression.

  9. Characterization of Human Disease Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1

    Science.gov (United States)

    Crow, Yanick J.; Chase, Diana S.; Schmidt, Johanna Lowenstein; Szynkiewicz, Marcin; Forte, Gabriella M.A.; Gornall, Hannah L.; Oojageer, Anthony; Anderson, Beverley; Pizzino, Amy; Helman, Guy; Abdel-Hamid, Mohamed S.; Abdel-Salam, Ghada M.; Ackroyd, Sam; Aeby, Alec; Agosta, Guillermo; Albin, Catherine; Allon-Shalev, Stavit; Arellano, Montse; Ariaudo, Giada; Aswani, Vijay; Babul-Hirji, Riyana; Baildam, Eileen M.; Bahi-Buisson, Nadia; Bailey, Kathryn M.; Barnerias, Christine; Barth, Magalie; Battini, Roberta; Beresford, Michael W.; Bernard, Geneviève; Bianchi, Marika; de Villemeur, Thierry Billette; Blair, Edward M.; Bloom, Miriam; Burlina, Alberto B.; Carpanelli, Maria Luisa; Carvalho, Daniel R.; Castro-Gago, Manuel; Cavallini, Anna; Cereda, Cristina; Chandler, Kate E.; Chitayat, David A.; Collins, Abigail E.; Corcoles, Concepcion Sierra; Cordeiro, Nuno J.V.; Crichiutti, Giovanni; Dabydeen, Lyvia; Dale, Russell C.; D’Arrigo, Stefano; De Goede, Christian G.E.L.; De Laet, Corinne; De Waele, Liesbeth M.H.; Denzler, Ines; Desguerre, Isabelle; Devriendt, Koenraad; Di Rocco, Maja; Fahey, Michael C.; Fazzi, Elisa; Ferrie, Colin D.; Figueiredo, António; Gener, Blanca; Goizet, Cyril; Gowrinathan, Nirmala R.; Gowrishankar, Kalpana; Hanrahan, Donncha; Isidor, Bertrand; Kara, Bülent; Khan, Nasaim; King, Mary D.; Kirk, Edwin P.; Kumar, Ram; Lagae, Lieven; Landrieu, Pierre; Lauffer, Heinz; Laugel, Vincent; La Piana, Roberta; Lim, Ming J.; Lin, Jean-Pierre S.-M.; Linnankivi, Tarja; Mackay, Mark T.; Marom, Daphna R.; Lourenço, Charles Marques; McKee, Shane A.; Moroni, Isabella; Morton, Jenny E.V.; Moutard, Marie-Laure; Murray, Kevin; Nabbout, Rima; Nampoothiri, Sheela; Nunez-Enamorado, Noemi; Oades, Patrick J.; Olivieri, Ivana; Ostergaard, John R.; Pérez-Dueñas, Belén; Prendiville, Julie S.; Ramesh, Venkateswaran; Rasmussen, Magnhild; Régal, Luc; Ricci, Federica; Rio, Marlène; Rodriguez, Diana; Roubertie, Agathe; Salvatici, Elisabetta; Segers, Karin A.; Sinha, Gyanranjan P.; Soler, Doriette; Spiegel, Ronen; Stödberg, Tommy I.; Straussberg, Rachel; Swoboda, Kathryn J.; Suri, Mohnish; Tacke, Uta; Tan, Tiong Y.; Naude, Johann te Water; Teik, Keng Wee; Thomas, Maya Mary; Till, Marianne; Tonduti, Davide; Valente, Enza Maria; Van Coster, Rudy Noel; van der Knaap, Marjo S.; Vassallo, Grace; Vijzelaar, Raymon; Vogt, Julie; Wallace, Geoffrey B.; Wassmer, Evangeline; Webb, Hannah J.; Whitehouse, William P.; Whitney, Robyn N.; Zaki, Maha S.; Zuberi, Sameer M.; Livingston, John H.; Rozenberg, Flore; Lebon, Pierre; Vanderver, Adeline; Orcesi, Simona; Rice, Gillian I.

    2015-01-01

    Aicardi–Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi–Goutières syndrome

  10. Compound Heterozygous SCN5A Mutations in a Toddler - Are they Associated with a More Severe Phenotype?

    Science.gov (United States)

    Sacilotto, Luciana; Epifanio, Hindalis Ballesteros; Darrieux, Francisco Carlos da Costa; Wulkan, Fanny; Oliveira, Theo Gremen Mimary; Hachul, Denise Tessariol; Pereira, Alexandre da Costa; Scanavacca, Mauricio Ibrahim

    2017-01-01

    Compound heterozygosity has been described in inherited arrhythmias, and usually associated with a more severe phenotype. Reports of this occurrence in Brugada syndrome patients are still rare. We report a study of genotype-phenotype correlation after the identification of new variants by genetic testing. We describe the case of an affected child with a combination of two different likely pathogenic SCN5A variants, presenting sinus node dysfunction, flutter and atrial fibrillation, prolonged HV interval, spontaneous type 1 Brugada pattern in the prepubescent age and familiar history of sudden death. PMID:28146213

  11. Evaluation of von Willebrand factor phenotypes and genotypes in Hemophilia A patients with and without identified F8 mutations

    Science.gov (United States)

    Boylan, Brian; Rice, Anne S.; De Staercke, Christine; Eyster, M. Elaine; Yaish, Hassan M.; Knoll, Christine M.; Bean, Christopher J.; Miller, Connie H.

    2015-01-01

    Summary Background Hemophilia A (HA) is an X-linked bleeding disorder caused by a deficiency in factor VIII (FVIII). von Willebrand disease (VWD) is characterized by a quantitative or qualitative defect in von Willebrand Factor (VWF). Patients with VWD with severely low VWF or VWD Type 2N (VWD2N), a VWD subtype distinguished by defective VWF binding to FVIII, may have reduced FVIII levels secondary to their VWD. These patients superficially resemble patients with HA, and pose a potential for misdiagnosis. Objectives Investigate the unexplained cause of bleeding in HA patients without known FVIII mutations by assessing plasma VWF antigen (VWF:Ag), FVIII binding capacities, and VWF genotypes. Patients/Methods Thirty-seven of 1027 patients with HA studied as part of the Hemophilia Inhibitor Research Study lacked identifiable F8 mutations. These patients (cases) and 73 patients with identified F8 mutations (controls) were evaluated for VWF:Ag, patient's VWF capacity to bind FVIII (VWF:FVIIIB), and VWF sequence. Results Four cases had VWF:Ag <3 IU/dL and VWF mutations consistent with Type3 VWD. Six cases and one control were heterozygous for mutations previously reported to cause Type1 VWD (VWD1) (n=5 cases and 1 control) or predicted to be deleterious by Polyphen2 and SIFT prediction tools (n=1 case). One control had VWF:Ag <30 IU/dl, and seven patients (4 cases and 3 controls), including two cases who were heterozygous for a known VWD2N mutation, had reduced VWF:FVIIIB. Conclusions These data emphasize that some patients diagnosed with HA require VWF assessments in order to achieve a comprehensive diagnosis and an optimal treatment strategy. PMID:25780857

  12. Interaction of nucleus and plastome in sunflower. III. Suppression of phenotypic expression of plastid mutation by alien nucleus

    Energy Technology Data Exchange (ETDEWEB)

    Beletskii, Yu.D.; Razoriteleva, E.K.

    1988-11-01

    Four plastome mutations of type chlorina were crossed as female parents with variety Mayak. It was demonstrated that a three-phases hybridization led to the loss of chlorophyll defect in F/sub 1/. The suppression of plastic mutation is controlled by a single dominant gene. Four viable plastid mutants were used in the study-en: chlorina-1 (1-24), en:chlorina-3 (1-138), en:chlorina-5 (2-25), and en:chlorina-7 (2-43).

  13. Immunohistochemical expression of mismatch repair genes: A screening tool for predicting mutator phenotype in liver fluke infection-associated intrahepatic cholangiocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Upama Liengswangwong; Anant Karalak; Yukio Morishita; Masayuki Noguchi; Thiravud Khuhaprema; Petcharin Srivatanakul; Masanao Miwa

    2006-01-01

    AIM: To clarify possible contributions of DNA mismatch repair (MMR) system in carcinogenesis of liver fluke infection-associated intrahepatic cholangiocarcinoma (ICC) by using immunohistochemical assay.METHODS: A total of 29 ICC samples, which had been assessed for genomic instability by a PCR-based method, were used for study. They were examined immunohistochemically to demonstrate protein expression of two MMR genes, hMSH2 and hMLH1.Results obtained were compared with their mutator phenotype assessed previously.RESULTS: Either hMSH2or hMLH1 protein was obviously expressed in 28 of 29 (96.6%) ICC samples.Positive nuclear localization of hMSH2 or hMLH1 protein was observed in 86.2% (25/29) or 93.1% (27/29) ICC cases, respectively, while their negative nuclear reactivity was only detected in 13.8% (4/29) or 6.9% (2/29) ICC cases analyzed, respectively.CONCLUSION: Our study, probably for the first time,showed through immunohistochemical detection of hMSH2 and hMLH1 gene that DNA MMR system does not play a prominent role in liver fluke infection-associated cholangiocarcinogenesis. These results confirm previous findings on mutational status of these genes assessed through a PCR-based method. The immunohistochemical analysis has proven to be an effective and sensitive approach for screening MMR deficiency regardless of somatic inactivation or promoter hypermethylation of hMSH2 and/or hMLH1 gene. Furthermore,immunohistochemistry is more advantageous compared to mutator phenotyping assay in terms of simplicity,less time consuming and cost effectiveness for screening possible involvements of target MMR genes in tumorigenesis.

  14. A Novel Nonsense Mutation in CEP290 Induces Exon Skipping and Leads to a Relatively Mild Retinal Phenotype

    NARCIS (Netherlands)

    Littink, Karin W.; Pott, Jan-Willem R.; Collin, Rob W. J.; Kroes, Hester Y.; Verheij, Joke B. G. M.; Blokland, Ellen A. W.; Miro, Marta de Castro; Hoyng, Carel B.; Klaver, Caroline C. W.; Koenekoop, Robert K.; Rohrschneider, Klaus; Cremers, Frans P. M.; van den Born, L. Ingeborgh; den Hollander, Anneke I.

    2010-01-01

    PURPOSE. To identify the genetic defect in a family with variable retinal phenotypes. The proband had a diagnosis of Leber congenital amaurosis (LCA), whereas her two cousins had an early-onset severe retinal dystrophy (EOSRD) with useful vision. A distant family member had retinitis pigmentosa (RP)

  15. Phenotype diversity in familial cylindromatosis: a frameshift mutation in the tumor suppressor gene CYLD underlies different tumors of skin appendages.

    Science.gov (United States)

    Poblete Gutiérrez, Pamela; Eggermann, Thomas; Höller, Daniela; Jugert, Frank K; Beermann, Torsten; Grussendorf-Conen, Elke-Ingrid; Zerres, Klaus; Merk, Hans F; Frank, Jorge

    2002-08-01

    Familial cylindromatosis (turban tumor syndrome; Brooke-Spiegler syndrome) (OMIM numbers 123850, 132700, 313100, and 605041) is a rare autosomal dominantly inherited tumor syndrome. The disorder can present with cutaneous adnexal tumors such as cylindromas, trichoepitheliomas, and spiradenomas, and tumors preferably develop in hairy areas of the body such as head and neck. In affected families, mutations have been demonstrated in the CYLD gene located on chromosome 16q12-13 and reveal the characteristic attributes of a tumor suppressor. Here, we studied familial cylindromatosis in a multigeneration family of German origin. Clinically, some individuals only revealed discrete small skin-colored tumors localized in the nasolabial region whereas one family member showed expansion of multiple big tumors on the trunk and in a turban-like fashion on the scalp. Histologically, cylindromas as well as epithelioma adenoides cysticum were found. We detected a frameshift mutation in the CYLD gene, designated 2253delG, underlying the disorder and were able to show that a single mutation can result in distinct clinical and histologic expression in familial cylindromatosis. The reasons for different expression patterns of the same genetic defect in this disease remain elusive, however. Identification of mutations in the CYLD gene enable us to rapidly confirm putative diagnoses on the genetic level and to provide affected families with genetic counseling.

  16. EHLERS-DANLOS SYNDROME TYPE-IV - PHENOTYPIC CONSEQUENCES OF A SPLICING MUTATION IN ONE COL3A1 ALLELE

    NARCIS (Netherlands)

    SILLENCE, DO; CHIODO, AA; CAMPBELL, PE; COLE, WG

    1991-01-01

    The features of a child with Ehlers-Danlos syndrome type IV (EDS IV) resulting from a mutation in one COL3A1 allele were studied. The child was heterozygous for a G- to A-transition at the splice donor site of intron 41. It resulted in the splicing out of the exon 41 encoded sequence from alpha-1(II

  17. Genotype phenotype correlations of cardiac beta-myosin heavy chain mutations in Indian patients with hypertrophic and dilated cardiomyopathy

    DEFF Research Database (Denmark)

    Rai, Taranjit Singh; Ahmad, Shamim; Bahl, Ajay;

    2009-01-01

    consecutive patients diagnosed with HCM or DCM (69 with HCM and 61 with DCM) attending the cardiology clinic of Post Graduate Institute of Medical Education and Research were screened for mutations in the MYH7 gene. The control group for genetic studies consisted of 100 healthy subjects. We report 14...

  18. Ten novel FBN2 mutations in congenital contractural arachnodactyly : Delineation of the molecular pathogenesis and clinical phenotype

    NARCIS (Netherlands)

    Gupta, PA; Putnam, EA; Carmical, SG; Kaitila, [No Value; Steinmann, B; Child, A; Danesino, C; Metcalfe, K; Berry, SA; Chen, E; Delorme, CV; Thong, MK; Ades, LC; Milewicz, DM

    2002-01-01

    Congenital contractural arachnodactyly (CCA) is an autosomal dominant condition that shares skeletal features with Marfan syndrome (MFS), but does not have the ocular and cardiovascular complications that characterize MFS. CCA and MFS result from mutations in highly similar genes, FBN2 and FBN1, res

  19. The phenotype of Floating-Harbor syndrome: Clinical characterization of 52 individuals with mutations in exon 34 of SRCAP

    NARCIS (Netherlands)

    S.M. Nikkel (Sarah); A. Dauber (Andrew); S. de Munnik (Sonja); M. Connolly (Meghan); R.L. Hood (Rebecca L); O. Caluseriu (Oana); J.A. Hurst (Jane); U. Kini (Usha); M.J.M. Nowaczyk; A. Afenjar (Alexandra); B. Albrecht; J.E. Allanson (Judith E); P. Balestri (Paolo); T. Ben-Omran (Tawfeg); F. Brancati (Fred); I. Cordeiro (Isabel); B.S. Da Cunha (Bruna Santos); P.F. Delaney (Peter); A. Destrée (Anne); D.R. Fitzpatrick (David); F. Forzano (Francesca); N. Ghali (Neeti); G. Gillies (Greta); J. Harwood; Y. Hendriks; D. Héron (Delphine); A. Hoischen (Alex); E.M. Honey (Engela Magdalena); E.H. Hoefsloot (Lies); J. Ibrahim (Jennifer); C. Jacob (Claire); S.G. Kant (Sarina); C.A. Kim (Chong); E.P. Kirk (Edwin P); N.V.A.M. Knoers (Nine); D. Lacombe (Denis); C. van der Lee (Christiaan); I.F.M. Lo (Ivan F M); L.S. Lucas (Luiza S); F. Mari (Francesca); V. Mericq (Veronica); J.S. Moilanen (Jukka S); S.T. Møller (Sanne Traasdahl); S. Moortgat (Stephanie); D.T. Pilz (Daniela); K. Pope (Kate); S. Price (Susan); A. Renieri (Alessandra); J. Sá (Joaquim); J. Schoots (Jeroen); E.L. Silveira (Elizabeth L); M.E.H. Simon (Marleen); A. Slavotinek (Anne); I.K. Temple; I. van der Burgt (Ineke); B.B.A. de Vries (Bert); J.D. Weisfeld-Adams (James D); M.L. Whiteford (Margo L); D. Wierczorek (Dagmar); J.M. Wit (Jan); C.F.O. Yee (Connie Fung On); P. Beaulieu (Patrick); S.M. White (Sue M); B. Bulman; E. Bongers (Ernie); H. Brunner (Han); M. Feingold (Murray); K.M. Boycott (Kym)

    2013-01-01

    textabstractBackground: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA ba

  20. De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes

    NARCIS (Netherlands)

    Gil-Rodriguez, M.C.; Deardorff, M.A.; Ansari, M.; Tan, C.A.; Parenti, I.; Baquero-Montoya, C.; Ousager, L.B.; Puisac, B.; Hernandez-Marcos, M.; Teresa-Rodrigo, M.E.; Marcos-Alcalde, I.; Wesselink, J.J.; Lusa-Bernal, S.; Bijlsma, E.K.; Braunholz, D.; Bueno-Martinez, I.; Clark, D.; Cooper, N.S.; Curry, C.J.; Fisher, R.; Fryer, A.; Ganesh, J.; Gervasini, C.; Gillessen-Kaesbach, G.; Guo, Y.; Hakonarson, H.; Hopkin, R.J.; Kaur, M.; Keating, B.J.; Kibaek, M.; Kinning, E.; Kleefstra, T.; Kline, A.D.; Kuchinskaya, E.; Larizza, L.; Li, Y.R.; Liu, X.; Mariani, M.; Picker, J.D.; Pie, A.; Pozojevic, J.; Queralt, E.; Richer, J.; Roeder, E.; Sinha, A.; Scott, R.H.; So, J.; Wusik, K.A.; Wilson, L.; Zhang, Jianguo; Gomez-Puertas, P.; Casale, C.H.; Strom, L.; Selicorni, A.; Ramos, F.J.; Jackson, L.G.; Krantz, I.D.; Das, S.; Hennekam, R.C.; Kaiser, F.J.; FitzPatrick, D.R.; Pie, J.

    2015-01-01

    Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for

  1. De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes

    DEFF Research Database (Denmark)

    Gil-Rodríguez, María Concepción; Deardorff, Matthew A; Ansari, Morad

    2015-01-01

    Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account ...

  2. Relative Contribution of Mutations in Genes for Autosomal Dominant Distal Hereditary Motor Neuropathies: A Genotype-Phenotype Correlation Study

    Science.gov (United States)

    Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, An; De Vriendt, Els; Deconinck, Tine; Merlini, Luciano; Van den Bergh, Peter; Rasic, Vedrana Milic; Robberecht, Wim; Fischer, Dirk; Morales, Raul Juntas; Mitrovic, Zoran; Seeman, Pavel; Mazanec, Radim; Kochanski, Andrzej; Jordanova, Albena; Auer-Grumbach, Michaela; Helderman-van den Enden, A. T. J. M.; Wokke, John H. J.; Nelis, Eva; De Jonghe, Peter; Timmerman, Vincent

    2008-01-01

    Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; "glycyl-tRNA synthetase (GARS)," "dynactin 1 (DCTN1)," "small heat shock 27 kDa protein 1 (HSPB1),"…

  3. The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families

    DEFF Research Database (Denmark)

    Grocock, Christopher J; Rebours, Vinciane; Delhaye, Myriam

    2010-01-01

    Pancreatic Cancer or via a collaborator. DNA samples were tested for mutations in PRSS1, SPINK1, CFTR and CTRC. PATIENTS: Participants were recruited on the basis of either family history of pancreatitis (acute or chronic), or the results of genetic testing. Families were categorised as having Hereditary...

  4. Mutation p.R156H of KRT10 responsible for severe phenotype of epidermolytic ichthyosis in a Chinese family

    Directory of Open Access Journals (Sweden)

    Li Z

    2014-09-01

    Full Text Available Zhiliang Li,1,* Qiao Liu,2,* Aimin Wang,2 Hongsheng Wang,1 Chengrang Li1 1Department of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, People's Republic of China; 2Hainan Provincial Hospital of Skin Disease, Hainan, People's Republic of China  *These authors contributed equally to this workEpidermolytic ichthyosis is a rare genetic disorder characterized by diffuse erythroderma from the time of birth with subsequent appearance of thick, brown scales and occasional blister formation. Mutation has been found in keratin 1 (K1 and keratin 10 (K10 genes.1 Epidermolytic hyperkeratosis (EHK is mostly inherited in a dominant mode. We report a Chinese family of EHK sufferers and their mutation findings. 

  5. A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype.

    OpenAIRE

    Gianluca Occhi; Daniela Regazzo; Giampaolo Trivellin; Francesca Boaretto; Denis Ciato; Sara Bobisse; Sergio Ferasin; Filomena Cetani; Elena Pardi; Márta Korbonits; Pellegata, Natalia S.; Viktoryia Sidarovich; Alessandro Quattrone; Giuseppe Opocher; Franco Mantero

    2013-01-01

    The CDKN1B gene encodes the cyclin-dependent kinase inhibitor p27(KIP1), an atypical tumor suppressor playing a key role in cell cycle regulation, cell proliferation, and differentiation. Impaired p27(KIP1) expression and/or localization are often observed in tumor cells, further confirming its central role in regulating the cell cycle. Recently, germline mutations in CDKN1B have been associated with the inherited multiple endocrine neoplasia syndrome type 4, an autosomal dominant syndrome ch...

  6. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.

    Science.gov (United States)

    Fertleman, Caroline R; Baker, Mark D; Parker, Keith A; Moffatt, Sarah; Elmslie, Frances V; Abrahamsen, Bjarke; Ostman, Johan; Klugbauer, Norbert; Wood, John N; Gardiner, R Mark; Rees, Michele

    2006-12-07

    Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, or OMIM 167400), is an inherited condition characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. A genome-wide linkage search followed by mutational analysis of the candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense mutations in 11 families and 2 sporadic cases. Functional analysis in vitro of three of these mutant Na(v)1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. Other mutations in SCN9A associated with more negative activation thresholds are known to cause primary erythermalgia (PE). Carbamazepine, a drug that is effective in PEPD, but not PE, showed selective block of persistent current associated with PEPD mutants, but did not affect the negative activation threshold of a PE mutant. PEPD and PE are allelic variants with distinct underlying biophysical mechanisms and represent a separate class of peripheral neuronal sodium channelopathy.

  7. Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype.

    Directory of Open Access Journals (Sweden)

    Isabelle Perrault

    Full Text Available Leber congenital amaurosis (LCA is the earliest and most severe retinal degeneration (RD, and the most common cause of incurable blindness diagnosed in children. It is occasionally the presenting symptom of multisystemic ciliopathies which diagnosis will require a specific care of patients. Nineteen LCA genes are currently identified and three of them account for both non-syndromic and syndromic forms of the disease. RD3 (LCA12 was implicated as a LCA gene based on the identification of homozygous truncating mutations in two LCA families despite the screening of large cohorts of patients. Here we provide a comprehensive survey of RD3 mutations and of their clinical expression through the screening of a cohort of 852 patients originating worldwide affected with LCA or early-onset and severe RD. We identified three RD3 mutations in seven unrelated consanguineous LCA families - i.e., a 2 bp deletion and two nonsense mutations - predicted to cause complete loss of function. Five families originating from the Southern Shores of the Mediterranean segregated a similar mutation (c.112C>T, p.R38* suggesting that this change may have resulted from an ancient founder effect. Considering the low frequency of RD3 carriers, the recurrence risk for LCA in non-consanguineous unions is negligible for both heterozygote and homozygote RD3 individuals. The LCA12 phenotype in our patients is highly similar to those of patients with mutant photoreceptor-specific guanylate cyclase (GUCY2D/LCA1. This observation is consistent with the report of the role of RD3 in trafficking of GUCYs and gives further support to a common mechanism of photoreceptor degeneration in LCA12 and LCA1, i.e., inability to increase cytoplasmic cGMP concentration in outer segments and thus to recover the dark-state. Similar to LCA1, LCA12 patients have no extraocular symptoms despite complete inactivation of both RD3 alleles, supporting the view that extraocular investigations in LCA infants

  8. Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype.

    Science.gov (United States)

    Perrault, Isabelle; Estrada-Cuzcano, Alejandro; Lopez, Irma; Kohl, Susanne; Li, Shiqiang; Testa, Francesco; Zekveld-Vroon, Renate; Wang, Xia; Pomares, Esther; Andorf, Jean; Aboussair, Nisrine; Banfi, Sandro; Delphin, Nathalie; den Hollander, Anneke I; Edelson, Catherine; Florijn, Ralph; Jean-Pierre, Marc; Leowski, Corinne; Megarbane, Andre; Villanueva, Cristina; Flores, Blanca; Munnich, Arnold; Ren, Huanan; Zobor, Ditta; Bergen, Arthur; Chen, Rui; Cremers, Frans P M; Gonzalez-Duarte, Roser; Koenekoop, Robert K; Simonelli, Francesca; Stone, Edwin; Wissinger, Bernd; Zhang, Qingjiong; Kaplan, Josseline; Rozet, Jean-Michel

    2013-01-01

    Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration (RD), and the most common cause of incurable blindness diagnosed in children. It is occasionally the presenting symptom of multisystemic ciliopathies which diagnosis will require a specific care of patients. Nineteen LCA genes are currently identified and three of them account for both non-syndromic and syndromic forms of the disease. RD3 (LCA12) was implicated as a LCA gene based on the identification of homozygous truncating mutations in two LCA families despite the screening of large cohorts of patients. Here we provide a comprehensive survey of RD3 mutations and of their clinical expression through the screening of a cohort of 852 patients originating worldwide affected with LCA or early-onset and severe RD. We identified three RD3 mutations in seven unrelated consanguineous LCA families - i.e., a 2 bp deletion and two nonsense mutations - predicted to cause complete loss of function. Five families originating from the Southern Shores of the Mediterranean segregated a similar mutation (c.112C>T, p.R38*) suggesting that this change may have resulted from an ancient founder effect. Considering the low frequency of RD3 carriers, the recurrence risk for LCA in non-consanguineous unions is negligible for both heterozygote and homozygote RD3 individuals. The LCA12 phenotype in our patients is highly similar to those of patients with mutant photoreceptor-specific guanylate cyclase (GUCY2D/LCA1). This observation is consistent with the report of the role of RD3 in trafficking of GUCYs and gives further support to a common mechanism of photoreceptor degeneration in LCA12 and LCA1, i.e., inability to increase cytoplasmic cGMP concentration in outer segments and thus to recover the dark-state. Similar to LCA1, LCA12 patients have no extraocular symptoms despite complete inactivation of both RD3 alleles, supporting the view that extraocular investigations in LCA infants with RD3 mutations

  9. Union Makes Strength: A Worldwide Collaborative Genetic and Clinical Study to Provide a Comprehensive Survey of RD3 Mutations and Delineate the Associated Phenotype

    Science.gov (United States)

    Perrault, Isabelle; Estrada-Cuzcano, Alejandro; Lopez, Irma; Kohl, Susanne; Li, Shiqiang; Testa, Francesco; Zekveld-Vroon, Renate; Wang, Xia; Pomares, Esther; Andorf, Jean; Aboussair, Nisrine; Banfi, Sandro; Delphin, Nathalie; den Hollander, Anneke I.; Edelson, Catherine; Florijn, Ralph; Jean-Pierre, Marc; Leowski, Corinne; Megarbane, Andre; Villanueva, Cristina; Flores, Blanca; Munnich, Arnold; Ren, Huanan; Zobor, Ditta; Bergen, Arthur; Chen, Rui; Cremers, Frans P. M.; Gonzalez-Duarte, Roser; Koenekoop, Robert K.; Simonelli, Francesca; Stone, Edwin; Wissinger, Bernd; Zhang, Qingjiong; Kaplan, Josseline; Rozet, Jean-Michel

    2013-01-01

    Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration (RD), and the most common cause of incurable blindness diagnosed in children. It is occasionally the presenting symptom of multisystemic ciliopathies which diagnosis will require a specific care of patients. Nineteen LCA genes are currently identified and three of them account for both non-syndromic and syndromic forms of the disease. RD3 (LCA12) was implicated as a LCA gene based on the identification of homozygous truncating mutations in two LCA families despite the screening of large cohorts of patients. Here we provide a comprehensive survey of RD3 mutations and of their clinical expression through the screening of a cohort of 852 patients originating worldwide affected with LCA or early-onset and severe RD. We identified three RD3 mutations in seven unrelated consanguineous LCA families - i.e., a 2 bp deletion and two nonsense mutations – predicted to cause complete loss of function. Five families originating from the Southern Shores of the Mediterranean segregated a similar mutation (c.112C>T, p.R38*) suggesting that this change may have resulted from an ancient founder effect. Considering the low frequency of RD3 carriers, the recurrence risk for LCA in non-consanguineous unions is negligible for both heterozygote and homozygote RD3 individuals. The LCA12 phenotype in our patients is highly similar to those of patients with mutant photoreceptor-specific guanylate cyclase (GUCY2D/LCA1). This observation is consistent with the report of the role of RD3 in trafficking of GUCYs and gives further support to a common mechanism of photoreceptor degeneration in LCA12 and LCA1, i.e., inability to increase cytoplasmic cGMP concentration in outer segments and thus to recover the dark-state. Similar to LCA1, LCA12 patients have no extraocular symptoms despite complete inactivation of both RD3 alleles, supporting the view that extraocular investigations in LCA infants with RD3

  10. Prevalence and Phenotypic Expression of Mutations in the MYH7, MYBPC3 and TNNT2 Genes in Families with Hypertrophic Cardiomyopathy in the South of Brazil: A Cross-Sectional Study

    Science.gov (United States)

    Mattos, Beatriz Piva e; Scolari, Fernando Luís; Torres, Marco Antonio Rodrigues; Simon, Laura; de Freitas, Valéria Centeno; Giugliani, Roberto; Matte, Úrsula

    2016-01-01

    Background: Mutations in sarcomeric genes are found in 60-70% of individuals with familial forms of hypertrophic cardiomyopathy (HCM). However, this estimate refers to northern hemisphere populations. The molecular-genetic profile of HCM has been subject of few investigations in Brazil, particularly in the south of the country. Objective: To investigate mutations in the sarcomeric genes MYH7, MYBPC3 and TNNT2 in a cohort of HCM patients living in the extreme south of Brazil, and to evaluate genotype-phenotype associations. Methods: Direct DNA sequencing of all encoding regions of three sarcomeric genes was conducted in 43 consecutive individuals of ten unrelated families. Results: Mutations for CMH have been found in 25 (58%) patients of seven (70%) of the ten study families. Fourteen (56%) individuals were phenotype-positive. All mutations were missense, four (66%) in MYH7 and two (33%) in MYBPC3. We have not found mutations in the TNNT2 gene. Mutations in MYH7 were identified in 20 (47%) patients of six (60%) families. Two of them had not been previously described. Mutations in MYBPC3 were found in seven (16%) members of two (20%) families. Two (5%) patients showed double heterozygosis for both genes. The mutations affected different domains of encoded proteins and led to variable phenotypic expression. A family history of HCM was identified in all genotype-positive individuals. Conclusions: In this first genetic-molecular analysis carried out in the south of Brazil, we found mutations in the sarcomeric genes MYH7 and MYBPC3 in 58% of individuals. MYH7-related disease was identified in the majority of cases with mutation. PMID:27737317

  11. The phenotype of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C>T:R200W)

    Science.gov (United States)

    Tomasic, Nikica Ljubas; Piterkova, Lucie; Huff, Chad; Bilic, Ernest; Yoon, Donghoon; Miasnikova, Galina Y.; Sergueeva, Adelina I.; Niu, Xiaomei; Nekhai, Sergei; Gordeuk, Victor; Prchal, Josef T.

    2013-01-01

    Mutations of VHL (a negative regulator of hypoxia-inducible factors) have position-dependent distinct cancer phenotypes. Only two known inherited homozygous VHL mutations exist and they cause polycythemia: Chuvash R200W and Croatian H191D. We report a second polycythemic Croatian H191D homozygote distantly related to the first propositus. Three generations of both families were genotyped for analysis of shared ancestry. Biochemical and molecular tests were performed to better define their phenotypes, with an emphasis on a comparison with Chuvash polycythemia. The VHL H191D mutation did not segregate in the family defined by the known common ancestors of the two subjects, suggesting a high prevalence in Croatians, but haplotype analysis indicated an undocumented common ancestor ∼six generations ago as the founder of this mutation. We show that erythropoietin levels in homozygous VHL H191D individuals are higher than in VHL R200W patients of similar ages, and their native erythroid progenitors, unlike Chuvash R200W, are not hypersensitive to erythropoietin. This observation contrasts with a report suggesting that polycythemia in VHL R200W and H191D homozygotes is due to the loss of JAK2 regulation from VHL R200W and H191D binding to SOCS1. In conclusion, our studies further define the hematologic phenotype of VHL H191D and provide additional evidence for phenotypic heterogeneity associated with the positional effects of VHL mutations. PMID:23403324

  12. MICrocephaly, disproportionate pontine and cerebellar hypoplasia syndrome: A clinico-radiologic phenotype linked to calcium/calmodulin-dependent serine protein kinase gene mutation

    Directory of Open Access Journals (Sweden)

    Rashid Saleem

    2013-01-01

    Full Text Available MICrocephaly, disproportionate pontine and cerebellar hypoplasia (MICPCH syndrome, a rare X-linked disorder, generally seen in girls, is characterized by neurodevelopmental delay, microcephaly, and disproportionate pontine and cerebellar hypoplasia. It is caused by inactivating calcium/calmodulin-dependent serine protein kinase (CASK gene mutations. We report a 2-year-old girl with severe neurodevelopmental delay, microcephaly, minimal pontine hypoplasia, cerebellar hypoplasia, and normal looking corpus callosum, with whom the conventional cytogenetic studies turned out to be normal, and an array-comparative genomic hybridization (a-CGH analysis showed CASK gene duplication at Xp11.4. Our case highlights the importance of using clinico-radiologic phenotype to guide genetic investigation and it also confirms the role of a-CGH analysis in establishing the genetic diagnosis of MICPCH syndrome, when conventional cytogenetic studies are inconclusive.

  13. Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects

    DEFF Research Database (Denmark)

    Strandgren, Charlotte; Nasser, Hasina Abdul; McKenna, Tomás;

    2015-01-01

    model to study the possibility of recovering from HGPS bone disease upon silencing of the HGPS mutation, and the potential benefits from treatment with resveratrol. We show that complete silencing of the transgenic expression of progerin normalized bone morphology and mineralization already after 7...... weeks. The improvements included lower frequencies of rib fractures and callus formation, an increased number of osteocytes in remodeled bone, and normalized dentinogenesis. The beneficial effects from resveratrol treatment were less significant and to a large extent similar to mice treated with sucrose...... alone. However, the reversal of the dental phenotype of overgrown and laterally displaced lower incisors in HGPS mice could be attributed to resveratrol. Our results indicate that the HGPS bone defects were reversible upon suppressed transgenic expression and suggest that treatments targeting aberrant...

  14. A mutation in the gene encoding cytochrome c1 leads to a decreased ROS content and to a long-lived phenotype in the filamentous fungus Podospora anserina.

    Science.gov (United States)

    Sellem, Carole H; Marsy, Sophie; Boivin, Antoine; Lemaire, Claire; Sainsard-Chanet, Annie

    2007-07-01

    We present here the properties of a complex III loss-of-function mutant of the filamentous fungus Podospora anserina. The mutation corresponds to a single substitution in the second intron of the gene cyc1 encoding cytochrome c(1), leading to a splicing defect. The cyc1-1 mutant is long-lived, exhibits a defect in ascospore pigmentation, has a reduced growth rate and a reduced ROS production associated with a stabilisation of its mitochondrial DNA. We also show that increased longevity is linked with morphologically modified mitochondria and an increased number of mitochondrial genomes. Overexpression of the alternative oxidase rescues all these phenotypes and restores aging. Interestingly, the absence of complex III in this mutant is not paralleled with a deficiency in complex I activity as reported in mammals although the respiratory chain of P. anserina has recently been demonstrated to be organized according to the "respirasome" model.

  15. Dating the onset of some mutations in myostatin gene determining the double muscled phenotype in beef cattle

    Directory of Open Access Journals (Sweden)

    A. Nardone

    2011-03-01

    Full Text Available Growth differentiation factor 8 (GDF8 or myostatin is a member of the transforming growth factor β (TGF-β superfamily, which includes proteins that mediate key events in cell growth and development through signal transduction. In the absence of myostatin, the skeletal musculature of mice is two to three times greater in mass than that of wild-type mice (McPherron et al., 1997. Several cattle breeds are characterized by double muscling phenotype and GDF8 has been extensively investigated in cattle.A large number of variants have been identified in these species,most of which are silent or neutral.........

  16. Accelerating Gene Discovery by Phenotyping Whole-Genome Sequenced Multi-mutation Strains and Using the Sequence Kernel Association Test (SKAT.

    Directory of Open Access Journals (Sweden)

    Tiffany A Timbers

    2016-08-01

    Full Text Available Forward genetic screens represent powerful, unbiased approaches to uncover novel components in any biological process. Such screens suffer from a major bottleneck, however, namely the cloning of corresponding genes causing the phenotypic variation. Reverse genetic screens have been employed as a way to circumvent this issue, but can often be limited in scope. Here we demonstrate an innovative approach to gene discovery. Using C. elegans as a model system, we used a whole-genome sequenced multi-mutation library, from the Million Mutation Project, together with the Sequence Kernel Association Test (SKAT, to rapidly screen for and identify genes associated with a phenotype of interest, namely defects in dye-filling of ciliated sensory neurons. Such anomalies in dye-filling are often associated with the disruption of cilia, organelles which in humans are implicated in sensory physiology (including vision, smell and hearing, development and disease. Beyond identifying several well characterised dye-filling genes, our approach uncovered three genes not previously linked to ciliated sensory neuron development or function. From these putative novel dye-filling genes, we confirmed the involvement of BGNT-1.1 in ciliated sensory neuron function and morphogenesis. BGNT-1.1 functions at the trans-Golgi network of sheath cells (glia to influence dye-filling and cilium length, in a cell non-autonomous manner. Notably, BGNT-1.1 is the orthologue of human B3GNT1/B4GAT1, a glycosyltransferase associated with Walker-Warburg syndrome (WWS. WWS is a multigenic disorder characterised by muscular dystrophy as well as brain and eye anomalies. Together, our work unveils an effective and innovative approach to gene discovery, and provides the first evidence that B3GNT1-associated Walker-Warburg syndrome may be considered a ciliopathy.

  17. A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype.

    Directory of Open Access Journals (Sweden)

    Gianluca Occhi

    2013-03-01

    Full Text Available The CDKN1B gene encodes the cyclin-dependent kinase inhibitor p27(KIP1, an atypical tumor suppressor playing a key role in cell cycle regulation, cell proliferation, and differentiation. Impaired p27(KIP1 expression and/or localization are often observed in tumor cells, further confirming its central role in regulating the cell cycle. Recently, germline mutations in CDKN1B have been associated with the inherited multiple endocrine neoplasia syndrome type 4, an autosomal dominant syndrome characterized by varying combinations of tumors affecting at least two endocrine organs. In this study we identified a 4-bp deletion in a highly conserved regulatory upstream ORF (uORF in the 5'UTR of the CDKN1B gene in a patient with a pituitary adenoma and a well-differentiated pancreatic neoplasm. This deletion causes the shift of the uORF termination codon with the consequent lengthening of the uORF-encoded peptide and the drastic shortening of the intercistronic space. Our data on the immunohistochemical analysis of the patient's pancreatic lesion, functional studies based on dual-luciferase assays, site-directed mutagenesis, and on polysome profiling show a negative influence of this deletion on the translation reinitiation at the CDKN1B starting site, with a consequent reduction in p27(KIP1 expression. Our findings demonstrate that, in addition to the previously described mechanisms leading to reduced p27(KIP1 activity, such as degradation via the ubiquitin/proteasome pathway or non-covalent sequestration, p27(KIP1 activity can also be modulated by an uORF and mutations affecting uORF could change p27(KIP1 expression. This study adds the CDKN1B gene to the short list of genes for which mutations that either create, delete, or severely modify their regulatory uORFs have been associated with human diseases.

  18. A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype.

    Science.gov (United States)

    Occhi, Gianluca; Regazzo, Daniela; Trivellin, Giampaolo; Boaretto, Francesca; Ciato, Denis; Bobisse, Sara; Ferasin, Sergio; Cetani, Filomena; Pardi, Elena; Korbonits, Márta; Pellegata, Natalia S; Sidarovich, Viktoryia; Quattrone, Alessandro; Opocher, Giuseppe; Mantero, Franco; Scaroni, Carla

    2013-03-01

    The CDKN1B gene encodes the cyclin-dependent kinase inhibitor p27(KIP1), an atypical tumor suppressor playing a key role in cell cycle regulation, cell proliferation, and differentiation. Impaired p27(KIP1) expression and/or localization are often observed in tumor cells, further confirming its central role in regulating the cell cycle. Recently, germline mutations in CDKN1B have been associated with the inherited multiple endocrine neoplasia syndrome type 4, an autosomal dominant syndrome characterized by varying combinations of tumors affecting at least two endocrine organs. In this study we identified a 4-bp deletion in a highly conserved regulatory upstream ORF (uORF) in the 5'UTR of the CDKN1B gene in a patient with a pituitary adenoma and a well-differentiated pancreatic neoplasm. This deletion causes the shift of the uORF termination codon with the consequent lengthening of the uORF-encoded peptide and the drastic shortening of the intercistronic space. Our data on the immunohistochemical analysis of the patient's pancreatic lesion, functional studies based on dual-luciferase assays, site-directed mutagenesis, and on polysome profiling show a negative influence of this deletion on the translation reinitiation at the CDKN1B starting site, with a consequent reduction in p27(KIP1) expression. Our findings demonstrate that, in addition to the previously described mechanisms leading to reduced p27(KIP1) activity, such as degradation via the ubiquitin/proteasome pathway or non-covalent sequestration, p27(KIP1) activity can also be modulated by an uORF and mutations affecting uORF could change p27(KIP1) expression. This study adds the CDKN1B gene to the short list of genes for which mutations that either create, delete, or severely modify their regulatory uORFs have been associated with human diseases.

  19. Contribution of G71R mutation to Gilbert’s syndrome phenotype in a Greek patient:A case report

    Institute of Scientific and Technical Information of China (English)

    Vassiliki; Kalotychou; Maria; Karakosta; Revekka; Tzanetea; Aleka; Stamoulakatou; Kostas; Konstantopoulos; Yannis; Rombos

    2011-01-01

    Gilbert’s syndrome is characterized by a benign indirect hyperbilirubinemia.It has often been underestimated and undiagnosed because of its mild symptoms;al-though it is not as rare as was once believed when its frequency was estimated using data originating from biochemical tests.Based on molecular techniques,the occurrence of Gilbert’s syndrome has changed,increas-ing to 10% in the Caucasian population.This molecular defect was described,by Bosma et al,in 1995,and af-fects the promoter region of the UGT 1A1 gene.In this case report,our aim is to present a new combination of two molecular defects in a Greek patient with Gilbert’ s syndrome.A 13-year-old Greek girl was examined for Gilbert’s syndrome using molecular techniques,and an uncommon genotype was revealed comprising the rare mutation G71R in trans with A(TA)7TAA motif.TheG71R mutation according to the literature,as well as our epidemiological data,is rare in Caucasians,while it is common in Asian populations.This is the first case study in the Greek population to report a new genotype for Gilbert’s syndrome manifestation in the Caucasian population.

  20. Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects.

    Science.gov (United States)

    Strandgren, Charlotte; Nasser, Hasina Abdul; McKenna, Tomás; Koskela, Antti; Tuukkanen, Juha; Ohlsson, Claes; Rozell, Björn; Eriksson, Maria

    2015-08-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commonly caused by a de novo point mutation in exon 11 of the LMNA gene, c.1824C>T, which results in an increased production of a truncated form of lamin A known as progerin. In this study, we used a mouse model to study the possibility of recovering from HGPS bone disease upon silencing of the HGPS mutation, and the potential benefits from treatment with resveratrol. We show that complete silencing of the transgenic expression of progerin normalized bone morphology and mineralization already after 7 weeks. The improvements included lower frequencies of rib fractures and callus formation, an increased number of osteocytes in remodeled bone, and normalized dentinogenesis. The beneficial effects from resveratrol treatment were less significant and to a large extent similar to mice treated with sucrose alone. However, the reversal of the dental phenotype of overgrown and laterally displaced lower incisors in HGPS mice could be attributed to resveratrol. Our results indicate that the HGPS bone defects were reversible upon suppressed transgenic expression and suggest that treatments targeting aberrant progerin splicing give hope to patients who are affected by HGPS.

  1. Correct splicing despite mutation of the invariant first nucleotide of a 5[prime] splice site: A possible basis for disparate clinical phenotypes in siblings with adenosine deaminase deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Arredondo-Vega, F.X.; Santisteban, I.; Kelly, S.; Hershfield, M.S. (Duke Univ. Medical Center, Durham, NC (United States)); Umetsu, D.T. (Stanford Univ., CA (United States)); Schlossman, C.M.

    1994-05-01

    Adenosine deaminase (ADA) deficiency usually causes severe combined immune deficiency in infancy. Milder phenotypes also occur and are associated with less severely impaired deoxyadenosine (dAdo) catabolism. The authors have characterized the mutations responsible for ADA deficiency in siblings with disparity in clinical phenotype. Erythrocyte dAdo nucleotide pool size, which reflects total residual ADA activity, was lower in the older, more mildly affected sib (RG) than in her younger, more severely affected sister (EG). Cultured T cells, fibroblasts, and B lymphoblasts of RG had detectable residual ADA activity, while cells of EG did not. ADA mRNA was undetectable by northern analysis in cells of both patients. Both sibs were found to be compound heterozygotes for the following novel splicing defects: (1) a G[sup +1][yields]A substitution at the 5' splice site of IVS 2 and (2) a complex 17-bp rearrangement of the 3' splice site of IVS 8, which inserted a run of seven purines into the polypyrimidine tract and altered the reading frame of exon 9. PCR-amplified ADA cDNA clones with premature translation stop codons arising from aberrant pre-mRNA splicing were identified, which were consistent with these mutations. However, some cDNA clones from T cells of both patients and from fibroblasts and Epstein-Barr virus (EBV)-transformed B cells of RG, were normally spliced at both the exon 2/3 and exon 8/9 junctions. A normal coding sequence was documented for clones from both sibs. The normal cDNA clones did not appear to arise from either contamination or PCR artifact, and mosaicism seems unlikely to have been involved. These findings suggest (1) that a low level of normal pre-mRNA splicing may occur despite mutation of the invariant first nucleotide of the 5' splice sequence and (2) that differences in efficiency of such splicing may account for the difference in residual ADA activity, immune dysfunction, and clinical severity in these siblings. 66 refs

  2. A SPG3A mutation with a novel foot phenotype of hereditary spastic paraplegia in a Chinese Han family

    Institute of Scientific and Technical Information of China (English)

    LI Xun-hua; SONG Chun; CHEN Su-qin; ZHOU Yan; GUO Hui; ZHOU Chun-long; YANG Zhi-yun; LIANG Yin-xing; WANG Yi-ming

    2007-01-01

    @@ Hereditary spastic paraplegia (HSP) (MIM#182600) is a group of heterogeneous neurodegenerative disorders, with 35 underlying loci recognized by the HGNC (HUGO Gene Nomenclature Committee;http://www.gene.ucl.ac.uk/nomenclature/) and 10 identified genes ( http://www.gene.ucl.ac.uk/cgi-bin/nomenclature/searchgenes.pl plus NIPA1, last search July 2006). The mode of inheritance may be autosomal dominant,autosomal recessive or X-linked. Among these, autosomal dominant spastic paraplegia (AD-HSP) is the most common type, accounting for 70%-80% of all families.1The disease is characterized by lower limb spasticity,hyperreflexia, progressive spastic gait and an extensor plantar response. Pes cavus is one of the commonly reported foot phenotypes.2

  3. Mutations in a guanylate cyclase GCY-35/GCY-36 modify Bardet-Biedl syndrome-associated phenotypes in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Calvin A Mok

    2011-10-01

    Full Text Available Ciliopathies are pleiotropic and genetically heterogeneous disorders caused by defective development and function of the primary cilium. Bardet-Biedl syndrome (BBS proteins localize to the base of cilia and undergo intraflagellar transport, and the loss of their functions leads to a multisystemic ciliopathy. Here we report the identification of mutations in guanylate cyclases (GCYs as modifiers of Caenorhabditis elegans bbs endophenotypes. The loss of GCY-35 or GCY-36 results in suppression of the small body size, developmental delay, and exploration defects exhibited by multiple bbs mutants. Moreover, an effector of cGMP signalling, a cGMP-dependent protein kinase, EGL-4, also modifies bbs mutant defects. We propose that a misregulation of cGMP signalling, which underlies developmental and some behavioural defects of C. elegans bbs mutants, may also contribute to some BBS features in other organisms.

  4. Phenotypic presentation of thrombophilia in double heterozygote for factor v leiden and prothrombin 20210 G>A mutations: Case report

    Directory of Open Access Journals (Sweden)

    Nagorni-Obradović Ljudmila

    2014-01-01

    Full Text Available Physicians usually do not suspect pulmonary thromboembolism in younger patients except in those who have thrombophilia. In those latter patients some special conditions such as trauma or surgery may provoke the disease. In some adult persons, thrombophilia may still remain unrecognized, until appearance of additional conditions influence development of thrombosis. A 55-year-old Caucasian female, non-smoker, experienced sudden chest pain and hemoptysis without chest trauma. History taking revealed type 2 diabetes mellitus and hypothyroidism. She was overweight with body mass index 29.0. The review of the family history revealed that her father and mother died of brain infarction, while her 22-year-old son and 24-year-old daughter were healthy. Due to suspicion for thrombosis, multi-slice computerized tomography thorax scan was done and pulmonary embolism was diagnosed. Although without clear risk factor for thrombosis in our patient, we performed laboratory investigation for congenital thrombophilia. Genetic analysis showed double heterozygous for factor V Leiden and prothrombin 20210 G>A mutations. Congenital thrombophilia was risk factor for thrombosis in our patient but haemostatic imbalance was not previously clinically recognized. She had two pregnancies without complications. Appearance of other associative factors such as endocrine disorders - hypothyroidism and metabolic syndrome with diabetes type 2, and overweigh were additional potential triggers for clinical manifestation of pulmonary thromboembolism in her adult age. Her children underwent genetic analysis, too. The son was also double heterozygous for factor V Leiden and prothrombin 20210 G>A mutations, while daughter was heterozygous for factor V Leiden, and none had clinical signs of thrombosis. [Projekat Ministarstva nauke Republike Srbije, br. ON175081 i br. ON 175091

  5. A substitution mutation in OsCCD7 cosegregates with dwarf and increased tillering phenotype in rice

    Indian Academy of Sciences (India)

    Krishnanand P. Kulkarni; Chandrapal Vishwakarma; Sarada P. Sahoo; John M. Lima; Manoj Nath; Prasad Dokku; Rajesh N. Gacche; Trilochan Mohapatra; S. Robin; N. Sarla; M. Seshashayee; Ashok K. Singh; Kuldeep Singh; Nagendra K. Singh; R. P. Sharma

    2014-08-01

    Dwarf plant height and tillering ability are two of the most important agronomic traits that determine the plant architecture, and have profound influence on grain yield in rice. To understand the molecular mechanism controlling these two traits, an EMS-induced recessive dwarf and increased tillering1 (dit1) mutant was characterized. The mutant showed proportionate reduction in each internode as compared to wild type revealing that it belonged to the category of dn-type of dwarf mutants. Besides, exogenous application of GA3 and 24-epibrassinolide, did not have any effect on the phenotype of the mutant. The gene was mapped on the long arm of chromosome 4, identified through positional candidate approach and verified by cosegregation analysis. It was found to encode carotenoid cleavage dioxygenase7 (CCD7) and identified as an allele of htd1. The mutant carried substitution of two nucleotides CC to AA in the sixth exon of the gene that resulted in substitution of serine by a stop codon in the mutant, and thus formation of a truncated protein, unlike amino acid substitution event in htd1. The new allele will facilitate further functional characterization of this gene, which may lead to unfolding of newer signalling pathways involving plant development and architecture.

  6. Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations.

    Science.gov (United States)

    Snowden, Julie S; Adams, Jennifer; Harris, Jennifer; Thompson, Jennifer C; Rollinson, Sara; Richardson, Anna; Jones, Matthew; Neary, David; Mann, David M; Pickering-Brown, Stuart

    2015-01-01

    Our objective was to compare the clinical and pathological characteristics of frontotemporal dementia patients with MAPT, GRN and C9orf72 gene mutations. We carried out a cross-sectional comparative study of 74 gene-positive patients (15 MAPT, 17 GRN and 42 C9orf72). Thirty had post mortem pathological data permitting clinico-pathological correlation. MAPT patients were younger than other groups, and showed more frequent behavioural disinhibition, repetitive and stereotyped behaviours, semantic impairment and temporal predominance of atrophy. GRN patients were older at death and more likely to present with non-fluent aphasia. C9orf72 patients alone showed a co-occurrence of ALS. They showed more psychotic symptoms and irrational behaviour, yet were more often reported clinically as socially appropriate and warm. They showed less dietary change than other groups. C9orf72 patients with and without ALS differed only in frequency of psychosis. Greater clinical overlap was observed between GRN and C9orf72 compared to MAPT cases. MAPT cases had tau and GRN and C9orf72, with one exception, TDP-43 pathology. Non-fluent aphasia was linked to TDP subtype A in both GRN and C9orf72 cases and ALS with subtype B. In conclusion, the findings reinforce clinical heterogeneity in FTD and strengthen evidence that genotype influences clinical presentation. Clinical features may inform targeted genetic testing.

  7. BRCA1 p.His1673del is a pathogenic mutation associated with a predominant ovarian cancer phenotype.

    Science.gov (United States)

    Zuntini, Roberta; Cortesi, Laura; Calistri, Daniele; Pippucci, Tommaso; Luigi Martelli, Pier; Casadio, Rita; Capizzi, Elisa; Santini, Donatella; Miccoli, Sara; Medici, Veronica; Danesi, Rita; Marchi, Isabella; Zampiga, Valentina; Fiorentino, Michelangelo; Ferrari, Simona; Turchetti, Daniela

    2017-02-07

    We have investigated the clinical significance of the BRCA1 variant p.His1673del in 14 families from the Emilia-Romagna region of Italy, including 20 breast and 23 ovarian cancer cases; four families displayed site-specific ovarian cancer.The variant, absent in human variation databases, has been reported three times in BRCA1 specific databases; all probands shared the same rare haplotype at the BRCA1 locus, consistent with a common ancestor.The multifactorial likelihood method by Goldgar, used to estimate the probability of the variant being causative, gave a ratio of 2,263,474:1 in favor of causality. Moreover, in silico modeling suggested that His1673-lacking BRCA1 protein may have a decreased ability to bind BARD1 and other related proteins. All six ovarian carcinomas and two out of four breast carcinomas available showed a loss of the BRCA1 wild-type allele, which in three out of four ovarian carcinomas analyzed by FISH was associated with duplication of the chromosome 17 containing the variant. Although the pathogenicity of the allele is strongly supported by the multifactorial ratio,we cannot exclude that p.His1673del is not itself deleterious, but is linked to another undetected mutation on the same ancestral allele.

  8. Mutations of photosystem II D1 protein that empower efficient phenotypes of Chlamydomonas reinhardtii under extreme environment in space.

    Science.gov (United States)

    Giardi, Maria Teresa; Rea, Giuseppina; Lambreva, Maya D; Antonacci, Amina; Pastorelli, Sandro; Bertalan, Ivo; Johanningmeier, Udo; Mattoo, Autar K

    2013-01-01

    Space missions have enabled testing how microorganisms, animals and plants respond to extra-terrestrial, complex and hazardous environment in space. Photosynthetic organisms are thought to be relatively more prone to microgravity, weak magnetic field and cosmic radiation because oxygenic photosynthesis is intimately associated with capture and conversion of light energy into chemical energy, a process that has adapted to relatively less complex and contained environment on Earth. To study the direct effect of the space environment on the fundamental process of photosynthesis, we sent into low Earth orbit space engineered and mutated strains of the unicellular green alga, Chlamydomonas reinhardtii, which has been widely used as a model of photosynthetic organisms. The algal mutants contained specific amino acid substitutions in the functionally important regions of the pivotal Photosystem II (PSII) reaction centre D1 protein near the QB binding pocket and in the environment surrounding Tyr-161 (YZ) electron acceptor of the oxygen-evolving complex. Using real-time measurements of PSII photochemistry, here we show that during the space flight while the control strain and two D1 mutants (A250L and V160A) were inefficient in carrying out PSII activity, two other D1 mutants, I163N and A251C, performed efficient photosynthesis, and actively re-grew upon return to Earth. Mimicking the neutron irradiation component of cosmic rays on Earth yielded similar results. Experiments with I163N and A251C D1 mutants performed on ground showed that they are better able to modulate PSII excitation pressure and have higher capacity to reoxidize the QA (-) state of the primary electron acceptor. These results highlight the contribution of D1 conformation in relation to photosynthesis and oxygen production in space.

  9. LQTS-associated mutation A257G in α1-syntrophin interacts with the intragenic variant P74L to modify its biophysical phenotype

    Directory of Open Access Journals (Sweden)

    Michael J. Ackerman

    2011-08-01

    Full Text Available The SNTA1-encoded α1-syntrophin (SNTA1 missense mutation, p.A257G, causes long QT syndrome (LQTS by pathogenic accentuation of Nav1.5’s sodium current (INa. Subsequently, we found p.A257G in combination with the SNTA1 polymorphism, p.P74L in 4 victims of sudden infant death syndrome (SIDS as well as in 3 adult controls. We hypothesized that p.P74L-SNTA1 could functionally modify the pathogenic phenotype of p.A257G-SNTA1, thus explaining its occurrence in non-LQTS populations. The SNTA1 variants p.P74L, p.A257G, and the combination variant p.P74L/p.A257G were engineered using PCR-based overlapextension and were co-expressed heterologously with SCN5A in HEK293 cells. INa was recorded using the whole-cell method. Compared to wild-type (WT, the significant increase in peak INa and window current found with p.A257G was reversed by the intragenic variant p.P74L (p.P74L/p.A257G. These results report for the first time the intragenic rescue of an LQT-associated SNTA1 mutation when found in combination with the SNTA1 polymorphism p.P74L, suggesting an ever-increasing picture of complexity in terms of genetic risk stratification for arrhythmia.

  10. Hb Lansing (HBA2: c.264C > G) and a new β promoter transversion [-52 (G > T)]: an attempt to define the phenotype of two mutations found in the Omani population.

    Science.gov (United States)

    Hassan, Suha M; Harteveld, Cornelis L; Bakker, Engbert; Giordano, Piero C

    2015-01-01

    We report two examples showing how problematic it can be to define the phenotype of new or rare globin genes mutations. We describe two mutations observed for the first time in the Omani population: the first was found in the consanguineous parents of a deceased newborn with hepatomegaly, cardiomegaly and severe hemolytic anemia, putatively homozygous for the rare Hb Lansing (HBA2: c.264C > G) variant. The second is a novel β-globin gene promoter mutation [-52 (G > T)] observed in four independent patients. Two with borderline/elevated Hb A2, α-thalassemia (α-thal) and hypochromic red cell indices, and two heterozygotes for Hb S (HBB: c.20A > T), α-thal and with Hb A/Hb S ratios possibly indicating a very mild β(+)-thalassemia (β(+)-thal) mutation.

  11. Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4 G11778A mutation.

    Science.gov (United States)

    Zhang, Minglian; Zhou, Xiangtian; Li, Chengwu; Zhao, Fuxin; Zhang, Juanjuan; Yuan, Meixia; Sun, Yan-Hong; Wang, Jingzheng; Tong, Yi; Liang, Min; Yang, Li; Cai, Wanshi; Wang, Lifei; Qu, Jia; Guan, Min-Xin

    2010-01-01

    We report here the clinical, genetic and molecular characterization of four Han Chinese families with Leber's hereditary optic neuropathy (LHON). The penetrances of optic neuropathy in these Chinese pedigrees were 38%, 38%, 44% and 56%. This observation is in contrast with the previously identified 14 Chinese families with very low penetrance of LHON. The age-at-onset for visual impairment in matrilineal relatives in these Chinese families varied from 18 to 30years. Furthermore, the ratios between affected male and female matrilineal relatives in these families were 3:0, 3:0, 3:1 and 2:3, respectively. Molecular analysis of mitochondrial genomes identified the known ND4 G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M9a. Of these, the ND1 T3394C mutation caused the substitution of a highly conserved histidine for tyrosine (Y30H) at amino acid position 30. This mutation was associated with LHON in other families with low penetrance of optic neuropathy and other clinical abnormalities. The presence of both G11778A and T3394C mutations appears to contribute to higher penetrance of optic neuropathy in these four Chinese families than other Chinese families carrying only the G11778A mutation. Therefore, the mitochondrial haplogroup M9a specific variant T3394C may modulate the phenotypic manifestation of LHON-associated G11778A mutation in these Chinese pedigrees.

  12. A single missense mutation in a coiled-coil domain of Escherichia coli ribosomal protein S2 confers a thermosensitive phenotype that can be suppressed by ribosomal protein S1.

    Science.gov (United States)

    Aseev, Leonid V; Chugunov, Anton O; Efremov, Roman G; Boni, Irina V

    2013-01-01

    Ribosomal protein S2 is an essential component of translation machinery, and its viable mutated variants conferring distinct phenotypes serve as a valuable tool in studying the role of S2 in translation regulation. One of a few available rpsB mutants, rpsB1, shows thermosensitivity and ensures enhanced expression of leaderless mRNAs. In this study, we identified the nature of the rpsB1 mutation. Sequencing of the rpsB1 allele revealed a G-to-A transition in the part of the rpsB gene which encodes a coiled-coil domain of S2. The resulting E132K substitution resides in a highly conserved site, TKKE, a so-called N-terminal capping box, at the beginning of the second alpha helix. The protruding coiled-coil domain of S2 is known to provide binding with 16S rRNA in the head of the 30S subunit and, in addition, to interact with a key mRNA binding protein, S1. Molecular dynamics simulations revealed a detrimental impact of the E132K mutation on the coiled-coil structure and thereby on the interactions between S2 and 16S rRNA, providing a clue for the thermosensitivity of the rpsB1 mutant. Using a strain producing a leaderless lacZ transcript from the chromosomal lac promoter, we demonstrated that not only the rpsB1 mutation generating S2/S1-deficient ribosomes but also the rpsA::IS10 mutation leading to partial deficiency in S1 alone increased translation efficiency of the leaderless mRNA by about 10-fold. Moderate overexpression of S1 relieved all these effects and, moreover, suppressed the thermosensitive phenotype of rpsB1, indicating the role of S1 as an extragenic suppressor of the E132K mutation.

  13. Loss or gain of function in NIH3T3 and PC12 cells produced by different mutations in the RET tyrosine kinase domain may explain phenotypic diversity between Hirchsprung disease and MEN 2B

    Energy Technology Data Exchange (ETDEWEB)

    Pasini, B.; Seri, M.; Yin, L. [Laboratorio di Genetica Molecolare, Genova (Italy)] [and others

    1994-09-01

    The RET protooncogene encodes a receptor tyrosine kinase involved in the control differentiation of neural crest derived cells. Point mutations of the RET tyrosine kinase domain were identified among others in 2 distinct genetic disorders, Hirchsprung disease (HSCR) and Multiple Endocrine Neoplasia 2B (MEN 2B). In order to test the biological effect of HSCR and MEN 2B mutations we used a system based on RET-PTC2, a chimeric activated form of the RET protoocogene isolated from a papillary thyroid carcinoma, which shows a detectable transforming activity in NIH3T3 cells and induction of differentiation in PC12 cells. By site-direct mutagenesis we introduced into RET-PTC2 cDNA the mutations at codon 918 (Met{yields}thr, typical of MEN 2B), at codon 765 (Ser{yields}Pro, observed in HSCR) and at codon 897 (Arg{yields}Gln, also observed in HSCR). The former mutation appears to increase the transforming activity of RET-PTC2 in NIH3T3 cells. The latter two mutations abolish the oncogenic activity in NIH3T3 cells as well as its differentiating effect in PC12 cells. These results suggest that RET mutations may cause MEN 2B and HSCR phenotypes through a mechanism of gain or loss of function respectively. Finally, co-transfection experiments of wild-type RET-PTC2 with either HSCR mutation are in progress in order to test the hypothesis of a dominant negative effect in heterozygous state.

  14. A locus-specific database for mutations in GDAP1 allows analysis of genotype-phenotype correlations in Charcot-Marie-Tooth diseases type 4A and 2K

    Directory of Open Access Journals (Sweden)

    Cassereau Julien

    2011-12-01

    Full Text Available Abstract Background The ganglioside-induced differentiation-associated protein 1 gene (GDAP1, which is involved in the Charcot-Marie-Tooth disease (CMT, the most commonly inherited peripheral neuropathy, encodes a protein anchored to the mitochondrial outer membrane. The phenotypic presentations of patients carrying GDAP1 mutations are heterogeneous, making it difficult to determine genotype-phenotype correlations, since the majority of the mutations have been found in only a few unrelated patients. Locus-specific databases (LSDB established in the framework of the Human Variome Project provide powerful tools for the investigation of such rare diseases. Methods and Results We report the development of a publicly accessible LSDB for the GDAP1 gene. The GDAP1 LSDB has adopted the Leiden Open-source Variation Database (LOVD software platform. This database, which now contains 57 unique variants reported in 179 cases of CMT, offers a detailed description of the molecular, clinical and electrophysiological data of the patients. The usefulness of the GDAP1 database is illustrated by the finding that GDAP1 mutations lead to primary axonal damage in CMT, with secondary demyelination in the more severe cases of the disease. Conclusion Findings of this nature should lead to a better understanding of the pathophysiology of CMT. Finally, the GDAP1 LSDB, which is part of the mitodyn.org portal of databases of genes incriminated in disorders involving mitochondrial dynamics and bioenergetics, should yield new insights into mitochondrial diseases.

  15. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

    NARCIS (Netherlands)

    Johnston, J.J.; Olivos-Glander, I.; Killoran, C.; Elson, E.; Turner, J.T.; Peters, K.F.; Abbott, M.H.; Aughton, D.J.; Aylsworth, A.S.; Bamshad, M.; Booth, C.; Curry, C.J.; David, A.; Dinulos, M.B.; Flannery, D.B.; Fox, M.A.; Graham, J.M.; Grange, D.K.; Guttmacher, A.E.; Hannibal, M.C.; Henn, W.; Hennekam, R.C.M.; Holmes, L.B.; Hoyme, H.E.; Leppig, K.A.; Lin, A.E.; Macleod, P.; Manchester, D.K.; Marcelis, C.L.M.; Mazzanti, L.; McCann, E.; McDonald, M.T.; Mendelsohn, N.J.; Moeschler, J.B.; Moghaddam, B.; Neri, G.; Newbury-Ecob, R.; Pagon, R.A.; Phillips, J.A.; Sadler, L.S.; Stoler, J.M.; Tilstra, D.; Walsh Vockley, C.M.; Zackai, E.H.; Zadeh, T.M.; Brueton, L.; Black, G.C.M.; Biesecker, L.G.

    2005-01-01

    Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and

  16. Two mutations in the vif gene of maedi-visna virus have different phenotypes, indicating more than one function of Vif.

    Science.gov (United States)

    Franzdóttir, Sigrídur R; Ólafsdóttir, Katrín; Jónsson, Stefán R; Strobel, Hannah; Andrésson, Ólafur S; Andrésdóttir, Valgerdur

    2016-01-15

    Like most other lentiviruses, maedi-visna virus (MVV) requires Vif for replication in natural target cells and in vivo. Here, we show that Vif-deficient MVV accumulates G-A mutations in the sequence context characteristic of ovine APOBEC3, consistent with a role of MVV Vif in neutralizing APOBEC3. We studied two point mutations in the vif gene of MVV. One was a tryptophan to arginine mutation that affects the interaction with APOBEC3 and caused G-A hypermutation. The other mutation was a proline to serine mutation that together with a mutation in the capsid protein caused attenuated replication in fetal ovine synovial (FOS) cells but not in sheep choroid plexus (SCP) cells. There was no hypermutation associated with this mutation. These results suggest that MVV Vif exerts more than one function and that there may be interaction between Vif and the capsid. The results also suggest the involvement of an unknown host factor in MVV Vif function.

  17. Mutation Analysis of Gap Junction Protein Beta 1 and Genotype-Phenotype Correlation in X-linked Charcot-Marie-Tooth Disease in Chinese Patients

    Institute of Scientific and Technical Information of China (English)

    Bo Sun; Zhao-Hui Chen; Li Ling; Yi-Fan Li; Li-Zhi Liu; Fei Yang; Xu-Sheng Huang

    2016-01-01

    Background:Among patients with Charcot-Marie-Tooth disease (CMT),the X-linked variant (CMTX) caused by gap junction protein beta 1 (GJB1) gene mutation is the second most frequent type,accounting for approximately 90% of all CMTX.More than 400 mutations have been identified in the GJB1 gene that encodes connexin 32 (CX32).CX32 is thought to form gap junctions that promote the diffusion pathway between cells.GJB1 mutations interfere with the formation of the functional channel and impair the maintenance of peripheral myelin,and novel mutations are continually discovered.Methods:We included 79 unrelated patients clinically diagnosed with CMT at the Department of Neurology of the Chinese People's Liberation Army General Hospital from December 20,2012,to December 31,2015.Clinical examination,nerve conduction studies,and molecular and bioinformatics analyses were performed to identify patients with CMTX 1.Results:Nine GJB1 mutations (c.283G>A,c.77C>T,c.643C>T,c.515C>T,c.191G>A,c.610C>T,c.490C>T,c.491G>A,and c.44G>A) were discovered in nine patients.Median motor nerve conduction velocities of all nine patients were < 38 m/s,resembling CMT Type 1.Three novel mutations,c.643C>T,c.191G>A,and c.610C>T,were revealed and bioinformatics analyses indicated high pathogenicity.Conclusions:The three novel missense mutations within the GJB1 gene broaden the mutational diversity of CMT 1 X.Molecular analysis of family members and bioinformatics analyses of the afflicted patients confirmed the pathogenicity of these mutations.

  18. A mitochondrial tRNA(Met) mutation causing developmental delay, exercise intolerance and limb girdle phenotype with onset in early childhood

    DEFF Research Database (Denmark)

    Born, Alfred Peter; Duno, Morten; Rafiq, Jabin;

    2015-01-01

    , but 90% COX negative fibres and ragged blue fibres. Respiratory chain enzyme analysis in muscle showed a combined deficiency and mitochondrial DNA sequencing revealed the presence of an m.4450G>A mutation in the MT-TM gene encoding the tRNA for methionine. The mutation was only detected in mt......DNA extracted from muscle and skin fibroblast, and could not be found in other tissues or in the mother. This is the second patient reported in the literature with a mitochondrial myopathy due to a mt-tRNA(Met) mutation. The first patient, a 30-year-old woman, presented with exercise intolerance, limb girdle...

  19. Acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome: report of a child with phenotypic overlap with ulnar-mammary syndrome and a new mutation in TP63.

    Science.gov (United States)

    Slavotinek, Anne M; Tanaka, June; Winder, Alison; Vargervik, Karin; Haggstrom, Anita; Bamshad, Michael

    2005-10-01

    We report on a new patient with clinical findings consistent with acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome. The child had sparse hair, extensive freckling, lacrimal duct stenosis, oligodontia, dystrophic nails, reduced sweating, and bilateral athelia. Examination of his hands showed ulnar ray hypoplasia with bilateral fifth finger brachydactyly and camptodactyly. He also had surgical repair of an imperforate anus. Mutation analysis of TP63 showed a single nucleotide substitution, c.G518A, predicting a novel missense mutation, p.V114M in exon 4. This is the third mutation to be reported in TP63 in ADULT syndrome.

  20. Recessive multiple epiphyseal dysplasia (rMED with homozygosity for C653S mutation in the DTDST gene - Phenotype, molecular diagnosis and surgical treatment of habitual dislocation of multilayered patella: Case report

    Directory of Open Access Journals (Sweden)

    Bonafé Luisa

    2010-06-01

    Full Text Available Abstract Background Multiple epiphyseal dysplasia (MED is one of the more common generalised skeletal dysplasias. Due to its clinical heterogeneity diagnosis may be difficult. Mutations of at least six separate genes can cause MED. Joint deformities, joint pain and gait disorders are common symptoms. Case Presentation We report on a 27-year-old male patient suffering from clinical symptoms of autosomal recessive MED with habitual dislocation of a multilayered patella on both sides, on the surgical treatment and on short-term clinical outcome. Clinical findings were: bilateral hip and knee pain, instability of femorotibial and patellofemoral joints with habitual patella dislocation on both sides, contractures of hip, elbow and second metacarpophalangeal joints. Main radiographic findings were: bilateral dislocated multilayered patella, dysplastic medial tibial plateaus, deformity of both femoral heads and osteoarthritis of the hip joints, and deformity of both radial heads. In the molecular genetic analysis, the DTDST mutation g.1984T > A (p.C653S was found at the homozygote state. Carrier status was confirmed in the DNA of the patient's parents. The mutation could be considered to be the reason for the patient's disease. Surgical treatment of habitual patella dislocation with medialisation of the tibial tuberosity led to an excellent clinical outcome. Conclusions The knowledge of different phenotypes of skeletal dysplasias helps to select genes for genetic analysis. Compared to other DTDST mutations, this is a rather mild phenotype. Molecular diagnosis is important for genetic counselling and for an accurate prognosis. Even in case of a multilayered patella in MED, habitual patella dislocation could be managed successfully by medialisation of the tibial tuberosity.

  1. The mitochondrial tRNA(Thr) A15951G mutation may influence the phenotypic expression of the LHON-associated ND4 G11778A mutation in a Chinese family.

    Science.gov (United States)

    Li, Ronghua; Qu, Jia; Zhou, Xiangtian; Tong, Yi; Hu, Yongwu; Qian, Yaping; Lu, Fan; Mo, Jun Qin; West, Constance E; Guan, Min-Xin

    2006-07-01

    We report here the characterization of a three-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON). This Chinese family exhibited high penetrance and expressivity of visual impairment. The average age-of-onset was 19 years in this family. All male and 33% female matrilineal relatives in this Chinese family developed visual loss with a wide range of severity, ranging from blindness to normal vision. Sequence analysis of the complete mitochondrial DNA in this pedigree revealed the presence of the ND4 G11778A mutation and 40 other variants, belonging to the Asian haplogroup D4. The G11778A mutation is present at homoplasmy in matrilineal relatives of this Chinese family. Of other variants, the homoplasmic A15951G mutation is of special interest as it is located adjacent to 3' end, at conventional position 71 of tRNA(Thr). The adenine (A71) at this position of tRNA(Thr), highly conserved from bacteria to human mitochondria, has been implicated to be important for tRNA identity and pre-tRNA processing. In fact, the significant reduction of the steady-state levels in tRNA(Thr) was observed in cells carrying both the A15951G and G11778A mutations but not cells carrying only G11778A mutation. Thus, the A15951G mutation most probably leads to a failure in mitochondrial tRNA metabolism, worsening the mitochondrial dysfunction associated with the primary G11778A mutation. These imply that the tRNA(Thr) A15951G mutation may have a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in this Chinese family.

  2. The hands in health and disease of individuals with filaggrin loss-of-function mutations: clinical reflections on the hand eczema phenotype.

    Science.gov (United States)

    Kaae, Jeanette; Menné, Torkil; Carlsen, Berit C; Zachariae, Claus; Thyssen, Jacob P

    2012-09-01

    During the last 2 years, we have performed filaggrin genotyping in patients with eczema seen in our hand eczema clinic. We present pictures of healthy and diseased hands from individuals with filaggrin gene (FLG) mutations to describe a clinical entity of hand eczema. We show that xerosis and hyperkeratosis on the dorsal aspects of the hands and fingers, as well as palmar hyperlinearity, should alert the clinician about a possible inherited barrier abnormality of the skin resulting from FLG mutations. The series of photographs range from the hands of an individual with FLG mutations but no history of eczema, to the hands of individuals with typical and atypical filaggrin hand eczema, and finally to the hands of an individual with FLG mutations and hand eczema caused by exposure to irritants and allergens. We briefly discuss this possible subtype of hand eczema, present pathomechanisms, and indicate the signs that should alert the clinicians about a possible inherited skin barrier defect.

  3. Modifier factors influencing the phenotypic manifestation of the deafness-associated mitochondrial DNA mutations%修饰因子对线粒体DNA突变致聋的影响

    Institute of Scientific and Technical Information of China (English)

    杨爱芬; 郑静; 吕建新; 管敏鑫

    2011-01-01

    Mutations in the mitochondrial DNA have been found to be one of the most important causes of sensorineural hearing loss. In particular, these mutations often occur in the mitochondrial 12S rRNA and tRNA genes. Of these, the homoplasmic A1555G and C1494T mutations in the 12S rRNA have been associated with both aminoglycoside induced and nonsyndromic hearing impairment in many families worldwide. Children carrying the A1555G or C1494T mutation are susceptible to the exposure of ototoxic drugs, thereby inducing or worsening hearing loss. Individuals harboring A1555G or C1494T mutation can also develop hearing loss even in the absence of aminoglycoside exposure. However, matrilineal relatives of intra-families or inter-families carrying the A1555G or C1494T mutation exhibit a wide range of severity,age-at-onset, and audiometric configuration of hearing impairment. These indicate that the A1555G or C1494T mutation is a primary factor underlying the development of deafness but insufficient to produce the clinical phenotype. Thus, other modifier factors, such as aminoglycoside (s), mitochondrial DNA haplotype(s) or nuclear modifier gene(s), play a role in the phenotypic expression of the deafness-associated mitochondrial 12S rRNA A1555G or C1494T mutation. In this review, we summarize the modifier factors for the phenotypic expression of deafness-associated 12S rRNA A1555G and C1494T mutations and propose the molecular pathogenetic mechanism of maternally inherited deafness.%线粒体DNA突变是引起感音神经性耳聋的重要原因之一,这些突变主要位于线粒体12SrRNA和tRNA基因上.其中12S rRNA基因上的同质性A1555G和C1494T突变与氨基糖甙类抗生素造成的耳聋相关.携带这两个突变的个体对耳毒性药物高度敏感,导致临床上常见的"一针致聋"现象.但携带A1555G或C1494T突变的个体在没用药的情况下也能产生非综合征型耳聋,而且同一家系内和不同家系间的母系成员在听力损失

  4. "ATP1A3" Mutations in Infants: A New Rapid-Onset Dystonia-Parkinsonism Phenotype Characterized by Motor Delay and Ataxia

    Science.gov (United States)

    Brashear, Allison; Mink, Jonathan W.; Hill, Deborah F.; Boggs, Niki; McCall, W. Vaughn; Stacy, Mark A.; Snively, Beverly; Light, Laney S.; Sweadner, Kathleen J.; Ozelius, Laurie J.; Morrison, Leslie

    2012-01-01

    We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the "ATP1A3" gene. In adults, mutations in "ATP1A3" cause rapid-onset dystonia-Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and…

  5. Two cystic fibrosis transmembrane conductance regulator mutations have different effects on both pulmonary phenotype and regulation of outwardly rectified chloride currents.

    OpenAIRE

    Fulmer, S B; Schwiebert, E M; M.M. Morales; Guggino, W B; Cutting, G R

    1995-01-01

    Cystic fibrosis (CF), a disorder of electrolyte transport manifest in the lungs, pancreas, sweat duct, and vas deferens, is caused by mutations in the CF transmembrane conductance regulator (CFTR). The CFTR protein has been shown to function as a cAMP-activated chloride channel and also regulates a separate protein, the outwardly rectifying chloride channel (ORCC). To determine the consequence of disease-producing mutations upon these functions, mutant CFTR was transiently expressed in Xenopu...

  6. Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated ND1 G3460A mutation in Chinese families.

    Science.gov (United States)

    Ji, Yanchun; Liang, Min; Zhang, Juanjuan; Zhang, Minglian; Zhu, Jinping; Meng, Xiangjuan; Zhang, Sai; Gao, Min; Zhao, Fuxin; Wei, Qi-Ping; Jiang, Pingping; Tong, Yi; Liu, Xiaoling; Qin Mo, Jun; Guan, Min-Xin

    2014-03-01

    To investigate the pathophysiology of Leber's hereditary optic neuropathy (LHON), a cohort of 1164 Han Chinese subjects with LHON were screened for ND1 G3460A mutation. A total of 295 subjects from 16 Han Chinese families carrying the G3460A mutation underwent a clinical and genetic evaluation and molecular analysis of mitochondrial (mt)DNA. The incidence of G3460A mutation was 1.4% in this cohort of Chinese subjects with LHON. Twenty-seven (20 males/7 females) of 109 matrilineal relatives among 10 Chinese pedigrees carrying this mutation exhibited a wide range of severity and age-at-onset in visual impairment. Penetrances of optic neuropathy ranged from 7.1% to 50%, with the average of 24.5%. The age-at-onset of 27 affected matrilineal relatives varied from 10 to 40 years, with the average of 22 years. Molecular analysis identified the homoplasmic G3460A mutation and distinct sets of variants belonging to eight haplogroups. Haplogroup M with G3460A mutation was of higher frequency than those in controls. The penetrances of visual loss in families carrying mitochondrial DNA haplogroups A, B and M were higher than those in other families. Furthermore, haplogroup-specific variants tRNA(Ser(AGY)) A12223G, tRNA(Thr) G15927A and tRNA(Glu) A14693G may enhance the penetrance of visual loss in these families. The G3460A mutation occurred through recurrent origins and founder events in Chinese population. Mitochondrial modifiers may modulate the penetrance and expressivity of optic neuropathy among Chinese pedigrees carrying the G3460A mutation. Thus, our findings may provide new insights into the understanding of pathophysiology and valuable information on the management of LHON.

  7. Phenotypic variability in a seven-generation Swedish family segregating autosomal dominant hearing impairment due to a novel EYA4 frameshift mutation.

    Science.gov (United States)

    Frykholm, Carina; Klar, Joakim; Arnesson, Hanna; Rehnman, Anna-Carin; Lodahl, Marianne; Wedén, Ulla; Dahl, Niklas; Tranebjærg, Lisbeth; Rendtorff, Nanna D

    2015-05-25

    Linkage to an interval overlapping the DFNA10 locus on chromosome 6q22-23 was found through genome wide linkage analysis in a seven-generation Swedish family segregating postlingual, autosomal dominant nonsyndromic sensorineural hearing impairment. A novel heterozygous frame-shift mutation (c.579_580insTACC, p.(Asp194Tyrfs*52)) in EYA4 was identified that truncates the so-called variable region of the protein. The mutation is predicted to result in haploinsufficiency of the EYA4 product. No evidence for dilated cardiomyopathy was found in the family, contrasting to a previous family with a deletion resulting in a similar truncation in the variable region. A highly variable age of onset was seen in the mutation carriers. For assessment of the aetiology of this variability, clinical and audiometric data analyses were performed. The affected family members all had similar cross-sectional and longitudinal deterioration of pure tone average (PTA) once the process of hearing deterioration had started, and no gender, parent-of-origin or family branch differences on PTA could be found. Age at onset varied between the family branches. In summary, this is the ninth published genetically verified DFNA10 family. The results imply that unidentified factors, genetic or environmental, other than the EYA4 mutation, are of importance for the age at onset of DFNA10, and that mutation early in the variable region of the EYA4 protein can occur in the absence of dilated cardiomyopathy.

  8. The phenotype characteristics of type 13 long QT syndrome with mutation in KCNJ5 (Kir3.4-G387R)

    DEFF Research Database (Denmark)

    Wang, Fan; Liu, Jinqiu; Hong, Li;

    2013-01-01

    Long QT syndrome type 13 (LQT13) is caused by loss-of-function mutation in the KCNJ5-encoded cardiac G-protein coupled inward rectifier potassium channel Kir3.4. The electrocardiographic (ECG) features of LQT13 are not described yet.......Long QT syndrome type 13 (LQT13) is caused by loss-of-function mutation in the KCNJ5-encoded cardiac G-protein coupled inward rectifier potassium channel Kir3.4. The electrocardiographic (ECG) features of LQT13 are not described yet....

  9. Phenotypic variability in a seven-generation Swedish family segregating autosomal dominant hearing impairment due to a novel EYA4 frameshift mutation

    DEFF Research Database (Denmark)

    Frykholm, Carina; Klar, Joakim; Arnesson, Hanna;

    2015-01-01

    -sectional and longitudinal deterioration of pure tone average (PTA) once the process of hearing deterioration had started, and no gender, parent-of-origin or family branch differences on PTA could be found. Age at onset varied between the family branches. In summary, this is the ninth published genetically verified DFNA10...... family. The results imply that unidentified factors, genetic or environmental, other than the EYA4 mutation, are of importance for the age at onset of DFNA10, and that mutation early in the variable region of the EYA4 protein can occur in the absence of dilated cardiomyopathy....

  10. TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in KRAS-mutated colorectal cancer cells

    DEFF Research Database (Denmark)

    Tarpgaard, Line S; Ørum-Madsen, Maj Sofie; Christensen, Ib J;

    2016-01-01

    It is now widely accepted that therapeutic antibodies targeting epidermal growth factor receptor (EGFR) can have efficacy in KRAS wild-type advanced colorectal cancer (CRC) patients. What remains to be ascertained is whether a subgroup of KRAS-mutated CRC patients might not also derive benefit fr....... The two sets of data, clinical and in vitro, are complementary and support each other, lending strength to our contention that TIMP- 1 plasma levels can identify a subset of patients with KRAS-mutated metastatic CRC that will have benefit from EGFR-inhibition therapy....

  11. Expression of three different mutations in the arginine vasopressin gene suggests genotype-phenotype correlation in familial neurohypophyseal diabetes insipidus kindreds

    DEFF Research Database (Denmark)

    Siggaard, Charlotte; Christensen, Jane Hvarregaard; Corydon, Thomas Juhl

    2005-01-01

    reduction of the amount of immunoreactive AVP in the cell culture medium and severe impairment of the intracellular trafficking and processing of the AVP prohormone, supporting the disease causing nature of all three mutations. However, the A19T mutation was associated with some capacity for processing...... and trafficking consistent with the clinical observations. Immunoflourescence studies provided evidence of reticular accumulation of protein within the ER in the A19T and C110X mutants but a unique accumulation of much larger aggregates in the L81P, which were localized both within and immediately outside the ER...

  12. Systemic vascular phenotypes of Loeys-Dietz syndrome in a child carrying a de novo R381P mutation in TGFBR2: a case report

    OpenAIRE

    Uike, Kiyoshi; Matsushita, Yuki; Sakai, Yasunari; Togao, Osamu; Nagao, Michinobu; Ishizaki, Yoshito; Nagata, Hazumu; Yamamura, Kenichiro; Torisu, Hiroyuki; Hara, Toshiro

    2013-01-01

    Background Loeys–Dietz syndrome, also known as Marfan syndrome type II, is a rare connective tissue disorder caused by dominant mutations in transforming growth factor-beta receptors (TGFBR1 and 2). Case presentation We report a 7-year-old Japanese boy with Loeys–Dietz syndrome who carried a novel, de novo missense mutation in TGFBR2 (c.1142g > c, R381P). He showed dysmorphic faces and skeletal malformations that were typical in previous cases with Loeys-Dietz syndrome. The cardiac studies di...

  13. Aire-Deficient C57BL/6 Mice Mimicking the Common Human 13-Base Pair Deletion Mutation Present with Only a Mild Autoimmune Phenotype

    NARCIS (Netherlands)

    Hubert, Francois-Xavier; Kinkel, Sarah A.; Crewther, Pauline E.; Cannon, Ping Z. F.; Webster, Kylie E.; Link, Maire; Uibo, Raivo; O'Bryan, Moira K.; Meager, Anthony; Forehan, Simon P.; Smyth, Gordon K.; Mittaz, Laureane; Antonarakis, Stylianos E.; Peterson, Paert; Heath, William R.; Scott, Hamish S.

    2009-01-01

    Autoimmune regulator (AIRE) is an important transcription regulator that mediates a role in central tolerance via promoting the "promiscuous" expression of tissue-specific Ags in the thymus. Although several mouse models of Aire deficiency have been described, none has analyzed the phenotype induced

  14. Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a Danish five-generation family with a novel FAM83H nonsense mutation

    DEFF Research Database (Denmark)

    Haubek, Dorte; Gjørup, Hans; Jensen, Lillian Gryesten

    2011-01-01

    BACKGROUND.  Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI) is a disease with severe dental manifestations. OBJECTIVES.  The aims were by means of a genome-wide linkage scan to search for the gene underlying the ADHCAI phenotype in a Danish five-generation family and to study...

  15. An overlapping phenotype of Osteogenesis imperfecta and Ehlers-Danlos syndrome due to a heterozygous mutation in COL1A1 and biallelic missense variants in TNXB identified by whole exome sequencing.

    Science.gov (United States)

    Mackenroth, Luisa; Fischer-Zirnsak, Björn; Egerer, Johannes; Hecht, Jochen; Kallinich, Tilmann; Stenzel, Werner; Spors, Birgit; von Moers, Arpad; Mundlos, Stefan; Kornak, Uwe; Gerhold, Kerstin; Horn, Denise

    2016-04-01

    Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006-1G > A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p.Val1213Ile, p.Gly2592Ser). Analysis of cDNA showed that the COL1A1 splice site mutation led to intron retention causing a frameshift (p.Phe1336Valfs*72). Type 1 collagen secretion by the patient's skin fibroblasts was reduced. Immunostaining of a muscle biopsy obtained from the patient revealed a clear reduction of tenascin-X in the extracellular matrix compared to a healthy control. These findings imply that the combination of the COL1A1 mutation with the TNXB variants might cause the patient's unique phenotype.

  16. Pubertal androgenization and gonadal histology in two 46, XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

    NARCIS (Netherlands)

    M.L. Cools (Martine); P. Hoebeke (Piet); K.P. Wolffenbuttel (Katja); J.A. Stoop (Hans); R. Hersmus (Remko); M. Barbaro (M.); A. Wedell; H.T. Brüggenwirth (Hennie); L.H.J. Looijenga (Leendert); S.L.S. Drop (Stenvert)

    2012-01-01

    textabstractObjective: Most patients with NR5A1 (SF-1) mutations and poor virilization at birth are sex-assigned female and receive early gonadectomy. Although studies in pituitary-specific Sf-1 knockout mice suggest hypogonadotropic hypogonadism, little is known about endocrine function at puberty

  17. Thoracic aortic aneurysm in infancy in aneurysms-osteoarthritis syndrome due to a novel SMAD3 mutation: further delineation of the phenotype

    NARCIS (Netherlands)

    Wischmeijer, A.; Laer, L. van; Tortora, G.; Bolar, N.A.; Camp, G. van; Fransen, E.; Peeters, N.; Bartolomeo, R. di; Pacini, D.; Gargiulo, G.; Turci, S.; Bonvicini, M.; Mariucci, E.; Lovato, L.; Brusori, S.; Ritelli, M.; Colombi, M.; Garavelli, L.; Seri, M.; Loeys, B.L.

    2013-01-01

    Recently, mutations in the SMAD3 gene were found to cause a new autosomal dominant aneurysm condition similar to Loeys-Dietz syndrome (LDS), mostly with osteoarthritis, called aneurysms-osteoarthritis syndrome (AOS). Our 3-year-old propositus underwent correction of an inguinal hernia at 3 months an

  18. Triallelic Inheritance of TGM1 and ALOXE3 Mutations Associated with Severe Phenotype of Ichtyosis in an Iranian Family - A Case Report

    Directory of Open Access Journals (Sweden)

    MohammadTaghi AKBARI

    2015-10-01

    Full Text Available Lamellar ichthyosis is one form of congenital autosomal recessive ichthyosis. To date, seven causative genes for ARCI have been identified. To understand further the genetic spectrum of the disease, we analyzed a four-generation Iranian family with ARCI that had observable inheritance. Exome sequencing data for one of the affected individuals with ichthyosis from a consanguineous Iranian family was analyzed. Potential candidate mutations were analyzed in addi-tional family members to determine if the putative mutation segregated with disease status. A novel homozygous mu-tation (p.D414V in TGM1 and rs3027232 in ALOXE3 gene in heterozygous form were identified which segregated with disease status in the family. Bioinformatic studies with Polyphen-2 and SIFT showed that these variants are dam-aging. We identified a possible triallelic inheritance in this study. Moreover, this paper illustrates how advances in ge-nome sequencing technologies could be utilized to rapidly elucidate the molecular basis of inherited skin diseases which can be caused by mutations in multiple disease genes.

  19. Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers

    NARCIS (Netherlands)

    Ghorbanoghli, Z.; Nieuwenhuis, M. H.; Houwing-Duistermaat, J. J.; Jagmohan-Changur, S.; Hes, F. J.; Tops, C. M.; Wagner, A.; Aalfs, C. M.; Verhoef, S.; Garcia, E. B. Gomez; Sijmons, R. H.; Menko, F. H.; Letteboer, T. G.; Hoogerbrugge, N.; van Wezel, T.; Vasen, H. F. A.; Wijnen, J. T.

    2016-01-01

    Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of th

  20. Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis.

    NARCIS (Netherlands)

    Munnik, S.A. de; Bicknell, L.S.; Aftimos, S.; Al-Aama, J.Y.; Bever, Y. Van; Bober, M.B.; Clayton-Smith, J.; Edrees, A.Y.; Feingold, M.; Fryer, A.; Hagen, J.M. van; Hennekam, R.C.M.; Jansweijer, M.C.E.; Johnson, D.; Kant, S.G.; Opitz, J.M.; Ramadevi, A.R.; Reardon, W.; Ross, A.; Sarda, P.; Schrander-Stumpel, C.T.R.M.; Schoots, J.; Temple, I.K.; Terhal, P.A.; Toutain, A.; Wise, C.A.; Wright, M.; Skidmore, D.L.; Samuels, M.E.; Hoefsloot, L.H.; Knoers, N.V.A.M.; Brunner, H.G.; Jackson, A.P.; Bongers, M.H.F.

    2012-01-01

    Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identifi

  1. Genotype-phenotype correlation between the cardiac myosin binding protein C mutation A31P and hypertrophic cardiomyopathy in a cohort of Maine Coon cats

    DEFF Research Database (Denmark)

    Granström, S; Godiksen, M T N; Christiansen, M;

    2015-01-01

    OBJECTIVES: A missense mutation (A31P) in the cardiac myosin binding protein C gene has been associated with hypertrophic cardiomyopathy (HCM) in Maine Coon cats. The aim of this study was to investigate the effect of A31P on development of HCM, myocardial diastolic dysfunction detected by color ...

  2. A New Mouse Model of Limb-Girdle Muscular Dystrophy Type 2I Homozygous for the Common L276I Mutation Mimicking the Mild Phenotype in Humans

    DEFF Research Database (Denmark)

    Krag, Thomas O; Vissing, John

    2015-01-01

    Limb-girdle muscular dystrophy type 2I (LGMD2I) is caused by mutations in the Fukutin-related protein (FKRP) gene, leading to inadequate glycosylation of α-dystroglycan, an important protein linking the extracellular matrix to the cytoskeleton. We created a mouse model of the common FKRP L276I...

  3. Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations.

    Science.gov (United States)

    Guerini-Rocco, Elena; Piscuoglio, Salvatore; Ng, Charlotte K Y; Geyer, Felipe C; De Filippo, Maria R; Eberle, Carey A; Akram, Muzaffar; Fusco, Nicola; Ichihara, Shu; Sakr, Rita A; Yatabe, Yasushi; Vincent-Salomon, Anne; Rakha, Emad A; Ellis, Ian O; Wen, Y Hannah; Weigelt, Britta; Schnitt, Stuart J; Reis-Filho, Jorge S

    2016-04-01

    Microglandular adenosis (MGA) is a rare proliferative lesion of the breast composed of small glands lacking myoepithelial cells and lined by S100-positive, oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative epithelial cells. There is evidence to suggest that MGA may constitute a non-obligate precursor of triple-negative breast cancer (TNBC). We sought to define the genomic landscape of pure MGA and of MGA, atypical MGA (AMGA) and associated TNBCs, and to determine whether synchronous MGA, AMGA, and TNBCs would be clonally related. Two pure MGAs and eight cases of MGA and/or AMGA associated with in situ or invasive TNBC were collected, microdissected, and subjected to massively parallel sequencing targeting all coding regions of 236 genes recurrently mutated in breast cancer or related to DNA repair. Pure MGAs lacked clonal non-synonymous somatic mutations and displayed limited copy number alterations (CNAs); conversely, all MGAs (n = 7) and AMGAs (n = 3) associated with TNBC harboured at least one somatic non-synonymous mutation (range 3-14 and 1-10, respectively). In all cases where TNBCs were analyzed, identical TP53 mutations and similar patterns of gene CNAs were found in the MGA and/or AMGA and in the associated TNBC. In the MGA/AMGA associated with TNBC lacking TP53 mutations, somatic mutations affecting PI3K pathway-related genes (eg PTEN, PIK3CA, and INPP4B) and tyrosine kinase receptor signalling-related genes (eg ERBB3 and FGFR2) were identified. At diagnosis, MGAs associated with TNBC were found to display subclonal populations, and clonal shifts in the progression from MGA to AMGA and/or to TNBC were observed. Our results demonstrate the heterogeneity of MGAs, and that MGAs associated with TNBC, but not necessarily pure MGAs, are genetically advanced, clonal, and neoplastic lesions harbouring recurrent mutations in TP53 and/or other cancer genes, supporting the notion that a subset of MGAs and AMGAs may constitute

  4. Identical Mutation in SH3BP2 Gene Causes Clinical Phenotypes with Different Severity in Mother and Daughter – Case Report

    Science.gov (United States)

    Preda, L.; Dinca, O.; Bucur, A.; Dragomir, C.; Severin, E.

    2010-01-01

    Cherubism is a particular form of fibrous dysplasia of the jaws. Familial occurrence was reported in most cases. The condition is a rare hereditary disorder with autosomal dominant inheritance, with complete penetrance in males and incomplete penetrance in females and variable expressivity. It is known to be caused by mutations in the gene encoding SH3-domain binding protein 2, SH3BP2 gene. Major diagnostic criteria are cherubic facial appearance, painless hard enlargement of the jaws, and frequently associated dental abnormalities. The aim of the study was to analyze clinical and genetic features of cherubism in a family with 3 daughters in which the youngest one was affected. Clinical and radiographic examinations, hematological and biochemical evaluations and biopsy were performed. Molecular genetic analysis consisted of PCR amplification and direct sequencing of selected exons of the SH3BP2 gene. Cherubism was suspected based on clinical and radiographic examinations of the 9-year-old daughter. She presented asymmetrical enlargement of the mandible, speech and swallowing problems and dental abnormalities on the lower jaw. There was no history of similar clinical findings in any of the daughters or the parents of the affected girl. Abnormal results were obtained by genetic analysis. A c.1244G>A mutation was identified in exon 9 of the SH3BP2 gene in the asymptomatic mother and her affected daughter. The identified mutation in the SH3BP2 gene is probably disease-causing. The asymptomatic mother transmitted the gene mutation to her affected daughter. Our results confirm the reduced penetrance and variable expression of the gene mutation. PMID:21045962

  5. Phenotypic spectrum of GABRA1

    DEFF Research Database (Denmark)

    Johannesen, Katrine; Marini, Carla; Pfeffer, Siona

    2016-01-01

    OBJECTIVE: To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations. METHODS: Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected. Functional analy...

  6. TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in KRAS-mutated colorectal cancer cells

    DEFF Research Database (Denmark)

    Tarpgaard, Line S; Ørum-Madsen, Maj Sofie; Christensen, Ib J;

    2016-01-01

    It is now widely accepted that therapeutic antibodies targeting epidermal growth factor receptor (EGFR) can have efficacy in KRAS wild-type advanced colorectal cancer (CRC) patients. What remains to be ascertained is whether a subgroup of KRAS-mutated CRC patients might not also derive benefit from....... The two sets of data, clinical and in vitro, are complementary and support each other, lending strength to our contention that TIMP- 1 plasma levels can identify a subset of patients with KRAS-mutated metastatic CRC that will have benefit from EGFR-inhibition therapy....... EGFR inhibitors. Metalloproteinase inhibitor 1 (TIMP-1) is a pleiotropic factor predictive of survival outcome of CRC patients. Levels of TIMP-1 were measured in pre-treatment plasma samples (n = 426) of metastatic CRC patients randomized to Nordic FLOX (5-fluorouracil and oxaliplatin) +/- cetuximab...

  7. A New Mouse Model of Limb-Girdle Muscular Dystrophy Type 2I Homozygous for the Common L276I Mutation Mimicking the Mild Phenotype in Humans

    DEFF Research Database (Denmark)

    Krag, Thomas O; Vissing, John

    2015-01-01

    Limb-girdle muscular dystrophy type 2I (LGMD2I) is caused by mutations in the Fukutin-related protein (FKRP) gene, leading to inadequate glycosylation of α-dystroglycan, an important protein linking the extracellular matrix to the cytoskeleton. We created a mouse model of the common FKRP L276I...... mutation and a hemizygous FKRP L276I knockout model. We studied histopathology and protein expression in the models at different ages and found that homozygous FKRP L276I mice developed a mild progressive myopathy with increased muscle regeneration and fibrosis starting from 1 year of age. This was likely...... caused by progressive loss of α-dystroglycan-specific glycosylation, which was decreased by 78% at 20 months. The homozygous FKRP knockout was embryonic lethal, but the hemizygous L276I model resembled the homozygous FKRP L276I model at comparable ages. These models emphasize the importance of FKRP...

  8. A point mutation in AgrC determines cytotoxic or colonizing properties associated with phenotypic variants of ST22 MRSA strains

    Science.gov (United States)

    Mairpady Shambat, Srikanth; Siemens, Nikolai; Monk, Ian R.; Mohan, Disha B.; Mukundan, Santhosh; Krishnan, Karthickeyan Chella; Prabhakara, Sushma; Snäll, Johanna; Kearns, Angela; Vandenesch, Francois; Svensson, Mattias; Kotb, Malak; Gopal, Balasubramanian; Arakere, Gayathri; Norrby-Teglund, Anna

    2016-01-01

    Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of skin and soft tissue infections. One of the highly successful and rapidly disseminating clones is MRSA ST22 commonly associated with skin tropism. Here we show that a naturally occurring single amino acid substitution (tyrosine to cysteine) at position 223 of AgrC determines starkly different ST22 S. aureus virulence phenotypes, e.g. cytotoxic or colonizing, as evident in both in vitro and in vivo skin infections. Y223C amino acid substitution destabilizes AgrC-AgrA interaction leading to a colonizing phenotype characterized by upregulation of bacterial surface proteins. The colonizing phenotype strains cause less severe skin tissue damage, show decreased susceptibility towards the antimicrobial LL-37 and induce autophagy. In contrast, cytotoxic strains with tyrosine at position 223 of AgrC cause infections characterized by inflammasome activation and severe skin tissue pathology. Taken together, the study demonstrates how a single amino acid substitution in the histidine kinase receptor AgrC of ST22 strains determines virulence properties and infection outcome. PMID:27511873

  9. FMF Genotype-phenotype correlation in Iranian Azeri Turks: Association between M694V/R761H mutation and amyloidosis

    Directory of Open Access Journals (Sweden)

    Morteza Jabbarpour Bonyadi

    2015-07-01

    Conclusion:In contrast to previous studies, there was no significant association between M694V mutation and development of amyloidosis. The M680I/M680I, M680I, M694I, and M694V/R761H genotypes were found to be associated with the development of amyloidosis. These results indicate that physicians need to pay careful attention to patients with asymptomatic or mildly symptomatic FMF with these genotypes.

  10. Scoliosis in osteogenesis imperfecta caused by COL1A1/COL1A2 mutations - genotype-phenotype correlations and effect of bisphosphonate treatment.

    Science.gov (United States)

    Sato, Atsuko; Ouellet, Jean; Muneta, Takeshi; Glorieux, Francis H; Rauch, Frank

    2016-05-01

    Bisphosphonates are widely used to treat children with osteogenesis imperfecta (OI), a bone fragility disorder that is most often caused by mutations in COL1A1 or COL1A2. However, it is unclear whether this treatment decreases the risk of developing scoliosis. We retrospectively evaluated spine radiographs and charts of 437 patients (227 female) with OI caused by mutations in COL1A1 or COL1A2 and compared the relationship between scoliosis, genotype and bisphosphonate treatment history. At the last follow-up (mean age 11.9 [SD: 5.9] years), 242 (55%) patients had scoliosis. The prevalence of scoliosis was highest in OI type III (89%), followed by OI type IV (61%) and OI type I (36%). Moderate to severe scoliosis (Cobb angle ≥25°) was rare in individuals with COL1A1 haploinsufficiency mutations but was present in about two fifth of patients with triple helical glycine substitutions or C-propeptide mutations. During the first 2 to 4years of bisphosphonate therapy, patients with OI type III had lower Cobb angle progression rates than before bisphosphonate treatment, whereas in OI types I and IV bisphosphonate treatment was not associated with a change in Cobb angle progression rates. At skeletal maturity, the prevalence of scoliosis (Cobb angle >10°) was similar in patients who had started bisphosphonate treatment early in life (before 5.0years of age) and in patients who had started therapy later (after the age of 10.0years) or had never received bisphosphonate therapy. Bisphosphonate treatment decreased progression rate of scoliosis in OI type III but there was no evidence of a positive effect on scoliosis in OI types I and IV. The prevalence of scoliosis at maturity was not influenced by the bisphosphonate treatment history in any OI type.

  11. Mutational spectrum of the CYP1B1 gene in Pakistani patients with primary congenital glaucoma: Novel variants and genotype-phenotype correlations

    OpenAIRE

    Sheikh, Shakeel Ahmed; Waryah, Ali Muhammad; Narsani, Ashok Kumar; Shaikh, Hina; Gilal, Imtiaz Ahmed; Shah, Khairuddin; Qasim, Muhammad; Memon, Azam Iqbal; Kewalramani, Pitambar; Shaikh, Naila

    2014-01-01

    Purpose This study aimed to investigate the role of CYP1B1 mutations in primary congenital glaucoma (PCG) in Pakistani patients. Methods After consent was received, 20 families with at least more than one member affected with primary congenital glaucoma were enrolled in the study. The disease was confirmed with standard ophthalmological investigations. Genomic DNA was extracted from whole blood for localization of linkage and sequencing. Bioinformatics tools were used to assess the predicted ...

  12. Identification of Factors Interacting with hMSH2 and hMLH1 in the Fetal Liver and Investigations of how Mitochondrial Dysfunction Creates a Mutator Phenotype

    DEFF Research Database (Denmark)

    Rasmussen, Anne Karin

    Increased spontaneous mutation frequency is associated with increased cancer risk. However, the relative contribution of spontaneous endogenous mutagenesis to carcinogenesis is not known today. Defects in the postreplication DNA mismatch repair (MMR) pathway are recognized to increase spontaneous...... decided to investigate O6-methylguanine- DNA methyltransferase (MGMT) because of the fact that its sub-cellular localization has not been determined. We determined that it was localized to nucleus but not to mitochondria in HeLa and breast epithelial cells....

  13. Urea Cycle Defects: Early-Onset Disease Associated with A208T Mutation in OTC Gene—Expanding the Clinical Phenotype

    Science.gov (United States)

    Sánchez, Ana Isabel; Rincón, Alejandra; García, Mary

    2017-01-01

    Ornithine transcarbamylase deficiency (OMIM: 311250) is the most common disorder of urea cycle disorders, accounting for nearly 50% of all cases. We report a case of a two-month- old male patient, who attends our medical genetics consultation because of low citrulline levels and elevated glutamine to citrulline ratio detected by expanded newborn screening with tandem mass spectrometry. He is an asymptomatic male with a normal physical examination and appropriate neurodevelopmental milestones. The patient has a family history of one older brother who died at 18 months old from severe and sudden hyperammonemia and a maternal aunt who suddenly died at two years old. He had high plasma ammonium concentration and a confirmed OTC mutation (p.A208T). Usually, this mutation causes OTC deficiency of late onset in adult males. However, this report raises awareness about mutations previously described as a late-onset causing disease, which can cause severe hyperammonemia and high risk of dying at an early age. PMID:28261508

  14. Phenotypic patterns of MELAS/LS overlap syndrome associated with m.13513G>A mutation, and neuropathological findings in one autopsy case.

    Science.gov (United States)

    Wang, Zhaoxia; Qi, Xiao Kun; Yao, Sheng; Chen, Bin; Luan, Xinghua; Zhang, Wei; Han, Manfu; Yuan, Yun

    2010-12-01

    The 13513G>A mutation in the ND5 gene of mitochondrial DNA (mtDNA) is usually associated with mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS), or Leigh syndrome (LS). In this study, we describe three young Chinese patients with MELAS/LS overlap syndrome who carried the m.13513G>A mutation. Clinical and MRI features were characteristic of both MELAS and LS. Interestingly, the clinical presentation of this overlap syndrome could be variable depending on the degree of relative contribution of MELAS and LS, that is, MELAS as the initial presenting syndrome, LS as the predominant syndrome, or both MELAS and LS appearing at the same time. The final brain MRI showed findings characteristic of both MELAS and LS, with asymmetrical lesions in the cortex and subcortical white matter of the occipital, temporal, and frontal lobes (MELAS), and bilateral and symmetrical lesions in the basal ganglia and brainstem (LS). Brain autopsy in one case revealed infarct-like lesions in the cerebral cortex, basal ganglia and brainstem, providing further insight into the distribution of the pathological lesions in MELAS/LS overlap syndrome. This is the first report of the brain pathological changes in a patient with m.13513G>A mutation. The spatial distribution of infarct-like lesions in the brain could explain the symptoms in MELAS/LS overlap syndrome.

  15. A New Mouse Model of Limb-Girdle Muscular Dystrophy Type 2I Homozygous for the Common L276I Mutation Mimicking the Mild Phenotype in Humans.

    Science.gov (United States)

    Krag, Thomas O; Vissing, John

    2015-12-01

    Limb-girdle muscular dystrophy type 2I (LGMD2I) is caused by mutations in the Fukutin-related protein (FKRP) gene, leading to inadequate glycosylation of α-dystroglycan, an important protein linking the extracellular matrix to the cytoskeleton. We created a mouse model of the common FKRP L276I mutation and a hemizygous FKRP L276I knockout model. We studied histopathology and protein expression in the models at different ages and found that homozygous FKRP L276I mice developed a mild progressive myopathy with increased muscle regeneration and fibrosis starting from 1 year of age. This was likely caused by progressive loss of α-dystroglycan-specific glycosylation, which was decreased by 78% at 20 months. The homozygous FKRP knockout was embryonic lethal, but the hemizygous L276I model resembled the homozygous FKRP L276I model at comparable ages. These models emphasize the importance of FKRP in maintaining proper glycosylation of α-dystroglycan. The mild progression in the homozygous FKRP L276I model resembles that in patients with LGMD2I who are homozygous for the L276I mutation. This animal model could, therefore, be relevant for understanding the pathophysiology of and developing a treatment strategy for the human disorder.

  16. Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL in humans.

    Directory of Open Access Journals (Sweden)

    Vafa Bayat

    Full Text Available An increasing number of genes required for mitochondrial biogenesis, dynamics, or function have been found to be mutated in metabolic disorders and neurological diseases such as Leigh Syndrome. In a forward genetic screen to identify genes required for neuronal function and survival in Drosophila photoreceptor neurons, we have identified mutations in the mitochondrial methionyl-tRNA synthetase, Aats-met, the homologue of human MARS2. The fly mutants exhibit age-dependent degeneration of photoreceptors, shortened lifespan, and reduced cell proliferation in epithelial tissues. We further observed that these mutants display defects in oxidative phosphorylation, increased Reactive Oxygen Species (ROS, and an upregulated mitochondrial Unfolded Protein Response. With the aid of this knowledge, we identified MARS2 to be mutated in Autosomal Recessive Spastic Ataxia with Leukoencephalopathy (ARSAL patients. We uncovered complex rearrangements in the MARS2 gene in all ARSAL patients. Analysis of patient cells revealed decreased levels of MARS2 protein and a reduced rate of mitochondrial protein synthesis. Patient cells also exhibited reduced Complex I activity, increased ROS, and a slower cell proliferation rate, similar to Drosophila Aats-met mutants.

  17. Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn's disease: Phenotype-genotype correlations

    Institute of Scientific and Technical Information of China (English)

    Peter Laszlo Lakatos; Gyula Mozsik; Hungarian IBD Study Group; Peter Ferenci; Laszlo Lakatos; Ferenc Szalay; Claudia Willheim-Polli; Christoph (O)sterreicher; Zsolt Tulassay; Tamas Molnar; Walter Reinisch; Janos Papp

    2005-01-01

    AIM: To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD.METHODS: A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 healthy subjects were included. DNA was screened for possible NOD2/CARD15 mutations by denaturing highperformance liquid chromatography (confirmed by direct sequencing). TLR4 D299G was tested by PCR-RFLP.RESULTS: NOD2/CARD15 mutations were found in 185patients (35.1%) and in 33 controls (16.5%, P<0.0001).SNP8/R702W (10.8% vs 6%, P = 0.02), SNP13/3020insC (19.4% vs 5%, P<0.0001) and exon4 R703C (2.1% vs 0%, P = 0.02) mutations were more frequent in CD, while the frequency of SNP12/G908R was not increased. The frequency of TLR4 D299G was not different (CD: 9.9% vscontrols: 12.0%). Variant NOD2/CARD15 allele was associated with an increased risk for CD (ORhet = 1.71,95%CI = 1.12-2.6, P= 0.0001, ORtwo-riskalleles = 25.2,95%CI = 4.37- , P<0.0001), early disease onset (carrier:26.4 years vs non-carrier: 29.8 years, P = 0.0006), ileal disease (81.9% vs 69.5%, OR = 1.99, 95%CI = 1.29-3.08,P = 0.02, presence of NOD2/CARD15 and TLR4: 86.7% vs64.8%), stricturing behavior (OR = 1.69, 95%CI = 1.13-2.55,P = 0.026) and increased need for resection (OR=1.71,95%CI: 1.13-2.62, P= 0.01), but not with duration, extraintestinal manifestations, familial disease or smoking. TLR4exhibited a modifier effect: age of onset in wt/TLR4 D299G carriers: 27.4 years vs NOD2mut/TLR D299G: 23 years (P= 0.06), in NOD2mut/wt: 26.7 years.CONCLUSION: These results confirm that variant NOD2/CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease,stricturing disease behavior in Hungarian CD patients. In contrast, although the frequency of TLR4 D299G polymorphism was not different from controls, NOD2/TLR4mutation carriers tended to present at earlier age.

  18. Features of gene mutation and clinical phenotype in Alport syndrome%Alport 综合征家系的基因突变及临床表型分析

    Institute of Scientific and Technical Information of China (English)

    何威; 高春林; 夏正坤

    2016-01-01

    目的: Alport综合征( Alport syndrome,AS)是常见的遗传性肾小球疾病,且目前认为有3种遗传方式,文中分析AS家系的基因突变特征,总结临床表型特点。方法应用二代测序外显子序列捕获技术对30例确诊或疑似AS患儿的COL4A3、COL4A4、COL4A5基因进行测序,对其家系成员针对突变位点进行Sanger测序验证;并经Provean对基因突变进行蛋白功能预测。收集临床资料,并结合基因突变结果进行分析。结果30例患儿经基因测序后均可明确诊断为AS。其中常染色体隐性遗传4例,均为男性患儿;X连锁显性遗传26例,男性患儿16例,女性患儿10例。二代测序结果共检测出不同的COL4A3、COL4A4、COL4A5基因突变35个,其中包括错义突变19个、同义突变2个、剪切位点突变4个、无义突变3个、插入突变2个、缺失突变4个、复杂突变1个。通过Sanger测序对家系成员进行验证,结果发现20个突变来源于母亲、8个突变来源于父亲、8个为新生突变、1个先证者纯合基因突变分别来自父母双方、1个突变来源不详。30例患儿均以血尿和(或)蛋白尿起病,17例患儿合并阳性家族史,1例合并高频神经性耳聋,无患儿出现眼部病变及肾功能不全。23例患儿行肾穿刺活检,光镜可见肾小球微小病变为13例,系膜增生性病变10例。电镜下,仅9例表现为肾小球基膜致密层分层撕裂等AS典型改变。结论 AS以X连锁显性遗传多见,致病性突变以错义突变为主。 AS患儿病理多表现为肾小球轻微病变,电镜表现常不典型,肾外表现少见。%Objective The article was to analyze the features of gene mutation and clinical phenotype in Alport syndrome. Methods Next-generation sequencing was applied to capture the exons of COL4A3, COL4A4, COL4A5 genes in 30 cases of children with suspected or confirmed diagnosis of Alport syndrome and Sanger method

  19. MIDD or MELAS : that's not the question MIDD evolving into MELAS : a severe phenotype of the m.3243A>G mutation due to paternal co-inheritance of type 2 diabetes and a high heteroplasmy level.

    Science.gov (United States)

    de Wit, H M; Westeneng, H J; van Engelen, B G M; Mudde, A H

    2012-12-01

    Maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) are different syndromes, but are caused by the same m.3243A>G mutation in mitochondrial DNA. Why some patients develop MIDD while others MELAS is unknown, but may be related to heteroplasmy level. Progression from MIDD to MELAS has not been described. Here we report a patient with MIDD who over time developed severe insulin resistance and symptoms and signs consistent with MELAS. The most likely explanation here was paternal co-inheritance of type 2 diabetes in combination with a high heteroplasmy level. The present case showing evolution of MIDD to MELAS supports the concept that both syndromes can be regarded as two phenotypes of the same disease.

  20. Homozygosity for a severe novel medium-chain acyl-CoA dehydrogenase (MCAD) mutation IVS3-1G > C that leads to introduction of a premature termination codon by complete missplicing of the MCAD mRNA and is associated with phenotypic diversity ranging from sudden neonatal death to asymptomatic

    DEFF Research Database (Denmark)

    Korman, Stanley H; Gutman, Alisa; Brooks, Rivka

    2004-01-01

    sibling had also died in similar circumstances aged 3 weeks. Urine organic acid and bloodspot acylcarnitine analysis were consistent with MCADD. He was homozygous for a novel MCAD splice mutation, IVS3-1G > C. This mutation leads to deletion of 7 bp and introduction of a premature termination codon...... > A susceptibility variant. Interestingly, all family members were 625G > A homozygous. Additional genetic and/or environmental factors must play a major role in determining the phenotypic diversity of MCADD....

  1. Frequency and phenotype of patients carrying TPM2 and TPM3 gene mutations in a cohort of 94 patients with congenital myopathy

    DEFF Research Database (Denmark)

    Citirak, Gulsenay; Witting, Nanna; Duno, Morten;

    2014-01-01

    Congenital myopathies are difficult to classify correctly through molecular testing due to the size and heterogeneity of the genes involved. Therefore, the prevalence of the various genetic causes of congenital myopathies is largely unknown. In our cohort of 94 patients with congenital myopathy...... patients carrying the same mutations as found in our study (c.503G>A, and c.502C>T in TPM3, and c.415_417delGAG in TPM2), clinical presentation and muscle morphological findings differed in our patients. Differences included variation in distribution of muscle weakness, presence of scoliosis and ptosis...

  2. [A case of Charcot-Marie-Tooth disease 1 B with Val 146Phe mutation of myelin protein zero showing a severe clinical phenotype].

    Science.gov (United States)

    Ohnishi, A; Aoki, A; Yamamoto, T; Tsuji, S

    2000-03-01

    A 15-year-old boy had complaints of progressive gait disturbance and foot deformity. He started to walk at the age of 18 months. Since two years of age, he had noticed unstable gait. He showed evident scoliosis and enlarged great auricular nerves. Moderate to slight degrees of muscular atrophy and weakness of distal upper, and proximal and distal lower limbs were observed. Pes equinovarus deformity of both feet was obvious. Muscle stretch reflexes were absent in both limbs except decreased triceps brachii reflex. Vibratory sensation was decreased severely in the toes and mildly in the fingers. In cerebrospinal fluid, protein was mildly elevated. Median nerve motor conduction velocity was 5.0 m/sec. On sural nerve biopsy, both demyelinated and remyelinated axons and onion-bulbs without hypomyelination were observed. Therefore, the diagnosis of Charcot-Marie-Tooth disease 1 was made. The direct sequencing of the genomic DNA encoding the Po gene revealed a mutant allele, a guanine to thymine substitution of nucleotide position 436, which caused a substitution of phenylalanine for valine at amino acid position 146. This type of Po mutation is different from any type of Po mutation reported in the literature.

  3. Trans-complementation by human apurinic endonuclease (Ape) of hypersensitivity to DNA damage and spontaneous mutator phenotype in apn1-yeast.

    Science.gov (United States)

    Wilson, D M; Bennett, R A; Marquis, J C; Ansari, P; Demple, B

    1995-01-01

    Abasic (AP) sites in DNA are potentially lethal and mutagenic. 'Class II' AP endonucleases initiate the repair of these and other DNA lesions. In yeast, the predominant enzyme of this type is Apn1, and its elimination sensitizes the cells to killing by simple alkylating agents or oxidants, and raises the rate of spontaneous mutation. We investigated the ability of the major human class II AP endonuclease, Ape, which is structurally unrelated to Apn1, to replace the yeast enzyme in vivo. Confocal immunomicroscopy studies indicate that approximately 25% of the Ape expressed in yeast is present in the nucleus. High-level Ape expression corresponding to approximately 7000 molecules per nucleus, equal to the normal Apn1 copy number, restored resistance to methyl methanesulfonate to near wild-type levels in Apn1-deficient (apn1-) yeast. Ape expression in apn1- yeast provided little protection against H2O2 challenges, consistent with the weak 3'-repair diesterase activity of the human enzyme. Ape expression at approximately 2000 molecules per nucleus reduced the spontaneous mutation rate of apn1- yeast to that seen for wild-type cells. Because Ape has a powerful AP endonuclease but weak 3'-diesterase activity, these findings indicate that endogenously generated AP sites can drive spontaneous mutagenesis. Images PMID:8559661

  4. Mutations in human C2CD3 cause skeletal dysplasia and provide new insights into phenotypic and cellular consequences of altered C2CD3 function

    Science.gov (United States)

    Cortés, Claudio R.; McInerney-Leo, Aideen M.; Vogel, Ida; Rondón Galeano, Maria C.; Leo, Paul J.; Harris, Jessica E.; Anderson, Lisa K.; Keith, Patricia A.; Brown, Matthew A.; Ramsing, Mette; Duncan, Emma L.; Zankl, Andreas; Wicking, Carol

    2016-01-01

    Ciliopathies are a group of genetic disorders caused by defective assembly or dysfunction of the primary cilium, a microtubule-based cellular organelle that plays a key role in developmental signalling. Ciliopathies are clinically grouped in a large number of overlapping disorders, including the orofaciodigital syndromes (OFDS), the short rib polydactyly syndromes and Jeune asphyxiating thoracic dystrophy. Recently, mutations in the gene encoding the centriolar protein C2CD3 have been described in two families with a new sub-type of OFDS (OFD14), with microcephaly and cerebral malformations. Here we describe a third family with novel compound heterozygous C2CD3 mutations in two fetuses with a different clinical presentation, dominated by skeletal dysplasia with no microcephaly. Analysis of fibroblast cultures derived from one of these fetuses revealed a reduced ability to form cilia, consistent with previous studies in C2cd3-mutant mouse and chicken cells. More detailed analyses support a role for C2CD3 in basal body maturation; but in contrast to previous mouse studies the normal recruitment of the distal appendage protein CEP164 suggests that this protein is not sufficient for efficient basal body maturation and subsequent axonemal extension in a C2CD3-defective background. PMID:27094867

  5. The expanding clinical phenotype of the tRNA{sup Leu(UUR)} A{r_arrow}G mutation at np 3243 of mitochondrial DNA: Diabetic embryopathy associated with mitochondrial cytopathy

    Energy Technology Data Exchange (ETDEWEB)

    Feigenbaum, A.; Chitayat, D.; Robinson, B.; MacGregor, D.; Myint, T. [Univ. of Toronto, Ontario (Canada)] [and others

    1996-04-24

    We describe a family which demonstrates and expands the extreme clinical variability now known to be associated with the A{r_arrow}G transition at nucleotide position 3243 of the mitochondrial DNA. The propositus presented at birth with clinical manifestations consistent with diabetic embryopathy including anal atresia, caudal dysgenesis, and multicystic dysplastic kidneys. His co-twin was normal at birth, but at 3 months of life, presented with intractable seizures later associated with developmental delay. The twins` mother developed diabetes mellitus type I at the age of 20 years and gastrointestinal problems at 22 years. Since age 19 years, the maternal aunt has had recurrent strokes, seizures, mental deterioration and deafness, later diagnosed as MELAS syndrome due to the tRNA{sup Leu(UUR)} A{r_arrow}G mutation. A maternal uncle had diabetes mellitus type I, deafness, and normal intellect, and died at 35 years after recurrent strokes. This pedigree expands the known clinical phenotype associated with tRNA{sup Leu(UUR)} A{r_arrow}G mutation and raises the possibility that, in some cases, diabetic embryopathy may be due to a mitochondrial cytopathy that affects both the mother`s pancreas (and results in diabetes mellitus and the metabolic dysfunction associated with it) and the embryonic/fetal and placental tissues which make the embryo more vulnerable to this insult. 33 refs., 1 tab.

  6. Differences in the phenotypic effects of mutations in homologous MrpA and MrpD subunits of the multi-subunit Mrp-type Na(+)/H(+) antiporter.

    Science.gov (United States)

    Morino, Masato; Ogoda, Shinichiro; Krulwich, Terry Ann; Ito, Masahiro

    2017-01-01

    Mrp antiporters are the sole antiporters in the Cation/Proton Antiporter 3 family of transporter databases because of their unusual structural complexity, 6-7 hydrophobic proteins that function as a hetero-oligomeric complex. The two largest and homologous subunits, MrpA and MrpD, are essential for antiport activity and have direct roles in ion transport. They also show striking homology with proton-conducting, membrane-embedded Nuo subunits of respiratory chain complex I of bacteria, e.g., Escherichia coli. MrpA has the closest homology to the complex I NuoL subunit and MrpD has the closest homology to the complex I NuoM and N subunits. Here, introduction of mutations in MrpD, in residues that are also present in MrpA, led to defects in antiport function and/or complex formation. No significant phenotypes were detected in strains with mutations in corresponding residues of MrpA, but site-directed changes in the C-terminal region of MrpA had profound effects, showing that the MrpA C-terminal region has indispensable roles in antiport function. The results are consistent with a divergence in adaptations that support the roles of MrpA and MrpD in secondary antiport, as compared to later adaptations supporting homologs in primary proton pumping by the respiratory chain complex I.

  7. Somatic mosaicism caused by monoallelic reversion of a mutation in T cells of a patient with ADA-SCID and the effects of enzyme replacement therapy on the revertant phenotype.

    Science.gov (United States)

    Moncada-Vélez, M; Vélez-Ortega, A; Orrego, J; Santisteban, I; Jagadeesh, J; Olivares, M; Olaya, N; Hershfield, M; Candotti, F; Franco, J

    2011-11-01

    Patients with adenosine deaminase (ADA) deficiency exhibit spontaneous and partial clinical remission associated with somatic reversion of inherited mutations. We report a child with severe combined immunodeficiency (T-B- SCID) due to ADA deficiency diagnosed at the age of 1 month, whose lymphocyte counts including CD4+ and CD8+ T and NK cells began to improve after several months with normalization of ADA activity in Peripheral blood lymphocytes (PBL), as a result of somatic mosaicism caused by monoallelic reversion of the causative mutation in the ADA gene. He was not eligible for haematopoietic stem cell transplantation (HSCT) or gene therapy (GT); therefore he was placed on enzyme replacement therapy (ERT) with bovine PEG-ADA. The follow-up of metabolic and immunologic responses to ERT included gradual improvement in ADA activity in erythrocytes and transient expansion of most lymphocyte subsets, followed by gradual stabilization of CD4+ and CD8+ T (with naïve phenotype) and NK cells, and sustained expansion of TCRγδ+ T cells. This was accompanied by the disappearance of the revertant T cells as shown by DNA sequencing from PBL. Although the patient's clinical condition improved marginally, he later developed a germinal cell tumour and eventually died at the age of 67 months from sepsis. This case adds to our current knowledge of spontaneous reversion of mutations in ADA deficiency and shows that the effects of the ERT may vary among these patients, suggesting that it could depend on the cell and type in which the somatic mosaicism is established upon reversion.

  8. Genotype and phenotype of female Dravet syndrome with PCDH19 mutations%PCDH19基因突变导致的女性Dravet综合征的基因型和表型特点

    Institute of Scientific and Technical Information of China (English)

    刘爱杰; 张月华; 许小菁; 杨小玲; 杨志仙; 吴晔; 刘晓燕; 姜玉武; 吴希如

    2016-01-01

    目的 探讨PCDH19基因突变阳性的女性Dravet综合征(DS)患儿的基因型和表型特点.方法 前瞻性收集2005年2月至2015年5月在北京大学第一医院儿科就诊的DS患儿及其家系成员的临床资料和外周血DNA.以SCN1A基因突变筛查阴性的女性DS患儿为研究对象,采用Sanger测序的方法筛查PCDH19基因突变,分析PCDH19基因突变阳性女性患儿的基因型和临床特点.结果 共收集75例SCN1A基因突变阴性的女性DS患儿,其中6例发现PCDH19基因杂合突变,突变率8% (6/75);5例为新生突变,1例为遗传性突变.共检测到5种突变类型,均位于第1外显子,其中错义突变3种,碱基插入突变2种.6例携带PCDH19基因突变的患儿起病年龄为5~9月龄,平均6.8个月;首次发作由发热诱发者4例,接种疫苗后发作1例,无热发作1例.6例病程中表现为多种发作类型,均有全面强直-阵挛发作和局灶性发作,3例有肌阵挛发作,不典型失神发作和失张力发作各1例.6例患儿病程中癫痫发作均有热敏感和丛集性的特点,均有智力发育落后;2例有孤独症样表现,3例有共济失调.结论 PCDH19是继SCN1A之后DS的另一个重要致病基因,且以新生突变为主,该基因突变导致的女性DS患儿以全面强直-阵挛发作和局灶性发作为主,发作具有热敏感和丛集性的特点,且多数发作持续时间短,常有智力发育落后,部分可有孤独症样表现.%Objective To explore the genotype and phenotype of female Dravet syndrome (DS) patients with PCDH19 mutations.Method Clinical data of all DS patients seen at Pediatric Department of Peking University First Hospital from February 2005 to May 2015 were prospectively collected.Genomic DNAs were extracted from the patients and their family members.Female DS patients without SCN1A mutation were enrolled.PCR and Sanger sequencing were performed to identify PCDH19 mutations.Clinical data of DS patients with PCDH19 mutations were

  9. Loss-of-function mutations of retromer large subunit genes suppress the phenotype of an Arabidopsis zig mutant that lacks Qb-SNARE VTI11.

    Science.gov (United States)

    Hashiguchi, Yasuko; Niihama, Mitsuru; Takahashi, Tetsuya; Saito, Chieko; Nakano, Akihiko; Tasaka, Masao; Morita, Miyo Terao

    2010-01-01

    Arabidopsis thaliana zigzag (zig) is a loss-of-function mutant of Qb-SNARE VTI11, which is involved in membrane trafficking between the trans-Golgi network and the vacuole. zig-1 exhibits abnormalities in shoot gravitropism and morphology. Here, we report that loss-of-function mutants of the retromer large subunit partially suppress the zig-1 phenotype. Moreover, we demonstrate that three paralogous VPS35 genes of Arabidopsis have partially overlapping but distinct genetic functions with respect to zig-1 suppression. Tissue-specific complementation experiments using an endodermis-specific SCR promoter show that expression of VPS35B or VPS35C cannot complement the function of VPS35A. The data suggest the existence of functionally specialized paralogous VPS35 genes that nevertheless share common functions.

  10. Loss-of-Function Mutations of Retromer Large Subunit Genes Suppress the Phenotype of an Arabidopsis zig Mutant That Lacks Qb-SNARE VTI11[C][W

    Science.gov (United States)

    Hashiguchi, Yasuko; Niihama, Mitsuru; Takahashi, Tetsuya; Saito, Chieko; Nakano, Akihiko; Tasaka, Masao; Morita, Miyo Terao

    2010-01-01

    Arabidopsis thaliana zigzag (zig) is a loss-of-function mutant of Qb-SNARE VTI11, which is involved in membrane trafficking between the trans-Golgi network and the vacuole. zig-1 exhibits abnormalities in shoot gravitropism and morphology. Here, we report that loss-of-function mutants of the retromer large subunit partially suppress the zig-1 phenotype. Moreover, we demonstrate that three paralogous VPS35 genes of Arabidopsis have partially overlapping but distinct genetic functions with respect to zig-1 suppression. Tissue-specific complementation experiments using an endodermis-specific SCR promoter show that expression of VPS35B or VPS35C cannot complement the function of VPS35A. The data suggest the existence of functionally specialized paralogous VPS35 genes that nevertheless share common functions. PMID:20086190

  11. Correlation of the level of full-length CFTR transcript with pulmonary phenotype in patients carrying R117H and 1342-1,-2delAG mutations

    Energy Technology Data Exchange (ETDEWEB)

    Hamosh, A.; Cutting, G.R. [Johns Hopkins Univ. School of Medicine, Balitmore, MD (United States); Oates, R.; Amos, J. [Boston Univ. School of Medicine, Boston, MA (United States)

    1994-09-01

    The R117H mutation occurs on two chromosome backgrounds, one associated with a 7 thymidine tract (7T-R11H) in the splice-acceptor site of intron 8, the other with a 5 thymidine tract (5T-R117H). We examined exon 9 splicing efficiency in 5 patients of genotype R117H/{delta}F508 and one carrying 1342-1,-2delAG{delta}F508, an obligate exon 9 slice site mutation. Four patients carried R117H on a 7T background -- three adult men with congenital bilateral absence of the vas deferens and one adolescent female with pancreatitis and borderline sweat chloride concentration. The patient with R117H on a 5T background had pancreatic sufficient CF (PS-CF). The 1342-1,-2delAG patient has classic pancreatic insufficient CF (PI-CF). cDNA was synthesized from total RNA extracted from nasal epithlial cells and analyzed for CFTR splicing by 35 cycle PCR using primers in exon 7 and 11. The quantity of full length transcript derived from the R117H or {delta}F508 alleles was assessed by allele-specific oligonucleotide hybridization. While 91.4% of transcript from the 5T-R117H allele was full-length, only 42.2% of CFTR transcript from the 5T-R117H allele was full length. Since CBAVD patients have no lung disease and PS-CF patients do, this indicates that the threshold of developing CF lung disease is crossed when the amount of CFTR transcript bearing R117H is reduced by half. Interestingly, 17.1% of transcript derived from the 1342-1,-2delAG allele (or 8.6% of total CFTR transcript) was normal and full length. This suggests that up to 9% of full length wild-type CFTR transcript may be inadequate to escape the lung disease of CF and that a 9 thymidine tract followed by AAC (the result of the AG deletion) can be used as a splice donor with 2-9% efficiency.

  12. Meiotic and Mitotic Phenotypes Conferred by the blm1-1 Mutation in Saccharomyces cerevisiae and MSH4 Suppression of the Bleomycin Hypersusceptibility

    Directory of Open Access Journals (Sweden)

    Carol Wood Moore

    2003-01-01

    Full Text Available Abstract: Oxidative damage can lead to a number of diseases, and can be fatal. The blm1-1 mutation of Saccharomyces cerevisiae confers hypersusceptibility to lethal effects of the oxidative, anticancer and antifungal agent, bleomycin. For the current report, additional defects conferred by the mutation in meiosis and mitosis were investigated. The viability of spores produced during meiosis by homozygous normal BLM1/BLM1, heterozygous BLM1/blm1-1, and homozygous mutant blm1-1/blm1-1 diploid strains was studied and compared. Approximately 88% of the tetrads derived from homozygous blm1-1/blm1-1 mutant diploid cells only produced one or two viable spores. In contrast, just one tetrad among all BLM1/BLM1 and BLM1/blm1-1 tetrads only produced one or two viable spores. Rather, 94% of BLM1/BLM1 tetrads and 100% of BLM1/blm1-1 tetrads produced asci with four or three viable spores. Thus, at least one copy of the BLM1 gene is essential for the production of four viable spores after meiosis. During mitotic growth, mutant blm1-1 strains grew at reduced rates and produced cells with high frequencies of unusual morphologies compared to wild-type strains. These results indicated BLM1 is also essential for normal mitotic growth. We also investigated the suppression by the MSH4 gene, a meiosis-specific MutS homolog, of the bleomycin hypersusceptibility of blm1-1 mutant cells, and the relationship of MSH4 to BLM1. We screened a genomic library, and isolated the MSH4 gene on the basis of its ability to suppress lethal effects of bleomycin in blm1-1 cells. However, genetic mapping studies indicated that BLM1 and MSH4 are not the same gene. The possibility that chromosomal nondisjunction could be the basis for the inability of blm1-1/blm1-1 mutant cells to produce four viable spores after meiosis is discussed.

  13. Differential radiosensitivity phenotypes of DNA-PKcs mutations affecting NHEJ and HRR systems following irradiation with gamma-rays or very low fluences of alpha particles.

    Science.gov (United States)

    Lin, Yu-Fen; Nagasawa, Hatsumi; Little, John B; Kato, Takamitsu A; Shih, Hung-Ying; Xie, Xian-Jin; Wilson, Paul F; Brogan, John R; Kurimasa, Akihiro; Chen, David J; Bedford, Joel S; Chen, Benjamin P C

    2014-01-01

    We have examined cell-cycle dependence of chromosomal aberration induction and cell killing after high or low dose-rate γ irradiation in cells bearing DNA-PKcs mutations in the S2056 cluster, the T2609 cluster, or the kinase domain. We also compared sister chromatid exchanges (SCE) production by very low fluences of α-particles in DNA-PKcs mutant cells, and in homologous recombination repair (HRR) mutant cells including Rad51C, Rad51D, and Fancg/xrcc9. Generally, chromosomal aberrations and cell killing by γ-rays were similarly affected by mutations in DNA-PKcs, and these mutant cells were more sensitive in G1 than in S/G2 phase. In G1-irradiated DNA-PKcs mutant cells, both chromosome- and chromatid-type breaks and exchanges were in excess than wild-type cells. For cells irradiated in late S/G2 phase, mutant cells showed very high yields of chromatid breaks compared to wild-type cells. Few exchanges were seen in DNA-PKcs-null, Ku80-null, or DNA-PKcs kinase dead mutants, but exchanges in excess were detected in the S2506 or T2609 cluster mutants. SCE induction by very low doses of α-particles is resulted from bystander effects in cells not traversed by α-particles. SCE seen in wild-type cells was completely abolished in Rad51C- or Rad51D-deficient cells, but near normal in Fancg/xrcc9 cells. In marked contrast, very high levels of SCEs were observed in DNA-PKcs-null, DNA-PKcs kinase-dead and Ku80-null mutants. SCE induction was also abolished in T2609 cluster mutant cells, but was only slightly reduced in the S2056 cluster mutant cells. Since both non-homologous end-joining (NHEJ) and HRR systems utilize initial DNA lesions as a substrate, these results suggest the possibility of a competitive interference phenomenon operating between NHEJ and at least the Rad51C/D components of HRR; the level of interaction between damaged DNA and a particular DNA-PK component may determine the level of interaction of such DNA with a relevant HRR component.

  14. Distinct Niemann-Pick Disease Type C Clinical, Cytological, and Biochemical Phenotype in an Adult Patient With 1 Mutated, Overexpressed NPC1 Allele

    Directory of Open Access Journals (Sweden)

    Julia Jecel MD

    2015-11-01

    Full Text Available Niemann-Pick disease type C (NP-C is a rare autosomal-recessive neurovisceral lysosomal storage disease. We report on a juvenile onset, now 25-year-old female patient with typical neurologic symptoms, including vertical gaze palsy, of NP-C. The diagnosis was supported by a positive filipin test (“variant biochemical phenotype” of cholesterol accumulation in cultured fibroblasts, high numbers of “Niemann-Pick cells” in the bone marrow, and 1 positive out of 3 NP-C biomarkers tested, but NP-C was not definitely confirmed genetically. She showed only 1 known NPC1 variant (3 bp deletion in exon 18; p.N916del; this allele, however, being distinctly overexpressed at the messenger RNA level as compared to the wild-type allele, as a not as yet clarified (copathogenic? phenomenon. The patient’s mother, also carrying the p.N916del allele but without overexpression, has a chronic inflammatory disease of the central nervous system classified as multiple sclerosis. However, her severe clinical phenotype includes some signs also consistent with NP-C. The laboratory diagnosis of NP-C can be challenging in detecting novel disease constellations.

  15. Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus.

    Science.gov (United States)

    Cacciagli, Pierre; Sutera-Sardo, Julie; Borges-Correia, Ana; Roux, Jean-Christophe; Dorboz, Imen; Desvignes, Jean-Pierre; Badens, Catherine; Delepine, Marc; Lathrop, Mark; Cau, Pierre; Lévy, Nicolas; Girard, Nadine; Sarda, Pierre; Boespflug-Tanguy, Odile; Villard, Laurent

    2013-09-05

    BAP31 is one of the most abundant endoplasmic reticulum (ER) membrane proteins. It is a chaperone protein involved in several pathways, including ER-associated degradation, export of ER proteins to the Golgi apparatus, and programmed cell death. BAP31 is encoded by BCAP31, located in human Xq28 and highly expressed in neurons. We identified loss-of-function mutations in BCAP31 in seven individuals from three families. These persons suffered from motor and intellectual disabilities, dystonia, sensorineural deafness, and white-matter changes, which together define an X-linked syndrome. In the primary fibroblasts of affected individuals, we found that BCAP31 deficiency altered ER morphology and caused a disorganization of the Golgi apparatus in a significant proportion of cells. Contrary to what has been described with transient-RNA-interference experiments, we demonstrate that constitutive BCAP31 deficiency does not activate the unfolded protein response or cell-death effectors. Rather, our data demonstrate that the lack of BAP31 disturbs ER metabolism and impacts the Golgi apparatus, highlighting an important role for BAP31 in ER-to-Golgi crosstalk. These findings provide a molecular basis for a Mendelian syndrome and link intracellular protein trafficking to severe congenital brain dysfunction and deafness.

  16. Signature-tagging of a bacterial isolate demonstrates phenotypic variability of the progeny in vivo in the absence of defined mutations

    Science.gov (United States)

    Whitby, Paul W.; VanWagoner, Timothy M.; Morton, Daniel J.; Seale, Thomas W.; Springer, Jennifer M.; Hempel, Randy J.; Stull, Terrence L.

    2012-01-01

    Awareness of the high degree of redundancy that occurs in several nutrient uptake pathways of H. influenzae led us to attempt to develop a quantitative STM method that could identify both null mutants and mutants with decreased fitness that remain viable in vivo. To accomplish this task we designed a modified STM approach that utilized a set of signature tagged wild-type (STWT) strains (in a single genetic background) as carriers for mutations in genes of interest located elsewhere in the genome. Each STWT strain differed from the others by insertion of a unique, Q-PCR-detectable, seven base pair tag into the same redundant gene locus. Initially ten STWTs were created and characterized in vitro and in vivo. As anticipated, the STWT strains were not significantly different in their in vitro growth. However, in the chinchilla model of otitis media, certain STWTs outgrew others by several orders of magnitude in mixed infections. Removal of the predominant STWT resulted in its replacement by a different predominant STWT on retesting. Unexpectedly we observed that the STWT exhibiting the greatest proliferation was animal dependent. These findings identify an inherent inability of the signature tag methodologies to accurately elucidate fitness in this animal model of infection and underscore the subtleties of H. influenzae gene regulation. PMID:23085534

  17. 雄激素受体基因的表型异种突变%Phenotypic heterogeneity of mutations in androgen receptor gene

    Institute of Scientific and Technical Information of China (English)

    Singh Rajender; Lalji Singh; Kumarasamy Thangaraj

    2007-01-01

    Androgen receptor (AR) gene has been extensively studied in diverse clinical conditions. In addition to the point mutations, trinucleotide repeat (CAG and GGN) length polymorphisms have been an additional subject of interest and controversy among geneticists. The polymorphic variations in triplet repeats have been associated with a number of disorders, but at the same time contradictory findings have also been reported. Further, studies on the same disorder in different populations have generated different results. Therefore, combined analysis or review of the published studies has been of much value to extract information on the significance of variations in the gene in various clinical conditions. AR genetics has been reviewed extensively but until now review articles have focused on individual clinical categories such as androgen insensitivity, male infertility, prostate cancer, and so on. We have made the first effort to review most the aspects of AR genetics. The impact of androgens in various disorders and polymorphic variations in the AR gene is the main focus of this review. Additionally, the correlations observed in various studies have been discussed in the light of in vitro evidences available for the effect of AR gene variations on the action of androgens.

  18. A novel deletion mutation in IL2RG gene results in X-linked severe combined immunodeficiency with an atypical phenotype.

    Science.gov (United States)

    Mou, Wenjun; He, Jianxin; Chen, Xi; Zhang, Hui; Ren, Xiaoya; Wu, Xunyao; Ni, Xin; Xu, Baoping; Gui, Jingang

    2017-01-01

    Severe combined immunodeficiency (SCID) is the most serious disorder among primary immunodeficiency diseases threatening children's life. Atypical SCID variant, presenting with mild reduced T cells subsets, is often associated with infection susceptibility but poor clinical diagnosis. The atypical X-SCID patient in the present study showed a mild clinical presentation with a T(low)NK(+)B(+) immunophenotype. The patient has reduced T- cell subpopulations with a subdued thymic output measured by sjTRECs. Further analysis showed that T cells maintained a normal proliferation and a broad Vβ repertoire. NK cells, however, exhibited a skewed development toward immature CD3(-)CD16(+)CD56(-) cells. Genetic analysis revealed a novel deletion at nucleotide 52 in exon 1 of IL2RG gene. Sequence alignment predicted a truncated IL2RG protein missing signal peptide derived from a possible alternative reading frame. The novel mutation in IL2RG gene identified in our study may help the early diagnosis of atypical X-SCID.

  19. Mutations in GABRB3

    DEFF Research Database (Denmark)

    Møller, Rikke S; Wuttke, Thomas V; Helbig, Ingo

    2017-01-01

    OBJECTIVE: To examine the role of mutations in GABRB3 encoding the β3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. METHODS: We performed massive parallel sequencing...... of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. RESULTS: We identified 22 patients with heterozygous mutations in GABRB3, including 3...... probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies...

  20. Genotype versus phenotype in families with androgen insensitivity syndrome

    NARCIS (Netherlands)

    Boehmer, ALM; Bruggenwirth, H; Van Assendelft, C; Otten, BJ; Verleun-Mooijman, MCT; Niermeijer, MF; Brunner, HG; Rouwe, CW; Waelkens, JJ; Oostdijk, W; Kleijer, WJ; Van der Kwast, TH; De Vroede, MA; Drop, SLS

    2001-01-01

    Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/ phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivit

  1. Phenotype in 6 patients with mitochondrial DNA G13513A mutation%线粒体基因G13513A突变导致的线粒体脑肌病六例临床表型分析

    Institute of Scientific and Technical Information of China (English)

    王朝霞; 赵丹华; 戚晓昆; 韩漫夫; 冯立群; 袁云

    2011-01-01

    Objective To report 6 Chinese patients with mitochondrial encephalomyopathy caused by mitochondrial DNA(mtDNA)G13513A mutation and discuss the mitochondrial phenotype associated with this mutation based on the data of our patient series as well as the reports by others.Methods Direct sequencing of polymerase chain reaction(PCR)products or PCR-RFLP analysis Was performed to screen mtDNA G13513A mutation in 35 cases with mitoehondrial encephalomyopathy.who carried no mtDNA common mutations(1arge 8eale deletion,A3243G,T3271 C,A8344G,or T8993G/C).The clinical features,MRI changes were retrospectively collected and analyzed.Published studies of all patients with mtDNA G13513A mutation were also reviewed.Results Six patients were identified carrying mtDNA G13513A mutation.All patients presented stroke-like episodes with hemianopsia.hemiparesis or hemiparesthesia.Three adult patients presented clinical and radiological features of adult-onset mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episodes(MELAS),including stroke-like episodes,epilepsy,headache,short stature,sensorineural deafness,multifocal lesions on parietal,occipital and temporal lobes on cranial MRI scans.Three iuvenile.onset patients presented the clinical and brain MRI features of MELAS-Leigh syndrome(LS)overlap syndrome.In addition to the stroke-like episodes,they also showed brain stem lesions with dysarthria,ataxia,and ophthalmopJegia. Brain MRI revealed asymmetrical lesions in the cortex of the oecipital and temporal lobes,as well as symmetrical lesions in the bilateral basal ganglia and brainstem.Muslce biopsy showed ragged redfibem in 5 patients.The infant-onset LS or Leigh-like syndrome with mtDNA G135 13A was described in the English literature.Conclusions mtDNA G13513A mutation is a common pathogenic mutmion for mitochondrial encephalomyopathy,which can result in Leigh syndrome,MELAS-LS overlap syndrome and adult MELAS.The onset of various phenotypes is relatively age

  2. Analysis on Mycoplasma pneumonia 23SrRNA gene mutation site and drug resistance phenotype%肺炎支原体23SrRNA基因突变位点与耐药表型的分析

    Institute of Scientific and Technical Information of China (English)

    叶芸; 李苏亮; 姜萍; 王瑶; 杨超

    2013-01-01

    Objective To investigate the infection situation of Mycoplasma pneumonia ( Mp ) in patients with community-acquired respiratory tract infection and the molecular drug resistance mechanisms of macrolide,and to analyze the relationship between 23SrRNA gene mutation site of isolates resistant to Mp and drug resistance phenotype. Methods A total of 400 throat swab specimens of community-acquired respiratory tract infection were cultured to isolate Mp,the clinical isolates were identified by nested polymerase chain reaction, and the in vitro antibiotic sensitivity test was performed for identifying macrolide-resistant isolates through the minimal inhibitory concentration( MIC).The sequences of macrolide-resistant 23SrRNA gene were detected. The sequences were compared to the corresponding sequences of Ml29. The relationship between mutation site and drug resistance phenotype was analyzed. Results A total of 50 Mp were isolated from 400 throat swab specimens. Of the 50 isolates, 32 isolates were susceptible to macrolide, and 18 isolates were resistant to macrolide. The 18 clinical isolates appeared mutation A2063G, A2064G and A2067G, separately. A2063G showed 14 ring macrolide resistance. A2064G showed 14 and 16 ring macrolide resistances. A2067G showed josamycin resistance. Conclusions Mp to macrolide resistance is serious, and the mutation of 23SrRNA gene is a predominant mechanism that contributes to the macrolide resistance. Through the analysis of 23SrRNA gene mutation site and drug resistance phenotype, the clinical Mp drug resistance situation is obtained. The theoretical guidance for reasonable selection and application of antibiotics is provided.%目的 了解本地区社区呼吸道感染肺炎支原体(Mycoplasma pneumoniae,Mp)感染状况,探讨肺炎支原体对大环内酯类抗菌药物的耐药分子机制,并分析肺炎支原体耐药菌株23SrRNA基因突变位点与耐药表型之间的关系.方法 对400例社区获得性呼吸道感染患儿咽拭

  3. Phenotypic and genetic consequences of protein damage.

    Directory of Open Access Journals (Sweden)

    Anita Krisko

    Full Text Available Although the genome contains all the information necessary for maintenance and perpetuation of life, it is the proteome that repairs, duplicates and expresses the genome and actually performs most cellular functions. Here we reveal strong phenotypes of physiological oxidative proteome damage at the functional and genomic levels. Genome-wide mutations rates and biosynthetic capacity were monitored in real time, in single Escherichia coli cells with identical levels of reactive oxygen species and oxidative DNA damage, but with different levels of irreversible oxidative proteome damage (carbonylation. Increased protein carbonylation correlates with a mutator phenotype, whereas reducing it below wild type level produces an anti-mutator phenotype identifying proteome damage as the leading cause of spontaneous mutations. Proteome oxidation elevates also UV-light induced mutagenesis and impairs cellular biosynthesis. In conclusion, protein damage reduces the efficacy and precision of vital cellular processes resulting in high mutation rates and functional degeneracy akin to cellular aging.

  4. 一个同时携带线粒体DNA A1555G突变和GJB2235delC单杂合突变家系的基因型与听力表型%GJB2 235delC single allelic mutation modulates the phenotype associated with the mitochondrial A1555G mutation

    Institute of Scientific and Technical Information of China (English)

    李琦; 方如平; 周洪根; 戴朴; 田莉; 林镝; 黄群; 宋建敏

    2010-01-01

    Objective To investigate a non-syndromic deafness family in which potential interaction between the GJB2 gene and a mitochondrial gene appeared to be the cause of hearing impairment. Methods Audiological examination was performed by pure-tone audiometry (PTA). Blood samples from 8 members of the pedigree were obtained. DNA was extracted from the leukocytes. The coding region of the GJB2 gene and mitochondrial DNA target fragments were amplified by polymerase chain reaction (PCR). The PCR products were analyzed by sequencing. Results Direct sequencing showed that the proband had both a heterozygous mutation of 235delC in the GJB2 gene and a mitochondrial 1555 A to G mutation. The proband had profound hearing loss. The maternal relatives had sensorineural hearing loss in the higher frequencies or no hearing loss. Conclusion The GJB2 mutations may bean aggravating factor in the phenotypic expression of the non-syndromic hearing loss associated with the A1555G mitochondrial mutation.%目的 调查一个同时携带线粒体DNA A1555G突变和GJB2 235delC突变的非综合征型耳聋家系,分析其基因型和听力表型的关系.方法 对家系成员进行临床听力测试,收集家系中8名成员的外周静脉血样本,从白细胞中提取DNA,聚合酶链反应扩增GJB2基因和线粒体DNA(mitochondric DNA,mtDNA)目的 片段,对扩增片段直接测序进行GJB2基因、mtDNA 12S rRNA及tRNASer(UCN)基因突变分析.结果 此家系先证者存在mtDNA A1555G突变和GJB2 235delC杂合突变,听力表型为极重度感音神经性耳聋.其他母系成员携带mtDNA A1555G突变,未发现tRNASer(UCN)基因突变,家系中其他母系成员听力表型为双侧对称高频下降或听力正常.结论 GJB2 235delC单杂合突变可能参与了mtDNA A1555G的听力损害.

  5. Delineating the GRIN1 phenotypic spectrum

    Science.gov (United States)

    Geider, Kirsten; Helbig, Katherine L.; Heyne, Henrike O.; Schütz, Hannah; Hentschel, Julia; Courage, Carolina; Depienne, Christel; Nava, Caroline; Heron, Delphine; Møller, Rikke S.; Hjalgrim, Helle; Lal, Dennis; Neubauer, Bernd A.; Nürnberg, Peter; Thiele, Holger; Kurlemann, Gerhard; Arnold, Georgianne L.; Bhambhani, Vikas; Bartholdi, Deborah; Pedurupillay, Christeen Ramane J.; Misceo, Doriana; Frengen, Eirik; Strømme, Petter; Dlugos, Dennis J.; Doherty, Emily S.; Bijlsma, Emilia K.; Ruivenkamp, Claudia A.; Hoffer, Mariette J.V.; Goldstein, Amy; Rajan, Deepa S.; Narayanan, Vinodh; Ramsey, Keri; Belnap, Newell; Schrauwen, Isabelle; Richholt, Ryan; Koeleman, Bobby P.C.; Sá, Joaquim; Mendonça, Carla; de Kovel, Carolien G.F.; Weckhuysen, Sarah; Hardies, Katia; De Jonghe, Peter; De Meirleir, Linda; Milh, Mathieu; Badens, Catherine; Lebrun, Marine; Busa, Tiffany; Francannet, Christine; Piton, Amélie; Riesch, Erik; Biskup, Saskia; Vogt, Heinrich; Dorn, Thomas; Helbig, Ingo; Michaud, Jacques L.; Laube, Bodo; Syrbe, Steffen

    2016-01-01

    Objective: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology. Methods: We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes. Results: We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families. Conclusions: De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders. PMID:27164704

  6. Mutation in domain II of IAA1 confers diverse auxin-related phenotypes and represses auxin-activated expression of Aux/IAA genes in steroid regulator-inducible system.

    Science.gov (United States)

    Park, Jin-Young; Kim, Hye-Joung; Kim, Jungmook

    2002-12-01

    Most of Aux/IAA genes are rapidly induced by auxin. The Aux/IAA proteins are short-lived nuclear proteins sharing the four conserved domains. Domain II is critical for rapid degradation of Aux/IAA proteins. Among these gene family members, IAA1 is one of the earliest auxin-inducible genes. We used a steroid hormone-inducible system to reveal putative roles and downstream signaling of IAA1 in auxin response. Arabidopsis transgenic plants were generated expressing fusion protein of IAA1 (IAA1-GR) or IAA1 with a mutation in domain II (iaa1-GR) and the glucocorticoid hormone-binding domain (GR). IAA1-GR transgenic plants did not exhibit any discernable phenotypic differences by DEX treatment that allows nuclear translocation of the fusion protein. In contrast, diverse auxin-related physiological processes including gravitropism and phototropism were impaired by DEX treatment in roots, hypocotyls, stems, and leaves in iaa1-GR transgenic plants. Auxin induction of seven Aux/IAA mRNAs including IAA1 itself was repressed by DEX treatment, suggesting that IAA1 functions in the nucleus by mediating auxin response and might act as a negative feedback regulator for the expression of Aux/IAA genes including IAA1 itself. Auxin induction of Aux/IAA genes in the presence of cycloheximide can be repressed by DEX treatment, showing that the repression of transcription of the Aux/IAAs by the iaa1 mutant protein is primary. Wild-type IAA1-GR could not suppress auxin induction of IAA1 and IAA2. These results indicate that inhibition of auxin-activated transcription of Aux/IAA genes by the iaa1 mutant protein might be responsible for alteration of various auxin responses.

  7. 先天性牙齿缺失患者 EDA 基因突变检测及其表现型分析%EDA mutation screening and phenotype analysis in patients with tooth agenesis

    Institute of Scientific and Technical Information of China (English)

    何慧莹; 刘洋; 韩冬; 刘浩辰; 白保晶; 冯海兰

    2016-01-01

    目的:探讨 EDA 基因突变在单纯型和综合征型先天性牙齿缺失患者中的检出率,并汇总 EDA 基因突变的患者口内恒牙缺失情况,尝试分析 EDA 基因突变相关的恒牙列缺失牙位分布特点。方法:临床收集到174例(143例单纯型、31例综合征型)先天性牙齿缺失患者以及451名正常对照者,通过采集外周静脉血或者取颊黏膜拭子,提取基因组 DNA,PCR 扩增 EDA 基因编码区并测序,与数据库筛查比对。对于 EDA 基因突变的患者,记录汇总口内缺失牙位,对比不同牙位缺失率的差异。结果:共检测出33例 EDA 突变患者,单纯型先天性牙齿缺失患者中 EDA 基因突变检出率为9.09%(13/143),综合征型先天性牙齿缺失患者中 EDA 基因突变检出率为64.52%(20/31),检测出10种尚未见报道的 EDA 基因突变。EDA 突变相关的先天缺牙患者中,牙列左、右同名牙缺失数目几乎没有差异,单纯型患者缺失恒牙数(15.9±6.4)比综合征型患者少(23.9±4.3)。EDA 突变相关的单纯型先天缺牙患者中,上颌中切牙,上、下颌第一磨牙缺牙率较低;下颌中切牙,上、下颌侧切牙,上颌第一前磨牙缺牙率较高。EDA 突变相关的综合征型先天缺牙患者中,各牙位缺牙率均较高,上颌中切牙,上、下颌尖牙,上、下颌第一磨牙缺牙率相对较低。结论:EDA 突变检测和表现型分析有助于更全面了解 EDA 基因以及其在外胚层器官发育中的功能。%Objective:To screen the ectodysplasin A (EDA)gene mutation in the patients with non-syndromic tooth agenesis and ectodermal dysplasia,and to analyze the phenotype of missing teeth pattern in these two groups of patients.Methods:In the study,174 patients with tooth agenesis (143:non-syn-dromic,31:ectodermal dysplasia)and 451 health control volunteers were enrolled from the clinic,and the genome DNA

  8. Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome

    NARCIS (Netherlands)

    Vega, H.; Trainer, A.H.; Gordillo, M.; Crosier, M.; Kayserili, H.; Skovby, F.; Uzielli, M.L.G.; Schnur, R.E.; Manouvrier, S.; Blair, E.; Hurst, J.A.; Forzano, F.; Meins, M.; Simola, K.O.J.; Raas-Rothschild, A; Hennekam, R.C.M.; Jabs, E.W.

    2010-01-01

    Background Roberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be trunc

  9. Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome

    DEFF Research Database (Denmark)

    Vega, H; Trainer, A H; Gordillo, M;

    2010-01-01

    Roberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating mu...

  10. Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome

    DEFF Research Database (Denmark)

    Vega, H; Trainer, A H; Gordillo, M;

    2010-01-01

    Roberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating...

  11. Large phenotype jumps in biomolecular evolution

    CERN Document Server

    Bardou, F

    2003-01-01

    By defining the phenotype of a biopolymer by its active three-dimensional shape, and its genotype by its primary sequence, we propose a model that predicts and characterizes the statistical distribution of a population of biopolymers with a specific phenotype, that originated from a given genotypic sequence by a single mutational event. Depending on the ratio g0 that characterizes the spread of potential energies of the mutated population with respect to temperature, three different statistical regimes have been identified. We suggest that biopolymers found in nature are in a critical regime with g0 in the range 1-6, corresponding to a broad, but not too broad, phenotypic distribution resembling a truncated Levy flight. Thus the biopolymer phenotype can be considerably modified in just a few mutations.

  12. MRI findings of Pelizaeus-Merzbacher disease correlated with phenotypes and genetic mutation%佩梅病的头颅MRI表现及其与临床、基因分型的关系

    Institute of Scientific and Technical Information of China (English)

    杨嵘; 谢晟; 肖江喜; 王静敏; 姜玉武

    2011-01-01

    Objective To investigate the correlation of MRI features and phenotypes and genetic mutations in Pelizaeus-Merzbacher disease.Methods Sixteen boys with clinical diagnosis of PelizaeusMerzbacher disease (PMD) were included in this study.Their ages ranged from 22 months to 9 years.They were examined by pediatric neurologists,and clinical classification was made according to the symptoms and physical signs.An experienced radiologist reviewed the cranial MRI images and analyzed the brain involvement,including pallidus globus,pyramidal tract,corpus callosum,cerebellar white matter,semiovale centrum,brain atrophy and ‘ tigroid sign’.Results There were 8 patients with classic form,7 patients with transitional form and one patient with connatal form.They all showed diffuse delayed myelination in the white matter,with involvement of pallidus globus in 13 cases,pyramidal tract in 7 cases,corpus callosum in 11 cases,cerebellar white matter in 7 cases,semiovale centrum in 12 cases.Cerebral atrophy was found in 5 patients and eerebellar atrophy was found in one patient.Five cases depicted ' tigroid sign'.In patients with PLP1 gene point mutation,pyramidal tract and cerebellar white matter involvement showed a high incidence.Cerebellar white matter lesions were relatively frequent in children with transitional form and connatal form.In contrast,‘ tigroid sign' was often related to classic form,which indicated a better myelination and outcome.Conclusion PMD patients show distinct imaging features in their brains,which may be correlated with the phenotype and genetic mutation.%目的 探讨佩梅病( PMD)患儿的头颅MRI特点,以及与临床及基因分型的关系.方法 回顾性分析16例经临床诊断为佩梅病患儿的临床和影像资料.患儿均为男性,年龄5个月至9岁8个月.由儿科神经医师对患儿的症状和体征进行检查,将其按照临床症状进行临床分型.由影像科医师对头颅MRI图像的特点进行分析,病灶的位置

  13. Analysis of clinical phenotype in 42 nuclear pedigrees carrying mitochondrial DNA A3243G mutation%42个携带线粒体基因组A3243G突变核心家系临床表型分析

    Institute of Scientific and Technical Information of China (English)

    马祎楠; 郑雪飞; 裴珮; 吴海蓉; 肖洋; 戚豫; 方方; 曹延延; 杨艳玲; 邹丽萍; 张英; 王松涛; 朱赛楠; 李琳

    2010-01-01

    目的 研究携带A3243G突变的家系成员的临床症状特点以及与A3243G突变负荷的关系.方法 收集42个携带A3243G突变的核心家系,对他们的临床表现、实验室检查和线粒体DNA 3243位点点突变检测结果进行分析.结果 (1)肌无力、癫痫发作、多毛、头痛、认知障碍、消瘦和身材矮小是A3243G突变家族中先证者最常见的临床症状,而且这些临床症状多同时存在.在实验室检查中,血乳酸、丙酮酸及MRI检查多有异常;(2)A3243G突变家族中的携带者大多表现正常,肌无力、消瘦和身材矮小是他们最常见的临床症状;(3)在先证者组中,尿液A3243G突变负荷高于血液(t=-15.06,P<0.001),在先证者母亲组中,尿液A3243G突变负荷也高于血液(z=-6.241,P<0.001);(4)先证者组血液和尿液中的A3243G突变负荷约是母亲组的2倍.结论 携带A3243G突变患者表型差异很大,先证者组的临床表现和实验室检查结果均较母亲组严重,可能与A3243G突变负荷有一定关系.%Objective A3243G mutation in mitochondrial DNA is the most common pathogenic point mutation causing a variety of phenotypes.The clinical phenotype and the relationship between the clinical phenotype and the ratio of A3243G mutation were studied in the members from nuclear families carrying A3243G mutation.Methods A total of 42 families carrying A3243G mutation were recruited and their clinical symptoms,laboratory results and the ratio of A3243G analyzed.Result ( 1 ) In probands,myopathy,seizure,hirsutism,headache,cognitive impairment,weight loss and short stature were the most common clinical features.They tended to occur simultaneously.Lactic acid,pyruvate and MRI were abnormal in most probands;( 2 ) most carriers had a normal phenotype.Myopathy,weight loss and short stature were their most common clinical features;(3)the ratio of A3243G mutation in urine was higher than that in blood in probands ( t = - 15.06,P < 0.001 ).And the ratio

  14. Quality Control Test for Sequence-Phenotype Assignments

    OpenAIRE

    Ortiz, Maria Teresa Lara; Rosario, Pablo Benjamín Leon; Luna-Nevarez, Pablo; Gamez, Alba Savin; Martínez-del Campo, Ana; del Rio, Gabriel

    2015-01-01

    Relating a gene mutation to a phenotype is a common task in different disciplines such as protein biochemistry. In this endeavour, it is common to find false relationships arising from mutations introduced by cells that may be depurated using a phenotypic assay; yet, such phenotypic assays may introduce additional false relationships arising from experimental errors. Here we introduce the use of high-throughput DNA sequencers and statistical analysis aimed to identify incorrect DNA sequence-p...

  15. Histologic and Phenotypic Factors and MC1R Status Associated with BRAF(V600E), BRAF(V600K), and NRAS Mutations in a Community-Based Sample of 414 Cutaneous Melanomas.

    Science.gov (United States)

    Hacker, Elke; Olsen, Catherine M; Kvaskoff, Marina; Pandeya, Nirmala; Yeo, Abrey; Green, Adèle C; Williamson, Richard M; Triscott, Joe; Wood, Dominic; Mortimore, Rohan; Hayward, Nicholas K; Whiteman, David C

    2016-04-01

    Cutaneous melanomas arise through causal pathways involving interplay between exposure to UV radiation and host factors, resulting in characteristic patterns of driver mutations in BRAF, NRAS, and other genes. To gain clearer insights into the factors contributing to somatic mutation genotypes in melanoma, we collected clinical and epidemiologic data, performed skin examinations, and collected saliva and tumor samples from a community-based series of 414 patients aged 18 to 79, newly diagnosed with cutaneous melanoma. We assessed constitutional DNA for nine common polymorphisms in melanocortin-1 receptor gene (MC1R). Tumor DNA was assessed for somatic mutations in 25 different genes. We observed mutually exclusive mutations in BRAF(V600E) (26%), BRAF(V600K) (8%), BRAF(other) (5%), and NRAS (9%). Compared to patients with BRAF wild-type melanomas, those with BRAF(V600E) mutants were significantly younger, had more nevi but fewer actinic keratoses, were more likely to report a family history of melanoma, and had tumors that were more likely to harbor neval remnants. BRAF(V600K) mutations were also associated with high nevus counts. Both BRAF(V600K) and NRAS mutants were associated with older age but not with high sun exposure. We also found no association between MC1R status and any somatic mutations in this community sample of cutaneous melanomas, contrary to earlier reports.

  16. Spectrum of phylalanine hydroxylase gene mutations and genotype-phenotype correlation in the patients with phenylketonuria in Beijing area of China%北京地区苯丙酮尿症基因突变构成及基因型与表型相关分析

    Institute of Scientific and Technical Information of China (English)

    瞿宇晋; 宋昉; 金煜炜; 王红; 张玉敏; 秦金莉; 裘蕾

    2008-01-01

    Objective To identify the mutation spectrum and the distribution of minihaplotypes (STR/VNTR)of phenylalanine hydroxylase(PAH)gene and explore the C01Te]ations between genotype and phenotype of patients with phenylketonuria(PKU)in Beijing area of China.Method (1)Fifty cases with PKU were involved in this study.PKU was identified by the Neonatal Screening Center of Beijing.All 13 exons and their flanking intronic sequences of PAH gene of these patients were amplified and then subjected to SSCP analysis and direct sequencing.(2)The distribution of polymorphic locus of short tandem repeat (STR)and variable number tandem repeat(VNTR)was analyzed by PCR and denaturing gel electrophoresis.(3)The correlations between genotype and phenotype were studied by analysis of the matching rate between the expected and observed phenotypes.The predicted phenotype was determined on the basis of the sum of the assigned values of the two mutant alleles.Results (1)A total of 34 different mutations were detected with the relative frequency of 95% among 50 PKU patients.The prevalent mutations in this study were:R243Q(20%),EX6-96A>G(11%),Y356X(9%),and V399V(7%).The next common mutations were R111X(5%),R413P(5%),R252Q(3%)and A434D(3%).Thirty-four detected mutations were distributed throughout the whole PAH gene,except exon 1,8 and 13.Exon 7 and 11,with the mutant rate 34% and 19% respectively,seemed to be the hot mutant areas/regions of PAH gene.(2)The minihaplotypes(STR/VNTR)of 34 mutations were identified in this research.The STR and VNTR showed 8 and 3 alleles,respectively.Among them,244 bp(44%)and 240 bp(34%)were the prevalent STR alleles.Meanwhile,the VNTR3(83%)was the most common VNTR allele in PKU patients.(3)A better consistency(81.5%)between expected and observed phenotypes was revealed by analysis of correlation between genotype and phenotype.Especially in classic PKU,the consistency rate was up to 87.5%.Conclusion(1)The frequency distribution of common PAH gene mutations in

  17. Mutational analysis of TARDBP in Parkinson's disease

    NARCIS (Netherlands)

    Blitterswijk, M. van; Es, M.A. van; Verbaan, D.; Hilten, J.J. van; Scheffer, H.; Warrenburg, B.P.C. van de; Veldink, J.H.; Berg, L.H. van den

    2013-01-01

    Mutations in TAR DNA-binding protein (TARDBP) are associated with heterogenic phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease. In this study, we investigated the presence of TARDBP mutations in a cohort of 429 Dutch patients with Parkinson's dise

  18. Is The Ribosome Targeted By Adaptive Mutations

    DEFF Research Database (Denmark)

    Jimenez Fernandez, Alicia; Molin, Søren; Johansen, Helle Krogh

    2015-01-01

    degree of evolutionary conservation of the cellular MMSM tend to support this view. However, under certain selective conditions the machinery itself may be targeted by adaptive mutations, which result in fitness-increasing phenotypic changes. Here we investigate and characterize the role of ribosomal...... mutations in adaptive evolution. Methods: Several mutations in ribosomal genes have been identified in the genome analysis of nearly 700 Pseudomonas aeruginosa isolates from infected cystic fibrosis patients. Among these mutations we have repeatedly identified insertions, deletions and substitutions...... in specific ribosomal genes. The bacterial phenotypes of the mutated strains will be investigated. Results: Preliminary assays show that mutant strains have reduced growth rate and an altered antibiotic resistance pattern. The selection for mutations in ribosomal protein genes is partly explainable...

  19. Impact of 226C>T MSH2 gene mutation on cancer phenotypes in two HNPCC-associated highly-consanguineous families from Kuwait: emphasis on premarital genetic testing.

    Science.gov (United States)

    Marafie, Makia J; Al-Awadi, Sadiqa; Al-Mosawi, Fatemah; Elshafey, Alaa; Al-Ali, Waleed; Al-Mulla, Fahd

    2009-01-01

    Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is one of the commonest cancer susceptibility syndromes. It is characterized by early onset colon cancer and a variety of extracolonic tumours. Germline mutations in the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS1, and PMS2) are responsible for this disorder. Identifying an affected individual depends on the tumour histopathology, family history that fulfils the Amsterdam and/or Bethesda criteria, tumour immunohistochemistry, microsatellite instability, and finally molecular analysis of an affected member. It is a laborious, time consuming and expensive procedure, which needs the effort of a multi-disciplinary team. However, once the diagnosis is established and germline defect is identified, other high risk pre-symptomatic carriers could be offered intensive surveillance and management as a preventive measure against cancer development. Here, we present two large highly consanguineous HNPCC-families from Kuwait in whom a founder MSH2 mutation was identified. The relationship between this mutation and cancer expressivity in two large consanguineous families harbouring other genetic defects is discussed. Moreover, we shed light on the challenges pertaining to diagnosis, screening, premarital counselling of couples and prenatal diagnosis of offspring with biallelic MSH2 gene mutation.

  20. Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome.

    Science.gov (United States)

    Polfus, Linda M; Boerwinkle, Eric; Gibbs, Richard A; Metcalf, Ginger; Muzny, Donna; Veeraraghavan, Narayanan; Grove, Megan; Shete, Sanjay; Wallace, Stephanie; Milewicz, Dianna; Hanchard, Neil; Lupski, James R; Hashmi, Syed Shahrukh; Gupta-Malhotra, Monesha

    2016-11-01

    To comprehensively evaluate a European-American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a multiple drug regimen including amiloride, spironolactone, and hydrochlorothiazide. We suspected a monogenic form of hypertension because of the persistent hypokalemia with low plasma levels of renin and aldosterone. To address this, we focused on rare functional variants and indels, and performed gene-based tests incorporating linkage scores and allele frequency and filtered on deleterious functional mutations. Drawing upon clinical presentation, 27 genes were selected evidenced to cause monogenic hypertension and matched to the gene-based results. This resulted in the identification of a stop-gain mutation in an epithelial sodium channel (ENaC), SCNN1B, an established Liddle syndrome gene, shared by the child and her father. Interestingly, the father also harbored a missense mutation (p.Trp552Arg) in the α-subunit of the ENaC trimer, SCNN1A, possibly pointing to pseudohypoaldosteronism type I. This case is unique in that we present the early-onset disease and treatment response caused by a canonical stop-gain mutation (p.Arg566*) as well as ENaC digenic hits in the father, emphasizing the utility of WES informing precision medicine.

  1. Delineating the GRIN1 phenotypic spectrum

    DEFF Research Database (Denmark)

    Lemke, Johannes R; Geider, Kirsten; Helbig, Katherine L

    2016-01-01

    impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1...

  2. Pathogenic mutations of nuclear genes associated with mitochondrial disorders

    Institute of Scientific and Technical Information of China (English)

    Xiaoyu Zhu; Xuerui Peng; Min-Xin Guan; Qingfeng Yan

    2009-01-01

    Mitochondrial disorders are clinical phenotypes associated with mitochondrial dysfunction, which can be caused by mutations in mitochondrial DNA (mtDNA) or nuclear genes. In this review, we summarized the pathogenic mutations of nuclear genes associated with mitochondrial disorders. These nuclear genes encode, components of mitochondrial translational machinery and structural subunits and assembly factors of the oxidative phosphorylation, that complex. The molecular mechanisms, that nuclear modifier genes modulate the phenotypic expression of mtDNA mutations, are discussed in detail.

  3. Study on the Relationship between the Pathogenic Mutations of GJB2、SLC26A4 and CT Phenotypes of Inner Ear in Patient with Sensorineural Hearing Loss%GJB2、SLC26A4基因致病性突变与内耳CT表型关系的研究

    Institute of Scientific and Technical Information of China (English)

    孙宝春; 代志瑶; 黄莎莎; 韩冰; 袁永一; 苏钰; 康东洋; 戴朴

    2014-01-01

    Objects Study on the relationship between the pathogenic mutations of GJB2、SLC26A4 and CT pheno-types of inner ear. Explore the feasibility of using the method of gene sequence analysis to help CT examination in diagnosing of patients with inner ear malformation. Methods 2686 cases of patients were detected by GJB2 and SLC26A4 with the meth-od of DNA sequence. CT phenotypes of those patients were classified according to the method proposed by Sennaroglu. We analyzed the relationship between the pathogenic mutations of gene and the CT phenotypes. Results 1、429 cases were de-tected with pathogenic mutations of GJB2 (220 cases were homozygous, 207 cases were compound heterozygous and 2 case carried dominant mutation). 596 cases were detected with pathogenic mutations of SLC26A4 (169 cases were homozygous, 427 cases were compound heterozygous). 2、873 cases of inner ear malformations were diagnosed by CT examination(371 cas-es of Mondini malformation, 338 cases of enlarged vestibular aqueduct malformation and 164 cases of other types), normal was 1813 cases. 3、99.30%(426/429) cases carried pathogenic mutation of GJB2 were detected in the normal group and 100%(596/596)cases carried pathogenic mutation of SLC26A4 were detected in the group related to vestibular aqueduct malforma-tion. Conclusion The results suggested that pathogenic mutations of GJB2 is closely related to the CT phenotype of normal and pathogenic mutations of SLC26A4 is closely related to the CT phenotype of vestibular aqueduct malformation.%目的:研究感音神经耳聋GJB2、SLC26A4基因致病性突变与内耳CT表型之间的关系,探讨这两种基因检测在诊断感音神经性耳聋患者是否存在内耳畸形方面的作用。方法按DNA测序的方法检测2686例感音神经性耳聋患者GJB2、SLC26A4基因致病性突变情况,以Sennaroglu分类为标准统计以上患者内耳CT表型情况,分析GJB2、SLC26A4基因型与CT表型之间的关系。结果1、2686

  4. Magnesium treatment for patients with refractory status epilepticus due to POLG1-mutations

    NARCIS (Netherlands)

    Visser, Nora A; Braun, Kees P J; Leijten, Frans S S; van Nieuwenhuizen, Onno; Wokke, John H J; van den Bergh, Walter M

    2011-01-01

    Mutations in the gene encoding of the catalytic subunit of mtDNA polymerase gamma (POLG1) can cause typical Alpers' syndrome. Recently, a new POLG1 mutation phenotype was described, the so-called juvenile-onset Alpers' syndrome. This POLG1 mutation phenotype is characterized by refractory epilepsy w

  5. Deciphering the Galaxy Guppy phenotype

    Directory of Open Access Journals (Sweden)

    Philip Shaddock

    2011-01-01

    Full Text Available Animal breeding hobbyists have been useful to science because they identify and isolate colorcoat mutations that geneticists can in turn use in their studies of the development and differentiation ofcolor cells. This paper discusses a very interesting color mutant, the Japanese Galaxy, tracing its creationfrom back to a self-educated genetics hobbyist, Hoskiki Tsutsui. The paper discusses a constituent genepreviously studied by Dr. Violet Phang, the snakeskin gene (the linked body and fin genes Ssb and Sst.And it discusses a gene previously unknown to science, the Schimmelpfennig Platinum gene (Sc.Through crossing experiments, the author determines that the combination of these two genes producesan intermediate phenotype, the Medusa. Incorporating the Grass (Gr, another gene unknown to sciencegene into the Medusa through a crossover produces the Galaxy phenotype. Microscope studies of thesnakeskin pattern in Galaxies and snakeskins reveals some parallels with similar studies made of theZebrafish Danio.

  6. Investigation of GRIN2A in common epilepsy phenotypes

    NARCIS (Netherlands)

    Lal, Dennis; Steinbrücker, Sandra; Schubert, Julian; Sander, Thomas; Becker, Felicitas; Weber, Yvonne; Lerche, Holger; Thiele, Holger; Krause, Roland; Lehesjoki, Anna Elina; Nürnberg, Peter; Palotie, Aarno; Neubauer, Bernd A.; Muhle, Hiltrud; Stephani, Ulrich; Helbig, Ingo; Becker, Albert J.; Schoch, Susanne; Hansen, Jörg; Dorn, Thomas; Hohl, Christin; Lüscher, Nicole; von Spiczak, Sarah; Lemke, Johannes R.; Zimprich, Fritz; Feucht, Martha; Suls, Arvid; Weckhuysen, Sarah; Claes, Lieve; Deprez, Liesbet; Smets, Katrien; Dyck, Tine Van; Deconinck, Tine; De Jonghe, Peter; Møller, Rikke S.; Klitten, Laura L.; Hjalgrim, Helle; Campus, Kiel; Ostertag, Philipp; Trucks, Hol ger; Elger, Christian E.; Kleefuß-Lie, Ailing A.; Kunz, Wolfram S.; Surges, Rainer; Gaus, Verena; Janz, Dieter; Schmitz, Bettina; Klein, Karl Martin; Reif, Philipp S.; Oertel, Wolfgang H.; Hamer, Hajo M.; Rosenow, Felix; Kapser, Claudia; Schankin, Christoph J.; Koeleman, Bobby P C; de Kovel, Carolien; Lindhout, Dick; Reinthaler, Eva M.; Steinboeck, Hannelore; Neo-phytou, Birgit; Geldner, Julia; Gruber-Sedlmayr, Ursula; Haberlandt, Edda; Ronen, Gabriel M.; Altmueller, Janine; Nuernberg, Peter; Neubauer, Bernd; Sirén, Auli

    2015-01-01

    Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the more severe phenotypes. This study aimed to explore the phenotypic boundaries of GRIN2A mutatio

  7. Investigation of GRIN2A> in common epilepsy phenotypes

    DEFF Research Database (Denmark)

    Lal, Dennis; Steinbrücker, Sandra; Schubert, Julian

    2015-01-01

    Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the more severe phenotypes. This study aimed to explore the phenotypic boundaries of GRIN2A muta...

  8. The phenotypic spectrum of SCN8A> encephalopathy

    DEFF Research Database (Denmark)

    Larsen, Jan; Carvill, Gemma L; Gardella, Elena

    2015-01-01

    OBJECTIVE: SCN8A encodes the sodium channel voltage-gated α8-subunit (Nav1.6). SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. We aimed to delineate the phenotype associated with SCN8A mutations. METHODS: We used high-throughput sequence analysis of t...

  9. A frequent splicing mutation and novel missense mutations color the updated mutational spectrum of classic galactosemia in Portugal.

    Science.gov (United States)

    Coelho, Ana I; Ramos, Ruben; Gaspar, Ana; Costa, Cláudia; Oliveira, Anabela; Diogo, Luísa; Garcia, Paula; Paiva, Sandra; Martins, Esmeralda; Teles, Elisa Leão; Rodrigues, Esmeralda; Cardoso, M Teresa; Ferreira, Elena; Sequeira, Sílvia; Leite, Margarida; Silva, Maria João; de Almeida, Isabel Tavares; Vicente, João B; Rivera, Isabel

    2014-01-01

    Classic galactosemia is an autosomal recessive disorder caused by deficient galactose-1-phosphate uridylyltransferase (GALT) activity. Patients develop symptoms in the neonatal period, which can be ameliorated by dietary restriction of galactose. Many patients develop long-term complications, with a broad range of clinical symptoms whose pathophysiology is poorly understood. The high allelic heterogeneity of GALT gene that characterizes this disorder is thought to play a determinant role in biochemical and clinical phenotypes. We aimed to characterize the mutational spectrum of GALT deficiency in Portugal and to assess potential genotype-phenotype correlations. Direct sequencing of the GALT gene and in silico analyses were employed to evaluate the impact of uncharacterized mutations upon GALT functionality. Molecular characterization of 42 galactosemic Portuguese patients revealed a mutational spectrum comprising 14 nucleotide substitutions: ten missense, two nonsense and two putative splicing mutations. Sixteen different genotypic combinations were detected, half of the patients being p.Q188R homozygotes. Notably, the second most frequent variation is a splicing mutation. In silico predictions complemented by a close-up on the mutations in the protein structure suggest that uncharacterized missense mutations have cumulative point effects on protein stability, oligomeric state, or substrate binding. One splicing mutation is predicted to cause an alternative splicing event. This study reinforces the difficulty in establishing a genotype-phenotype correlation in classic galactosemia, a monogenic disease whose complex pathogenesis and clinical features emphasize the need to expand the knowledge on this "cloudy" disorder.

  10. Clinical phenotype and maternal mutation analysis of Leber hereditary optic neuropathy%Leber遗传性视神经病变的临床特征及线粒体突变位点分析

    Institute of Scientific and Technical Information of China (English)

    黄旅珍; 李天琦; 王斌; 黎晓新

    2016-01-01

    Background Leber hereditary optic neuropathy (LHON) is a maternally inherited disease caused by mitochondrial DNA (mtDNA) mutation with the common mutation sites of m.3460 G>A,m.11778 G>A and m.14484 T>C,and other mutation sites are rare.Understanding the mutation type of mtDNA in LHON patients has an important clinical significance.Objective This study was to analyze the clinical features of LHON and detect the mitochondrial mutation.Methods Twelve unrelated Chinese patients who was diagnosed as LHON were included in Peking University People's Hospital from 2010 to 2014.The visual acuity,perimetry,ocular segment,visual evoked potential,fundus were binocularly examined.The peripheral blood of 4 ml was collected from each patient and mtDNA was amplified and sequenced by using PCR.Three common genetic mutation sites for LHON and other mutation sites were determined and analyzed.This study protocol was approved by Ethic Committee of Peking University People's Hospital and complied with Helsinki Declaration.Written informed consent was obtained from each patient prior to any medical examination.Results Of the 12 patients,11 were male and 1 was female.The visual acuity of both eyes reduced simultaneously in 7 patients,and the visual acuity of left eye and the right eye first reduced in 3 patients and 1 patient,respectively.There was no significant correlation in the visual impairment between the left and right eyes (P>0.05).In the near vision of the patients,J7 was invisible in 18 eyes,and J7 were obtained in 3 eyes,J6 were obtained in 2 eyes and J2 was obtained in 1 eye.In the distant vision of the patients,hand movement was obtained in 1 eye,light perception was obtained in 1 eye,0.01-0.1 were obtained in 18 eyes and 0.12-0.3 were obtained in 2 eyes.The visual field defect of nasal lateral was found in 7 eyes,visual field defect of temporal lateral was found in 3 eyes and the visual field defect of central was found in 8 eyes.mtDNA sequencing revealed that m

  11. The Mammalian Phenotype Ontology as a unifying standard for experimental and high-throughput phenotyping data.

    Science.gov (United States)

    Smith, Cynthia L; Eppig, Janan T

    2012-10-01

    The Mammalian Phenotype Ontology (MP) is a structured vocabulary for describing mammalian phenotypes and serves as a critical tool for efficient annotation and comprehensive retrieval of phenotype data. Importantly, the ontology contains broad and specific terms, facilitating annotation of data from initial observations or screens and detailed data from subsequent experimental research. Using the ontology structure, data are retrieved inclusively, i.e., data annotated to chosen terms and to terms subordinate in the hierarchy. Thus, searching for "abnormal craniofacial morphology" also returns annotations to "megacephaly" and "microcephaly," more specific terms in the hierarchy path. The development and refinement of the MP is ongoing, with new terms and modifications to its organization undergoing continuous assessment as users and expert reviewers propose expansions and revisions. A wealth of phenotype data on mouse mutations and variants annotated to the MP already exists in the Mouse Genome Informatics database. These data, along with data curated to the MP by many mouse mutagenesis programs and mouse repositories, provide a platform for comparative analyses and correlative discoveries. The MP provides a standard underpinning to mouse phenotype descriptions for existing and future experimental and large-scale phenotyping projects. In this review we describe the MP as it presently exists, its application to phenotype annotations, the relationship of the MP to other ontologies, and the integration of the MP within large-scale phenotyping projects. Finally we discuss future application of the MP in providing standard descriptors of the phenotype pipeline test results from the International Mouse Phenotype Consortium projects.

  12. 7个家系Wilson病同胞ATP7B基因突变分析及临床表型的研究%Study on the mutation of ATP7B gene in 7 Wilson disease sibling patients from 7 families and the relationship between genotypes and phenotypes

    Institute of Scientific and Technical Information of China (English)

    黄叶青; 危智盛; 刘爱群; 刁胜朋; 洪铭范

    2014-01-01

    Objective To examine the genotypes of the ATP7B mutant alleles in sibling patients with Wilson disease (WD) and investigate the relationship between genotypes and phenotypes. Methods Clinical data and blood samples were collected from the subjects of sibling patients with WD. Genomic DNA was extracted and potential mutations in the exons of ATP7B gene were detected with PCR-DNA sequencing. Results Mutations in ATP7B were identified in 7 pairs of sibling patients from 7 unrelated families. We identified 8 different ATP7B mutations that included 5 missense mutations, 1 splice-site mutations, 1 frameshift mutations and 1 nonsense mutations and c.3851_3876del was found to be novel. Each pair of siblings was detected to have the same mutations, but the clinical types were not all the same between them. Probands had more manifest symptoms than their siblings, and three probands was the younger among siblings, but no significant difference was found in the levels of serum copper or ceruloplasmin between them. Conclusion Same mutations as the WD sibling patients have, but the clinical type and severity of symptoms can be different;the variety of clinical manifestation between siblings may be related to another factors.%目的:对Wilson病(WD)患病同胞进行ATP7B基因外显子测序,分析其突变的特点并探讨基因型与表型的关系。方法收集WD患病同胞的临床资料,并留取患者的外周血,提取基因组DNA,并对外显子扩增产物进行直接测序。结果7个家系中7对同胞,共14例WD患者均检出致病突变,发现8种致病突变,包括5种错义突变,1种剪接位点突变,1种移码突变以及1种无义突变,其中,c.3851_3876del为新突变。7个家系同胞之间均为相同的基因突变形式,但同胞间临床分型不全相同,先证者临床症状多较其同胞明显,3个家系中表现为弟妹先发病。先证者与其同胞间血清铜及铜蓝蛋白水平无统计学

  13. Chromosome 19q13 disruption alters expressions of CYP2A7, MIA and MIA-RAB4B lncRNA and contributes to FAP-like phenotype in APC mutation-negative familial colorectal cancer patients.

    Science.gov (United States)

    Thean, Lai Fun; Wong, Yu Hui; Lo, Michelle; Loi, Carol; Chew, Min Hoe; Tang, Choong Leong; Cheah, Peh Yean

    2017-01-01

    Familial adenomatous polyposis (FAP) is an autosomal-dominantly inherited form of colorectal cancer (CRC) caused by mutation in the adenomatous polyposis coli (APC) gene. Our ability to exhaustively screen for APC mutations identify microsatellite-stable and APC-mutation negative familial CRC patients, enabling us to search for novel genes. We performed genome-wide scan on two affected siblings of one family and 88 ethnicity- and gender-matched healthy controls to identify deletions shared by the siblings. Combined loss of heterozygosity, copy number and allelic-specific copy number analysis uncovered 5 shared deletions. Long-range polymerase chain reaction (PCR) confirmed chromosome 19q13 deletion, which was subsequently found in one other family. The 32 kb deleted region harbors the CYP2A7 gene and was enriched with enhancer, repressor and insulator sites. The wildtype allele was lost in the polyps of the proband. Further, real-time RT-PCR assays showed that expressions of MIA and MIA-RAB4B located 35 kb upstream of the deletion, were up-regulated in the polyps compared to the matched mucosa of the proband. MIA-RAB4B, the read-through long non-coding RNA (lncRNA), RAB4B, PIM2 and TAOK1 share common binding site of a microRNA, miR-24, in their 3'UTRs. PIM2 and TAOK1, two target oncogenes of miR-24, were co-ordinately up-regulated with MIA-RAB4B in the polyps, suggesting that MIA-RAB4B could function as competitive endogenous RNA to titrate miR-24 away from its other targets. The data suggest that the 19.13 deletion disrupted chromatin boundary, leading to altered expression of several genes and lncRNA, could contribute to colorectal cancer via novel genetic and epigenetic mechanisms.

  14. Mutation induction by ion beams in plants

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Atsushi [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment

    2001-03-01

    The effect of ion beams such as C, He, and Ne ions was investigated on the mutation induction in plants with the expectation that ion beams of high linear energy transfer (LET) can frequently produce large DNA alternation such as inversion, translocation and large deletion rather than point mutation. Mutation frequency was investigated using Arabidopsis visible phenotype loci and was 8 to 33 fold higher for 220 MeV carbon ions than for electrons. Mutation spectrum was investigated on the flower color of chrysanthemum cv to find that flower mutants induced by ion beams show complex and stripe types rather than single color. Polymerase chain reaction analysis was performed to investigate DNA alteration of mutations. In conclusion, the characteristics of ion beams for the mutation induction are 1) high frequency, 2) broad mutation spectrum, and 3) novel mutants. (S. Ohno)

  15. Genotypic and phenotypic aspects of primary immunodeficiency diseases of the lymphoid system

    NARCIS (Netherlands)

    J.G. Noordzij

    2002-01-01

    textabstractThis thesis focuses on the immunological phenotype, the mutation analysis, and the residual activity of mutated proteins in patients with PID of the lymphoid system. During this project, we have investigated possible genotype-(immuno)phenotype relationships in patients with antibody defi

  16. Overlapping DSPP mutations cause dentin dysplasia and dentinogenesis imperfecta.

    Science.gov (United States)

    McKnight, D A; Simmer, J P; Hart, P S; Hart, T C; Fisher, L W

    2008-12-01

    Dentinogenesis imperfecta (DGI) and dentin dysplasia (DD) are allelic disorders due to mutations in DSPP. Typically, the phenotype breeds true within a family. Recently, two reports showed that 3 different net -1 bp frameshift mutations early in DSPP's repeat domain caused DD, whereas 6 more 3' frameshift mutations were associated with DGI. Here we identify a DD kindred with a novel -1 bp frameshift (c.3141delC) that falls within the portion of the DSPP repeat domain previously associated solely with the DGI phenotype. This new frameshift mutation shows that overlapping DSPP mutations can give rise to either DGI or DD phenotypes. Furthermore, the consistent kindred presentation of the DD or DGI phenotype appears to be dependent on an as-yet-undescribed genetic modifier closely linked to DSPP.

  17. Intronic mutation in the growth hormone (GH) receptor gene from a girl with Laron syndrome and extremely high serum GH binding protein: extended phenotypic study in a very large pedigree.

    Science.gov (United States)

    Silbergeld, A; Dastot, F; Klinger, B; Kanety, H; Eshet, R; Amselem, S; Laron, Z

    1997-01-01

    Laron syndrome (LS) is a hereditary form of GH resistance due to molecular defects in the GH receptor (GHR). Most of the identified mutations are located in the extracellular domain of the receptor, resulting in a lack of serum GHBP in the majority of LS patients. We present an LS patient with supranormal levels of serum GHBP, in addition to 35 of her relatives. The proband is a 3.5 year-old Druse girl with severe short stature (height SDS -5.1), high GH (250 micrograms/l), low IGF-I (2.7 nmol/l) and IGFBP-3 (410 micrograms/l), both unresponsive to exogenous GH. The binding capacity of the serum GHBP was 22 nM (adult reference serum, 0.7 nM), with an affinity constant Ka = 1.9 x 10(9) M-1 comparable to that of normal sera (Ka = 1.7-2.1 x 10(9) M-1). The apparent MW of the GHBP was approximately 60-80 kDa, similar to that of control sera. In the proband's sister, parents, grandparents and uncles, extremely high GHBP values were observed (43.0 +/- 4.8 RSB, n = 10) compared with normal adults (0.81 +/- 0.06 RSB) (p T substitution at nucleotide 785-1 preceding exon 8, a sequence that encodes the transmembrane domain. This mutation, which destroys the invariant dinucleotide of the splice acceptor site, is expected to alter GHR mRNA splicing and to be responsible for skipping exon 8. The resulting truncated protein that retains GH binding activity is probably no longer anchored in the cell membrane, affecting signal transmission in the homozygous patient and causing high GHBP levels in the heterozygous relatives.

  18. Evolution of molecular phenotypes under stabilizing selection

    Science.gov (United States)

    Nourmohammad, Armita; Schiffels, Stephan; Lässig, Michael

    2013-01-01

    Molecular phenotypes are important links between genomic information and organismic functions, fitness, and evolution. Complex phenotypes, which are also called quantitative traits, often depend on multiple genomic loci. Their evolution builds on genome evolution in a complicated way, which involves selection, genetic drift, mutations and recombination. Here we develop a coarse-grained evolutionary statistics for phenotypes, which decouples from details of the underlying genotypes. We derive approximate evolution equations for the distribution of phenotype values within and across populations. This dynamics covers evolutionary processes at high and low recombination rates, that is, it applies to sexual and asexual populations. In a fitness landscape with a single optimal phenotype value, the phenotypic diversity within populations and the divergence between populations reach evolutionary equilibria, which describe stabilizing selection. We compute the equilibrium distributions of both quantities analytically and we show that the ratio of mean divergence and diversity depends on the strength of selection in a universal way: it is largely independent of the phenotype’s genomic encoding and of the recombination rate. This establishes a new method for the inference of selection on molecular phenotypes beyond the genome level. We discuss the implications of our findings for the predictability of evolutionary processes.

  19. GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations

    Directory of Open Access Journals (Sweden)

    Eva Y. G. De Vilder

    2017-01-01

    Full Text Available Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX, is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP with important functions in various biological processes. Mutations in the encoding GGCX gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1 is best known. Other patients have skin, eye, heart or bone manifestations. As genotype–phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one GGCX mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations—a frequent problem in orphan diseases—we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype–phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management.

  20. Adaptive evolution of molecular phenotypes

    Science.gov (United States)

    Held, Torsten; Nourmohammad, Armita; Lässig, Michael

    2014-09-01

    Molecular phenotypes link genomic information with organismic functions, fitness, and evolution. Quantitative traits are complex phenotypes that depend on multiple genomic loci. In this paper, we study the adaptive evolution of a quantitative trait under time-dependent selection, which arises from environmental changes or through fitness interactions with other co-evolving phenotypes. We analyze a model of trait evolution under mutations and genetic drift in a single-peak fitness seascape. The fitness peak performs a constrained random walk in the trait amplitude, which determines the time-dependent trait optimum in a given population. We derive analytical expressions for the distribution of the time-dependent trait divergence between populations and of the trait diversity within populations. Based on this solution, we develop a method to infer adaptive evolution of quantitative traits. Specifically, we show that the ratio of the average trait divergence and the diversity is a universal function of evolutionary time, which predicts the stabilizing strength and the driving rate of the fitness seascape. From an information-theoretic point of view, this function measures the macro-evolutionary entropy in a population ensemble, which determines the predictability of the evolutionary process. Our solution also quantifies two key characteristics of adapting populations: the cumulative fitness flux, which measures the total amount of adaptation, and the adaptive load, which is the fitness cost due to a population's lag behind the fitness peak.

  1. High-throughput discovery of novel developmental phenotypes.

    Science.gov (United States)

    Dickinson, Mary E; Flenniken, Ann M; Ji, Xiao; Teboul, Lydia; Wong, Michael D; White, Jacqueline K; Meehan, Terrence F; Weninger, Wolfgang J; Westerberg, Henrik; Adissu, Hibret; Baker, Candice N; Bower, Lynette; Brown, James M; Caddle, L Brianna; Chiani, Francesco; Clary, Dave; Cleak, James; Daly, Mark J; Denegre, James M; Doe, Brendan; Dolan, Mary E; Edie, Sarah M; Fuchs, Helmut; Gailus-Durner, Valerie; Galli, Antonella; Gambadoro, Alessia; Gallegos, Juan; Guo, Shiying; Horner, Neil R; Hsu, Chih-Wei; Johnson, Sara J; Kalaga, Sowmya; Keith, Lance C; Lanoue, Louise; Lawson, Thomas N; Lek, Monkol; Mark, Manuel; Marschall, Susan; Mason, Jeremy; McElwee, Melissa L; Newbigging, Susan; Nutter, Lauryl M J; Peterson, Kevin A; Ramirez-Solis, Ramiro; Rowland, Douglas J; Ryder, Edward; Samocha, Kaitlin E; Seavitt, John R; Selloum, Mohammed; Szoke-Kovacs, Zsombor; Tamura, Masaru; Trainor, Amanda G; Tudose, Ilinca; Wakana, Shigeharu; Warren, Jonathan; Wendling, Olivia; West, David B; Wong, Leeyean; Yoshiki, Atsushi; MacArthur, Daniel G; Tocchini-Valentini, Glauco P; Gao, Xiang; Flicek, Paul; Bradley, Allan; Skarnes, William C; Justice, Monica J; Parkinson, Helen E; Moore, Mark; Wells, Sara; Braun, Robert E; Svenson, Karen L; de Angelis, Martin Hrabe; Herault, Yann; Mohun, Tim; Mallon, Ann-Marie; Henkelman, R Mark; Brown, Steve D M; Adams, David J; Lloyd, K C Kent; McKerlie, Colin; Beaudet, Arthur L; Bućan, Maja; Murray, Stephen A

    2016-09-22

    Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

  2. Quality control test for sequence-phenotype assignments.

    Directory of Open Access Journals (Sweden)

    Maria Teresa Lara Ortiz

    Full Text Available Relating a gene mutation to a phenotype is a common task in different disciplines such as protein biochemistry. In this endeavour, it is common to find false relationships arising from mutations introduced by cells that may be depurated using a phenotypic assay; yet, such phenotypic assays may introduce additional false relationships arising from experimental errors. Here we introduce the use of high-throughput DNA sequencers and statistical analysis aimed to identify incorrect DNA sequence-phenotype assignments and observed that 10-20% of these false assignments are expected in large screenings aimed to identify critical residues for protein function. We further show that this level of incorrect DNA sequence-phenotype assignments may significantly alter our understanding about the structure-function relationship of proteins. We have made available an implementation of our method at http://bis.ifc.unam.mx/en/software/chispas.

  3. Quality Control Test for Sequence-Phenotype Assignments

    Science.gov (United States)

    Ortiz, Maria Teresa Lara; Rosario, Pablo Benjamín Leon; Luna-Nevarez, Pablo; Gamez, Alba Savin; Martínez-del Campo, Ana; Del Rio, Gabriel

    2015-01-01

    Relating a gene mutation to a phenotype is a common task in different disciplines such as protein biochemistry. In this endeavour, it is common to find false relationships arising from mutations introduced by cells that may be depurated using a phenotypic assay; yet, such phenotypic assays may introduce additional false relationships arising from experimental errors. Here we introduce the use of high-throughput DNA sequencers and statistical analysis aimed to identify incorrect DNA sequence-phenotype assignments and observed that 10–20% of these false assignments are expected in large screenings aimed to identify critical residues for protein function. We further show that this level of incorrect DNA sequence-phenotype assignments may significantly alter our understanding about the structure-function relationship of proteins. We have made available an implementation of our method at http://bis.ifc.unam.mx/en/software/chispas. PMID:25700273

  4. Quality control test for sequence-phenotype assignments.

    Science.gov (United States)

    Ortiz, Maria Teresa Lara; Rosario, Pablo Benjamín Leon; Luna-Nevarez, Pablo; Gamez, Alba Savin; Martínez-del Campo, Ana; Del Rio, Gabriel

    2015-01-01

    Relating a gene mutation to a phenotype is a common task in different disciplines such as protein biochemistry. In this endeavour, it is common to find false relationships arising from mutations introduced by cells that may be depurated using a phenotypic assay; yet, such phenotypic assays may introduce additional false relationships arising from experimental errors. Here we introduce the use of high-throughput DNA sequencers and statistical analysis aimed to identify incorrect DNA sequence-phenotype assignments and observed that 10-20% of these false assignments are expected in large screenings aimed to identify critical residues for protein function. We further show that this level of incorrect DNA sequence-phenotype assignments may significantly alter our understanding about the structure-function relationship of proteins. We have made available an implementation of our method at http://bis.ifc.unam.mx/en/software/chispas.

  5. Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy.

    Science.gov (United States)

    Zou, Yubao; Wang, Jizheng; Liu, Xuan; Wang, Yilu; Chen, Yi; Sun, Kai; Gao, Shuo; Zhang, Channa; Wang, Zhimin; Zhang, Yin; Feng, Xinxing; Song, Ying; Wu, Yajie; Zhang, Hongju; Jia, Lei; Wang, Hu; Wang, Dong; Yan, Chaowu; Lu, Minjie; Zhou, Xianliang; Song, Lei; Hui, Rutai

    2013-06-01

    Genotype-phenotype correlation of hypertrophic cardiomyopathy (HCM) has been challenging because of the genetic and clinical heterogeneity. To determine the mutation profile of Chinese patients with HCM and to correlate genotypes with phenotypes, we performed a systematic mutation screening of the eight most commonly mutated genes encoding sarcomere proteins in 200 unrelated Chinese adult patients using direct DNA sequencing. A total of 98 mutations were identified in 102 mutation carriers. The frequency of mutations in MYH7, MYBPC3, TNNT2 and TNNI3 was 26.0, 18.0, 4.0 and 3.5 % respectively. Among the 200 genotyped HCM patients, 83 harbored a single mutation, and 19 (9.5 %) harbored multiple mutations. The number of mutations was positively correlated with the maximum wall thickness. We found that neither particular gene nor specific mutation was correlated to clinical phenotype. In summary, the frequency of multiple mutations was greater in Chinese HCM patients than in the Caucasian population. Multiple mutations in sarcomere protein may be a risk factor for left ventricular wall thickness.

  6. Microglia phenotype diversity

    NARCIS (Netherlands)

    Olah, M.; Biber, K.; Vinet, J.; Boddeke, H. W. G. M.

    2011-01-01

    Microglia, the tissue macrophages of the brain, have under healthy conditions a resting phenotype that is characterized by a ramified morphology. With their fine processes microglia are continuously scanning their environment. Upon any homeostatic disturbance microglia rapidly change their phenotype

  7. Mutation analysis of Australasian Gaucher disease patients

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, P.V.; Carey, W.F.; Morris, C.P.; Lewis, B.D. [Women`s and Children`s Hospital, North Adelaide, South Australia (Australia)

    1995-09-25

    We have previously reported phenotype and genotype analyses in 28 Australasian Gaucher patients who were screened for several of the common Gaucher mutations: N370S, L444P, 84GG, and R463C. Horowitz and Zimran have reported that the complex alleles recNciI and recTL, which contain several point mutations including L444P, are relatively common, especially in non-Jewish Gaucher patients. Zimran and Horowitz have also stated that these recombinant alleles could easily be missed by laboratories testing only for the common Gaucher point mutations. Failure to correctly identify these mutations would influence any attempt to correlate genotype with phenotype. We have therefore retested our Gaucher patients for recNciI (L444P, A456P, and V46OV) and recTL (D409H, L444P, A456P, and V46OV) by PCR amplification, followed by hybridization with allele-specific oligonucleotides. 4 refs.

  8. Genotype phenotype correlation in Wilson's disease within families-a report on four south Indian families

    Institute of Scientific and Technical Information of China (English)

    S Santhosh; GM Chandy; RV Shaji; CE Eapen; V Jayanthi; S Malathi; P Finny; N Thomas; M Chandy; G Kurian

    2008-01-01

    AIM: To study the genotype phenotype correlation inWilson's disease (WD) patients with in families.METHODS: We report four unrelated families from South India with nine members affected withWD. Phenotype was classified as per international consensus phenotypic classification of WD. DNA was extracted from peripheral blood and 21 exons of ATP7B gene and flanking introns were amplified by polymerase chain reaction (PCR). The PCR products were screened for mutations and the aberrant products noted on screening were sequenced.RESULTS: Four separate ATP7B mutations were found in the four families. ATP7B mutations were identical amongst affected members within each family.Three families had homozygous mutations of ATP7B gene while one family had compound heterozygous mutation, of which only one mutation was identified.We noted concordance between ATP7B gene mutation and Wilson's disease phenotype amongst members within each family. The age of onset of symptoms orof detection of asymptomatic disease, baseline serum ceruloplasmin and baseline urinary copper levelswere also similar in affected members of each family.Minor differences in phenotype and baseline serumceruloplasmin level were noted in one family.CONCLUSION: We report concordance between ATP7B mutation and WD phenotype within each familywith > 1 member affected with WD. Homozygous ATP7B mutation was present in 3 of the 4 families studied. Our report supports allelic dominance as adeterminant of WD phenotype. However, in one familywith compound heterozygous mutation, there was a similar WD phenotype which suggests that there may be other factors determining the phenotype.

  9. Mutation analysis of 28 gaucher disease patients: The Australasian experience

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, B.D.; Nelson, P.V.; Robertson, E.F.; Morris, C.P. [Women`s and Children`s Hospital, North Adelaide, South Australia (Australia)

    1994-01-15

    Gaucher disease is the most common lysomal storage disease. It is an autosomal recessive disorder that results from a deficiency of {beta}-glucocerrebrosidase. Three clinical phenotypes have been described: non-neuronopathic, acute neuronopathic, and subacuteneuronopathic. Genomic DNA from 28 Australasian patients of diverse ethnic origin with Gaucher disease was screened for 3 common mutations (1226G, 1448C and 84GG) using the amplification refractory mutation system (ARMS), and one uncommon mutation (1504T) by restriction enzyme digestion. Thirty-eight of the 56 independent alleles in these patients were characterized, with 1448C present in 42% and 1226G in 28% of the alleles. The 1226G mutation was associated only with the nonneuronopathic phenotype and 7 of the 15 patients who carried the 1448C mutation developed neuronopathic disease. Three infants who died in the neonatal period following a rapidly progressive neurodegenerative course carried no identifiable mutations. The 84GG mutation was carried by 2 Jewish patients and 1504T was present in one patient. It is now possible to rapidly identify the common Gaucher mutations using ARMS and restriction enzyme digestion, and our findings confirm the heterogeneity of mutations in Gaucher disease. It is also possible to predict in part the phenotypic outcome when screening patients for these mutations. The authors consider mutation analysis to be of most use in prenatal diagnosis and for carrier detection within affected families. 27 refs., 2 figs., 2 tabs.

  10. A case of cerebrotendinous xanthomatosis mimicking the clinical phenotype of mitochondrial disease with a novel frame-shift mutation (c. 43_44 delGG) in CYP27A1 gene exon 1.

    Science.gov (United States)

    Koge, Junpei; Hayashi, Shintaro; Yamaguchi, Hiroo; Tateishi, Takahisa; Murai, Hiroyuki; Kira, Jun-Ichi

    2016-10-28

    A 37-old-male with a history of early childhood mental retardation was admitted to our hospital. He experienced recurrent syncopes at 23 years old, and at age 35 gait disturbance and hearing impairment developed gradually and worsened over time. His grandparents were in a consanguineous marriage. He was of short stature and absent of tendon xanthomas. Neurological examinations revealed scanning speech, dysphagia, right sensorineural hearing loss, spasticity in both upper and lower extremities, and spastic gait. Tendon reflexes were brisk throughout, and Babinski and Chaddock reflexes were both positive bilaterally. Laboratory tests revealed elevated lactate and pyruvate concentrations in both serum and cerebrospinal fluid. Fluid attenuated inversion recovery magnetic resonance imaging showed high intensity lesions in the bilateral cerebellar hemispheres, pyramidal tracts in the brainstem, and internal capsules symmetrically. Brain magnetic resonance spectroscopy measurements revealed an elevated lactate/creatine plus phosphocreatine ratio and a decreased N-acetyl-aspartate/creatine plus phosphocreatine ratio in the cerebellum. At this point, mitochondrial diseases, particularly myoclonic epilepsy with ragged-red fibers (MERRF), to be the most likely cause. We performed a biopsy of his left biceps brachii muscle, showing variations in fiber size with occasional central nuclei and very few ragged-red fibers. Blood mitochondrial respiratory enzyme assays showed normal values with elevated citrate synthase activity, and mitochondrial DNA analyses for MERRF revealed no pathogenic mutations. We then explored other possibilities and detected an elevated serum cholestanol concentration of 20.4 μg/ml (reference value mimicking mitochondrial diseases, but with negative results for muscle pathology or genetic analyses. The measurements of serum cholestanol concentrations might be useful in diagnosing such atypical cases.

  11. Splice Site Mutations in the ATP7A Gene

    DEFF Research Database (Denmark)

    Skjørringe, Tina; Tümer, Zeynep; Møller, Lisbeth Birk

    2011-01-01

    Menkes disease (MD) is caused by mutations in the ATP7A gene. We describe 33 novel splice site mutations detected in patients with MD or the milder phenotypic form, Occipital Horn Syndrome. We review these 33 mutations together with 28 previously published splice site mutations. We investigate 12...... mutations for their effect on the mRNA transcript in vivo. Transcriptional data from another 16 mutations were collected from the literature. The theoretical consequences of splice site mutations, predicted with the bioinformatics tool Human Splice Finder, were investigated and evaluated in relation...... to in vivo results. Ninety-six percent of the mutations identified in 45 patients with classical MD were predicted to have a significant effect on splicing, which concurs with the absence of any detectable wild-type transcript in all 19 patients investigated in vivo. Sixty-seven percent of the mutations...

  12. Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

    Science.gov (United States)

    Rice, Gillian; Patrick, Teresa; Parmar, Rekha; Taylor, Claire F; Aeby, Alec; Aicardi, Jean; Artuch, Rafael; Montalto, Simon Attard; Bacino, Carlos A; Barroso, Bruno; Baxter, Peter; Benko, Willam S; Bergmann, Carsten; Bertini, Enrico; Biancheri, Roberta; Blair, Edward M; Blau, Nenad; Bonthron, David T; Briggs, Tracy; Brueton, Louise A; Brunner, Han G; Burke, Christopher J; Carr, Ian M; Carvalho, Daniel R; Chandler, Kate E; Christen, Hans-Jurgen; Corry, Peter C; Cowan, Frances M; Cox, Helen; D'Arrigo, Stefano; Dean, John; De Laet, Corinne; De Praeter, Claudine; Dery, Catherine; Ferrie, Colin D; Flintoff, Kim; Frints, Suzanna G M; Garcia-Cazorla, Angels; Gener, Blanca; Goizet, Cyril; Goutieres, Francoise; Green, Andrew J; Guet, Agnes; Hamel, Ben C J; Hayward, Bruce E; Heiberg, Arvid; Hennekam, Raoul C; Husson, Marie; Jackson, Andrew P; Jayatunga, Rasieka; Jiang, Yong-Hui; Kant, Sarina G; Kao, Amy; King, Mary D; Kingston, Helen M; Klepper, Joerg; van der Knaap, Marjo S; Kornberg, Andrew J; Kotzot, Dieter; Kratzer, Wilfried; Lacombe, Didier; Lagae, Lieven; Landrieu, Pierre Georges; Lanzi, Giovanni; Leitch, Andrea; Lim, Ming J; Livingston, John H; Lourenco, Charles M; Lyall, E G Hermione; Lynch, Sally A; Lyons, Michael J; Marom, Daphna; McClure, John P; McWilliam, Robert; Melancon, Serge B; Mewasingh, Leena D; Moutard, Marie-Laure; Nischal, Ken K; Ostergaard, John R; Prendiville, Julie; Rasmussen, Magnhild; Rogers, R Curtis; Roland, Dominique; Rosser, Elisabeth M; Rostasy, Kevin; Roubertie, Agathe; Sanchis, Amparo; Schiffmann, Raphael; Scholl-Burgi, Sabine; Seal, Sunita; Shalev, Stavit A; Corcoles, C Sierra; Sinha, Gyan P; Soler, Doriette; Spiegel, Ronen; Stephenson, John B P; Tacke, Uta; Tan, Tiong Yang; Till, Marianne; Tolmie, John L; Tomlin, Pam; Vagnarelli, Federica; Valente, Enza Maria; Van Coster, Rudy N A; Van der Aa, Nathalie; Vanderver, Adeline; Vles, Johannes S H; Voit, Thomas; Wassmer, Evangeline; Weschke, Bernhard; Whiteford, Margo L; Willemsen, Michel A A; Zankl, Andreas; Zuberi, Sameer M; Orcesi, Simona; Fazzi, Elisa; Lebon, Pierre; Crow, Yanick J

    2007-10-01

    Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

  13. X-Linked Dilated Cardiomyopathy: A Cardiospecific Phenotype of Dystrophinopathy

    Directory of Open Access Journals (Sweden)

    Akinori Nakamura

    2015-06-01

    Full Text Available X-linked dilated cardiomyopathy (XLDCM is a distinct phenotype of dystrophinopathy characterized by preferential cardiac involvement without any overt skeletal myopathy. XLDCM is caused by mutations of the Duchenne muscular dystrophy (DMD gene and results in lethal heart failure in individuals between 10 and 20 years. Patients with Becker muscular dystrophy, an allelic disorder, have a milder phenotype of skeletal muscle involvement compared to Duchenne muscular dystrophy (DMD and sometimes present with dilated cardiomyopathy. The precise relationship between mutations in the DMD gene and cardiomyopathy remain unclear. However, some hypothetical mechanisms are being considered to be associated with the presence of some several dystrophin isoforms, certain reported mutations, and an unknown dystrophin-related pathophysiological mechanism. Recent therapy for Duchenne muscular dystrophy, the severe dystrophinopathy phenotype, appears promising, but the presence of XLDCM highlights the importance of focusing on cardiomyopathy while elucidating the pathomechanism and developing treatment.

  14. Multiple origins of the phenol reaction negative phenotype in foxtail millet, Setaria italica (L.) P. Beauv., were caused by independent loss-of-function mutations of the polyphenol oxidase (Si7PPO) gene during domestication.

    Science.gov (United States)

    Inoue, Takahiko; Yuo, Takahisa; Ohta, Takeshi; Hitomi, Eriko; Ichitani, Katsuyuki; Kawase, Makoto; Taketa, Shin; Fukunaga, Kenji

    2015-08-01

    Foxtail millet shows variation in positive phenol color reaction (Phr) and negative Phr in grains, but predominant accessions of this crop are negative reaction type, and the molecular genetic basis of the Phr reaction remains unresolved. In this article, we isolated polyphenol oxidase (PPO) gene responsible for Phr using genome sequence information and investigated molecular genetic basis of negative Phr and crop evolution of foxtail millet. First of all, we searched for PPO gene homologs in a foxtail millet genome database using a rice PPO gene as a query and successfully found three copies of the PPO gene. One of the PPO gene homologs on chromosome 7 showed the highest similarity with PPO genes expressed in hulls (grains) of other cereal species including rice, wheat, and barley and was designated as Si7PPO. Phr phenotypes and Si7PPO genotypes completely co-segregated in a segregating population. We also analyzed the genetic variation conferring negative Phr reaction. Of 480 accessions of the landraces investigated, 87 (18.1 %) showed positive Phr and 393 (81.9 %) showed negative Phr. In the 393 Phr negative accessions, three types of loss-of-function Si7PPO gene were predominant and independently found in various locations. One of them has an SNP in exon 1 resulting in a premature stop codon and was designated as stop codon type, another has an insertion of a transposon (Si7PPO-TE1) in intron 2 and was designated as TE1-insertion type, and the other has a 6-bp duplication in exon 3 resulting in the duplication of 2 amino acids and was designated as 6-bp duplication type. As a rare variant of the stop codon type, one accession additionally has an insertion of a transposon, Si7PPO-TE2, in intron 2 and was designated as "stop codon +TE2 insertion type". The geographical distribution of accessions with positive Phr and those with three major types of negative Phr was also investigated. Accessions with positive Phr were found in subtropical and tropical regions at

  15. DRUMS: a human disease related unique gene mutation search engine.

    Science.gov (United States)

    Li, Zuofeng; Liu, Xingnan; Wen, Jingran; Xu, Ye; Zhao, Xin; Li, Xuan; Liu, Lei; Zhang, Xiaoyan

    2011-10-01

    With the completion of the human genome project and the development of new methods for gene variant detection, the integration of mutation data and its phenotypic consequences has become more important than ever. Among all available resources, locus-specific databases (LSDBs) curate one or more specific genes' mutation data along with high-quality phenotypes. Although some genotype-phenotype data from LSDB have been integrated into central databases little effort has been made to integrate all these data by a search engine approach. In this work, we have developed disease related unique gene mutation search engine (DRUMS), a search engine for human disease related unique gene mutation as a convenient tool for biologists or physicians to retrieve gene variant and related phenotype information. Gene variant and phenotype information were stored in a gene-centred relational database. Moreover, the relationships between mutations and diseases were indexed by the uniform resource identifier from LSDB, or another central database. By querying DRUMS, users can access the most popular mutation databases under one interface. DRUMS could be treated as a domain specific search engine. By using web crawling, indexing, and searching technologies, it provides a competitively efficient interface for searching and retrieving mutation data and their relationships to diseases. The present system is freely accessible at http://www.scbit.org/glif/new/drums/index.html.

  16. Single cell dynamic phenotyping

    OpenAIRE

    Katherin Patsch; Chi-Li Chiu; Mark Engeln; Agus, David B.; Parag Mallick; Shannon M. Mumenthaler; Daniel Ruderman

    2016-01-01

    Live cell imaging has improved our ability to measure phenotypic heterogeneity. However, bottlenecks in imaging and image processing often make it difficult to differentiate interesting biological behavior from technical artifact. Thus there is a need for new methods that improve data quality without sacrificing throughput. Here we present a 3-step workflow to improve dynamic phenotype measurements of heterogeneous cell populations. We provide guidelines for image acquisition, phenotype track...

  17. Spectrum of small mutations in the dystrophin coding region.

    Science.gov (United States)

    Prior, T W; Bartolo, C; Pearl, D K; Papp, A C; Snyder, P J; Sedra, M S; Burghes, A H; Mendell, J R

    1995-07-01

    Duchenne and Becker muscular dystrophies (DMD and BMD) are caused by defects in the dystrophin gene. About two-thirds of the affected patients have large deletions or duplications, which occur in the 5' and central portion of the gene. The nondeletion/duplication cases are most likely the result of smaller mutations that cannot be identified by current diagnostic screening strategies. We screened approximately 80% of the dystrophin coding sequence for small mutations in 158 patients without deletions or duplications and identified 29 mutations. The study indicates that many of the DMD and the majority of the BMD small mutations lie in nonc