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Sample records for werner syndrome gene

  1. Genetics Home Reference: Werner syndrome

    Science.gov (United States)

    ... for This Condition Adult premature aging syndrome Adult Progeria Werner's Syndrome Werners Syndrome WS Related Information How ... BK, Monnat RJ Jr. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat ...

  2. Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes.

    Science.gov (United States)

    Du, Xiaobing; Shen, Johnny; Kugan, Nishan; Furth, Emma E; Lombard, David B; Cheung, Catherine; Pak, Sally; Luo, Guangbin; Pignolo, Robert J; DePinho, Ronald A; Guarente, Leonard; Johnson, F Brad

    2004-10-01

    The Werner and Bloom syndromes are caused by loss-of-function mutations in WRN and BLM, respectively, which encode the RecQ family DNA helicases WRN and BLM, respectively. Persons with Werner syndrome displays premature aging of the skin, vasculature, reproductive system, and bone, and those with Bloom syndrome display more limited features of aging, including premature menopause; both syndromes involve genome instability and increased cancer. The proteins participate in recombinational repair of stalled replication forks or DNA breaks, but the precise functions of the proteins that prevent rapid aging are unknown. Accumulating evidence points to telomeres as targets of WRN and BLM, but the importance in vivo of the proteins in telomere biology has not been tested. We show that Wrn and Blm mutations each accentuate pathology in later-generation mice lacking the telomerase RNA template Terc, including acceleration of phenotypes characteristic of latest-generation Terc mutants. Furthermore, pathology not observed in Terc mutants but similar to that observed in Werner syndrome and Bloom syndrome, such as bone loss, was observed. The pathology was accompanied by enhanced telomere dysfunction, including end-to-end chromosome fusions and greater loss of telomere repeat DNA compared with Terc mutants. These findings indicate that telomere dysfunction may contribute to the pathogenesis of Werner syndrome and Bloom syndrome.

  3. Early Onset Werner Syndrome

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    Berna İmge Aydoğan

    2015-09-01

    Full Text Available Werner syndrome (WS is a rare autosomal recessive adult-onset progeroid disorder characterized by the early onset of aged-appearance and age-related metabolic disorders. Symptoms of premature aging usually first develop in the second-third decades of life. We report a 27-year-old female who was admitted to our clinic at the age of eighteen with hyperglycemia. She was diagnosed with diabetes and type 4 dyslipidemia at the age of seven. In her family history, her parents were first cousins and she had three healthy brothers. On her first physical examination; she had bird-like face appearance, global hair loss, beaked nose, short stature and she was overweight. She had global hair loss with gray and thin hair. Hoarseness of voice and hyperkeratosis of skin were observed. She had bilateral cataracts and moderate sensorineural hearing loss. On psychiatric examination, borderline mental retardation was detected. She had severe insulin resistance and hypertriglyceridemia despite levothyroxine, gemfibrozil, omega-3 and intensive insulin treatment. Routine lipid apheresis was performed to lower the triglyceride levels reaching 5256 mg/dL. She also had focal segmental glomerulosclerosis, hepatosteatosis, osteoporosis and epilepsy. Disease was accompanied by several congenital deformities, such as Rathke’s cleft cyst, angiomyolipoma and femoral neck hypoplasia. WS is a rare genetic disorder characterized by multiple endocrine manifestations as well as soft tissue changes. We present a case of early disturbances that were diagnosed before typical clinical signs and symptoms. We propose that WS should be kept in mind when type 2 diabetes and hyperlipidemia are diagnosed early in childhood. Turk Jem 2015; 19: 99-104

  4. Epigenetic Regulation of Werner Syndrome Gene in Age-Related Cataract

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    Xi Zhu

    2015-01-01

    Full Text Available Purpose. To examine the promoter methylation and histone modification of WRN (Werner syndrome gene, a DNA repair gene, and their relationship with the gene expression in age-related cataract (ARC lens. Methods. We collected the lenses after cataract surgery from 117ARC patients and 39 age-matched non-ARC. WRN expression, DNA methylation and histone modification around the CpG island were assessed. The methylation status of Human-lens-epithelium cell (HLEB-3 was chemically altered to observe the relationship between methylation and expression of WRN. Results. The WRN expression was significantly decreased in the ARC anterior lens capsules comparing with the control. The CpG island of WRN promoter in the ARC anterior lens capsules displayed hypermethylation comparing with the controls. The WRN promoter was almost fully methylated in the cortex of ARC and control lens. Acetylated H3 was lower while methylated H3-K9 was higher in ARC anterior lens capsules than that of the controls. The expression of WRN in HLEB-3 increased after demethylation of the cells. Conclusions. A hypermethylation in WRN promoter and altered histone modification in anterior lens capsules might contribute to the ARC mechanism. The data suggest an association of altered DNA repair capability in lens with ARC pathogenesis.

  5. Mutations in the consensus helicase domains of the Werner syndrome gene

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    Yu, Chang-En; Oshima, Junko; Wijsman, E.M. [Univ. of Washington, Seattle, WA (United States)] [and others

    1997-02-01

    Werner syndrome (WS) is an autosomal recessive disease with a complex phenotype that is suggestive of accelerated aging. WS is caused by mutations in a gene, WRN, that encodes a predicted 1,432-amino-acid protein with homology to DNA and RNA helicases. Previous work identified four WS mutations in the 3{prime} end of the gene, which resulted in predicted truncated protein products of 1,060-1,247 amino acids but did not disrupt the helicase domain region (amino acids 569-859). Here, additional WS subjects were screened for mutations, and the intron-exon structure of the gene was determined. A total of 35 exons were defined, with the coding sequences beginning in the second exon. Five new WS mutations were identified: two nonsense mutations at codons 369 and 889; a mutation at a splice-junction site, resulting in a predicted truncated protein of 760 amino acids; a 1-bp deletion causing a frameshift; and a predicted truncated protein of 391 amino acids. Another deletion is >15 kb of genomic DNA, including exons 19-23; the predicted protein is 1,186 amino acids long. Four of these new mutations either partially disrupt the helicase domain region or result in predicted protein products completely missing the helicase region. These results confirm that mutations in the WRN gene are responsible for WS. Also, the location of the mutations indicates that the presence or absence of the helicase domain does not influence the WS phenotype and suggests that WS is the result of complete loss of function of the WRN gene product. 63 refs., 1 fig., 5 tabs.

  6. Interaction of Werner and Bloom syndrome genes with p53 in familial breast cancer.

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    Wirtenberger, Michael; Frank, Bernd; Hemminki, Kari; Klaes, Rüdiger; Schmutzler, Rita K; Wappenschmidt, Barbara; Meindl, Alfons; Kiechle, Marion; Arnold, Norbert; Weber, Bernhard H F; Niederacher, Dieter; Bartram, Claus R; Burwinkel, Barbara

    2006-08-01

    Mutations of the human RecQ helicase genes WRN and BLM lead to rare autosomal recessive disorders, Werner and Bloom syndromes, which are associated with premature ageing and cancer predisposition. We tested the hypothesis whether three polymorphic, non-conservative amino acid exchanges in WRN and BLM act as low-penetrance familial breast cancer risk factors. Moreover, we examined the putative impact of p53 MspI 1798G>A, which is completely linked to p53PIN3, a 16 bp insertion/duplication that has been associated with reduced p53 expression, on familial breast cancer risk. Genotyping analyses, performed on 816 BRCA1/2 mutation-negative German familial breast cancer patients and 1012 German controls, revealed a significant association of the WRN Cys1367Arg polymorphism with familial breast cancer (OR = 1.28, 95% CI 1.06-1.54) and high-risk familial breast cancer (OR = 1.32, 95% CI 1.06-1.65). The analysis of p53 MspI 1798G>A, which is completely linked to p53PIN3, showed a significantly increased familial breast cancer risk for carriers of the 16 bp insertion/duplication, following a recessive mode (OR = 2.15, 95% CI = 1.12-4.11). WRN Cys1367Arg, located in the C-terminus, the binding site of p53, is predicted to be damaging. The joint effect of WRN Cys1367Arg and p53 MspI resulted in an increased breast cancer risk compared to the single polymorphisms (OR = 3.39, 95% CI 1.19-9.71). In conclusion, our study indicates the importance of inherited variants in the WRN and p53 genes for familial breast cancer susceptibility.

  7. Soft-tissue mineralization in Werner syndrome

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    Leone, Antonio; Costantini, Alessandro Maria; Brigida, Raffaela; Antoniol, Onorina Monica; Bonomo, Lorenzo [Universita Cattolica School of Medicine, Department of Radiology, Rome (Italy); Antonelli-Incalzi, Raffaele [Universita Cattolica School of Medicine, Department of Geriatrics, Rome (Italy)

    2005-01-01

    Werner syndrome is a rare autosomal recessive disorder characterized by clinical signs of premature aging, short stature, scleroderma-like skin changes, endocrine abnormalities, cataracts, and an increased incidence of malignancies. We report on a 48-year-old woman with Werner syndrome associated with intracranial meningiomas who had extensive musculoskeletal manifestations including osteoporosis of the extremities, extensive tendinopathy about the ankles, osteomyelitis of the phalanges of the first left toe, abundant soft-tissue calcification, and two dense ossified soft-tissue masses, with cortical bone and trabeculae arising from the posterosuperior aspect of the calcanei and extending into Kager fat pads. A review of previous descriptions of the radiological abnormalities of Werner syndrome indicates that the presence of soft-tissue calcifications has either not been noted or been mentioned only briefly. Moreover, there is no mention of bony masses associated with Werner syndrome in the world literature, and this would appear to be the first report of this kind. (orig.)

  8. Increased frequency of DNA deletions in pink-eyed unstable mice carrying a mutation in the Werner syndrome gene homologue.

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    Lebel, Michel

    2002-01-01

    Werner syndrome (WS) is a rare autosomal recessive disorder characterized by genomic instability and the premature onset of a number of age-related diseases, including cancers. Accumulating evidence indicates that the WS gene product is involved in resolving aberrant DNA structures that may arise during the process of DNA replication and/or transcription. To estimate the frequency of DNA deletions directly in the skin of mouse embryos, mice with a deletion of part of the murine WRN helicase domain were created. These mutant mice were then crossed to the pink-eyed unstable animals, which have a 70 kb internal duplication at the pink-eyed dilution (p) gene. This report indicates that the frequency of deletion of the duplicated sequence at the p locus is elevated in mice with a mutation in the WRN allele when compared with wild-type mice. In addition, the inhibitor of topoisomerase I camptothecin also increases the frequency of deletion at the p locus. This frequency is even more elevated in WRN mutant mice treated with camptothecin. In contrast, while the inhibition of poly(ADP-ribose) polymerase (PARP) activity by 3-aminobenzamide increases the frequency of DNA deletion, mutant WRN mice are not significantly more sensitive to the inhibition of PARP activity than wild-type animals.

  9. Oxidative stress and antioxidant response in fibroblasts from Werner and atypical Werner syndromes.

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    Seco-Cervera, Marta; Spis, Marta; García-Giménez, José Luis; Ibañez-Cabellos, José Santiago; Velázquez-Ledesma, Ana; Esmorís, Isabel; Bañuls, Sergio; Pérez-Machado, Giselle; Pallardó, Federico V

    2014-03-01

    Werner Syndrome (WS, ICD-10 E34.8, ORPHA902) and Atypical Werner Syndrome (AWS, ICD-10 E34.8, ORPHA79474) are very rare inherited syndromes characterized by premature aging. While approximately 90% of WS individuals have any of a range of mutations in theWRN gene, there exists a clinical subgroup in which the mutation occurs in the LMNA/C gene in heterozygosity. Although both syndromes exhibit an age-related pleiotropic phenotype, AWS manifests the onset of the disease during childhood, while major symptoms in WS appear between the ages of 20 and 30. To study the molecular mechanisms of progeroid diseases provides a useful insight into the normal aging process. Main changes found were the decrease in Cu/Zn and Mn SOD activities in the three cell lines. In AWS, both mRNA SOD and protein levels were also decreased. Catalase and glutathione peroxidases decrease, mainly in AWS. Glutaredoxin (Grx) and thioredoxin (Trx) protein expression was lower in the three progeroid cell lines. Grx and Trx were subjected to post-transcriptional regulation, because protein expression was reduced although mRNA levels were not greatly affected in WS. Low antioxidant defense and oxidative stress occur simultaneously in these rare genetic instability disorders at the onset of progeroid disease.

  10. Immortalization of Werner syndrome and progeria fibroblasts

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    Saito, H.; Moses, R.E. (Baylor College of Medicine, Houston, TX (USA))

    1991-02-01

    Human fibroblast cells from two different progeroid syndromes, Werner syndrome (WS) and progeria, were established as immortalized cell lines by transfection with plasmid DNA containing the SV40 early region. The lineage of each immortalized cell line was confirmed by VNTR analysis. Each of the immortalized cell lines maintained its original phenotype of slow growth. DNA repair ability of these cells was also studied by measuring sensitivity to killing by uv or the DNA-damaging drugs methyl methansulfonate, bleomycin, and cis-dichlorodiamine platinum. The results showed that both WS and progeria cells have normal sensitivity to these agents.

  11. A case of Werner's syndrome associated with osteosarcoma.

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    Murata, K; Hatamochi, A; Shinkai, H; Ishikawa, Y; Kawaguchi, N; Goto, M

    1999-10-01

    We described a case of Werner's syndrome associated with osteosarcoma. A 37-year-old Japanese man was diagnosed as having Werner's syndrome by the presence of juvenile cataracts, skin sclerosis and hyperpigmentation of the feet, high-pitched voice, characteristic bird-like appearance of the face with beak-shaped nose, thinning of the entire skin and hyperkeratoses on soles, hyperlipemia, hyperuricemia, diabetes melitus, and the mutated responsible gene (WRN). He had a 3-month history of a tumor on his left forearm. Histologically, the tumor included four histological patterns; a malignant fibrous histiocytoma-like, a desmoid-like, a dermatofibrosarcoma protuberans-like, and a chondrosarcoma-like pattern. Tumoral osteoid formation was also found in the tumor. Therefore, the tumor was diagnosed as osteosarcoma.

  12. Síndrome de Werner: Dos nuevos casos Werner´S Syndrome: Two New Cases

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    M Palombo

    2010-03-01

    Full Text Available Se comunican dos casos del síndrome de Werner, el primero es un hombre con canicie desde la tercera década de la vida y diabetes mellitus diagnosticada el año pasado. El segundo caso es un hombre con alopecia masculina desde los 30 años y cataratas. Ambos nos consultaron por úlceras muy dolorosas en piernas y tobillos. Se efectúa una revisión del síndrome de Werner.Two cases of Werner´s syndrome are reported. The first case is a man with grey hair since his 30s and diabetes mellitus diagnosed last year. The second case is a man with male alopecia since his 30s and cataracts, both consulted us for extremely painful ulcers in their legs and ankles. A review of the Werner´s syndrome is made.

  13. WERNER SYNDROME: A NEW CASE REPORT

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    Faida Ajili

    2013-10-01

    Full Text Available “Werner’s syndrome” or premature aging syndrome is a rare autosomal recessive genetic disease. It is responsible of several complications related to age, including atherosclerosis and association with cancer. We report the case of a 36 year-old-patient, admitted to department of Internal Medicine of the military hospital of Tunis for suspicion of systemic sclerosis. The patient had all the major signs of Werner syndrome (bilateral cataract, sclerotic skin, “bird face”, baldness, small size, parental consanguinity and 4 minor signs (type 2 diabetes, hypogonadism, squeaky voice, and flat feet. She has also a brother with the same morphotype died at the age of 32 by a myocardial infarction. The current follow-up time is 9 years..

  14. Differential expression of Werner and Bloom syndrome genes in the peripheral blood of HIV-1 infected patients.

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    Bordi, Licia; Gioia, Cristiana; Lalle, Eleonora; Piselli, Pierluca; Poccia, Fabrizio; Capobianchi, Maria R; Amendola, Alessandra

    2007-02-01

    Human immunodeficiency virus (HIV)-induced immunodeficiency and immune-system aging share some analogies. Since Werner (WRN) and Bloom (BLM) helicases are crucial in cell repair and aging, their peripheral blood mononuclear cells (PBMC) mRNA levels were compared in HIV-1 infected patients and in normal donors. The mean levels of WRN mRNA were 3.7-fold higher in PBMCs from HIV-1 infected individuals in comparison to healthy donors, whereas BLM mRNA mean levels were slightly higher, although not significantly. WRN increase was positively correlated to CD4 and CD8 T-cell numbers, and also the percentage of naive T lymphocytes, and was observed also in T-cell subsets. Interestingly, a general trend toward increased WRN mRNA levels in individuals with lower viral load was observed, without association with patient age, time of seroconversion, and on/off antiretroviral therapy regimen. On the whole, this study shows that WRN and BLM are differentially modulated in HIV infection, as WRN--but not BLM--is significantly increased, suggesting that mechanisms different from defect or loss of helicase function, observed in WRN and BLM syndromes, may be at the basis of T-cell aging in HIV infection.

  15. Transient overexpression of Werner protein rescues starvation induced autophagy in Werner syndrome cells.

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    Maity, Jyotirindra; Bohr, Vilhelm A; Laskar, Aparna; Karmakar, Parimal

    2014-12-01

    Reduced autophagy may be associated with normal and pathological aging. Here we report a link between autophagy and Werner protein (WRNp), mutated in Werner syndrome, the human premature aging Werner syndrome (WS). WRN mutant fibroblast AG11395 and AG05229 respond weakly to starvation induced autophagy compared to normal cells. While the fusion of phagosomes with lysosome is normal, WS cells contain fewer autophagy vacuoles. Cellular starvation autophagy in WS cells is restored after transfection with full length WRN. Further, siRNA mediated silencing of WRN in the normal fibroblast cell line WI-38 results in decreased autophagy and altered expression of autophagy related proteins. Thus, our observations suggest that WRN may have a role in controlling autophagy and hereby cellular maintenance.

  16. A missense single nucleotide polymorphism, V114I of the Werner syndrome gene, is associated with risk of osteoporosis and femoral fracture in the Japanese population.

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    Zhou, Heying; Mori, Seijiro; Tanaka, Masashi; Sawabe, Motoji; Arai, Tomio; Muramatsu, Masaaki; Mieno, Makiko Naka; Shinkai, Shoji; Yamada, Yoshiji; Miyachi, Motohiko; Murakami, Haruka; Sanada, Kiyoshi; Ito, Hideki

    2015-11-01

    Werner syndrome is a rare autosomal recessive disorder caused by mutations in the human WRN gene and characterized by the early onset of normal aging symptoms. Given that patients with this disease exhibit osteoporosis, the present study aimed to determine whether the WRN gene contributes to the etiology of osteoporosis. A genetic association study of eight non-synonymous polymorphisms in the WRN gene and the incidence of femoral fracture was undertaken in 1,632 consecutive Japanese autopsies in which 140 patients had experienced the fracture during their lifetime. The results were validated in 251 unrelated postmenopausal Japanese women with osteoporosis and 269 non-institutionalized, community-dwelling Japanese adults. A statistically significant association was observed between rs2230009 (c.340G > A)--which results in a Val to Ile substitution--and fracture risk; the incidence of femoral fracture increased dose-dependently with the number of A alleles (p = 0.0120). Femoral neck bone and whole bone densities were lower among postmenopausal women with osteoporosis and community-dwelling adults, respectively, if they were of the AG instead of the GG genotype. The results suggest that Japanese subjects bearing at least one A allele of rs2230009 of the WRN gene are at a significantly higher risk of femoral fracture, possibly due to decreased bone density.

  17. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases.

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    Kudlow, Brian A; Kennedy, Brian K; Monnat, Raymond J

    2007-05-01

    Progeroid syndromes have been the focus of intense research in part because they might provide a window into the pathology of normal ageing. Werner syndrome and Hutchinson-Gilford progeria syndrome are two of the best characterized human progeroid diseases. Mutated genes that are associated with these syndromes have been identified, mouse models of disease have been developed, and molecular studies have implicated decreased cell proliferation and altered DNA-damage responses as common causal mechanisms in the pathogenesis of both diseases.

  18. Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors

    DEFF Research Database (Denmark)

    Saydam, Nurten; Kanagaraj, Radhakrishnan; Dietschy, Tobias;

    2007-01-01

    Werner syndrome (WS) is a severe recessive disorder characterized by premature aging, cancer predisposition and genomic instability. The gene mutated in WS encodes a bi-functional enzyme called WRN that acts as a RecQ-type DNA helicase and a 3'-5' exonuclease, but its exact role in DNA metabolism...

  19. Hypermutable ligation of plasmid DNA ends in cells from patients with Werner syndrome.

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    Rünger, T M; Bauer, C; Dekant, B; Möller, K; Sobotta, P; Czerny, C; Poot, M; Martin, G M

    1994-01-01

    Werner Syndrome is a rare autosomal recessive disorder characterized by an increased cancer risk and by symptoms suggestive of premature aging. Cells from these patients demonstrate a typical pattern of chromosomal instability and a spontaneous hypermutability with a high rate of unusually large deletions. We have studied the in vivo DNA ligation in three lymphoblast cell lines from Werner syndrome patients and three from normal donors. In our host cell ligation assay we transfected linearized plasmid pZ189 and measured the amount of plasmid DNA ends rejoined by these host cells as the ability of the recovered plasmid to transform bacteria. A mutagenesis marker gene close to the ligation site allowed screening for mutations. Subsequent mutation analysis provided information about the accuracy of the ligation process. The cells from Werner syndrome patients were as effective as normal cells in ligating DNA ends. However, mutation analysis revealed that the three Werner syndrome cell lines introduced 2.4-4.6 times more mutations (p < 0.001) than the normal cell lines during ligation of the DNA ends: the mutation rates were 69.4, 97.2, and 58.7%, as compared to 23.6, 21.7, and 24.4% in the normal cell lines. These increased mutation frequencies in plasmids ligated during passage through Werner syndrome cells were mainly due to a significant (p < 0.001) increase in deletions. This error-prone DNA ligation might be responsible for the spontaneous hypermutability and the genomic instability in Werner syndrome cells and related to the apparently accelerated aging and high cancer risk in affected patients.

  20. Herlyn-Werner-Wunderlich syndrome: a rare presentation with pyocolpos

    OpenAIRE

    Cox, Deven; Ching, Brian H.

    2012-01-01

    Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA), also known as Herlyn-Werner-Wunderlich syndrome, is a rare syndrome with only a few hundred reported cases described since 1922. Only a handful of these cases have been associated with pyocolpos. Mullerian duct anomalies have an incidence of 2–3%. While OHVIRA constitutes 0.16–10% of these Mullerian duct anomalies. Symptoms usually present shortly after menarche when hematocolpos develops during menstruation resulting in dysmenorrh...

  1. Roles of Werner syndrome protein in protection of genome integrity

    DEFF Research Database (Denmark)

    Rossi, Marie L; Ghosh, Avik K; Bohr, Vilhelm A

    2010-01-01

    Werner syndrome protein (WRN) is one of a family of five human RecQ helicases implicated in the maintenance of genome stability. The conserved RecQ family also includes RecQ1, Bloom syndrome protein (BLM), RecQ4, and RecQ5 in humans, as well as Sgs1 in Saccharomyces cerevisiae, Rqh1...... syndrome (WS). WRN is one of the best characterized of the RecQ helicases and is known to have roles in DNA replication and repair, transcription, and telomere maintenance. Studies both in vitro and in vivo indicate that the roles of WRN in a variety of DNA processes are mediated by post...

  2. Leg ulcer in Werner syndrome (adult progeria): a case report.

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    Fumo, Giuseppe; Pau, Monica; Patta, Federico; Aste, Nicola; Atzori, Laura

    2013-03-15

    Werner syndrome (WS; MIM#277700) or adult progeria, is a rare disease, associated with mutations of a single gene (RECQL2 or WRN), located on chromosome 8 (8p12). It codes a DNA-helicase, whose defects cause genomic instability. The highest incidences are reported in Japan and Sardinia (Italy). On this major island of the Mediterranean Basin, the WS cases have been observed in the northern areas. The authors describe the apparently first case reported in southern Sardinia, a 51-year-old woman, who was born in and resides in the province of Cagliari. She presented with a 9-year history of an intractable leg ulcer and other characteristic symptoms, including "bird-like" face, high-pitched voice, premature greying, short stature, abdominal obesity in contrast with thin body type, scleroderma-like legs, decreased muscle mass, diabetes, atherosclerosis, and premature menopause. A specialized genetic Institute of Research (IRCCS-IDI, Rome) confirmed the clinical diagnosis. There is no cure or specific treatment and patients must be periodically screened for an increased risk of cardiovascular and cerebrovascular disease and malignancies. Among the many findings, leg ulcers significantly affect the patient's quality of life. This problem may send the patient to the dermatologist, who finally suspects the diagnosis. Poor response to medical treatment may require aggressive repeated surgery, with poor or temporary results.

  3. First Japanese case of atypical progeroid syndrome/atypical Werner syndrome with heterozygous LMNA mutation.

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    Motegi, Sei-ichiro; Yokoyama, Yoko; Uchiyama, Akihiko; Ogino, Sachiko; Takeuchi, Yuko; Yamada, Kazuya; Hattori, Tomoyasu; Hashizume, Hiroaki; Ishikawa, Yuichi; Goto, Makoto; Ishikawa, Osamu

    2014-12-01

    Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a progeroid syndrome involving heterozygous mutations in the LMNA gene encoding the nuclear protein lamin A/C. We report the first Japanese case of APS/AWS with a LMNA mutation (p.D300N). A 53-year-old Japanese man had a history of recurrent severe cardiovascular diseases as well as brain infarction and hemorrhages. Although our APS/AWS patient had overlapping features with Werner syndrome (WS), such as high-pitched voice, scleroderma, lipoatrophy and atherosclerosis, several cardinal features of WS, including short stature, premature graying/alopecia, cataract, bird-like face, flat feet, hyperkeratosis on the soles and diabetes mellitus, were absent. In immunofluorescence staining and electron microscopic analyses of the patient's cultured fibroblasts, abnormal nuclear morphology, an increase in small aggregation of heterochromatin and a decrease in interchromatin granules in nuclei of fibroblasts were observed, suggesting that abnormal nuclear morphology and chromatin disorganization may be associated with the pathogenesis of APS/AWS.

  4. WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations.

    NARCIS (Netherlands)

    Friedrich, K.; Lee, L.; Leistritz, D.F.; Nurnberg, G.; Saha, B.; Hisama, F.M.; Eyman, D.K.; Lessel, D.; Nurnberg, P.; Li, C.; Garcia-F-Villalta, M.J.; Kets, C.M.; Schmidtke, J.; Cruz, V.T.; Akker, P.C. van den; Boak, J.; Peter, D.; Compoginis, G.; Cefle, K.; Ozturk, S.; Lopez, N.; Wessel, T. van; Poot, M.; Ippel, P.F.; Groff-Kellermann, B.; Hoehn, H.; Martin, G.M.; Kubisch, C.; Oshima, J.

    2010-01-01

    Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 11

  5. WRN mutations in Werner syndrome patients : genomic rearrangements, unusual intronic mutations and ethnic-specific alterations

    NARCIS (Netherlands)

    Friedrich, Katrin; Lee, Lin; Leistritz, Dru F.; Nuernberg, Gudrun; Saha, Bidisha; Hisama, Fuki M.; Eyman, Daniel K.; Lessel, Davor; Nuernberg, Peter; Li, Chumei; Garcia-F-Villalta, Maria J.; Kets, Carolien M.; Schmidtke, Joerg; Cruz, Vitor Tedim; Van den Akker, Peter C.; Boak, Joseph; Peter, Dincy; Compoginis, Goli; Cefle, Kivanc; Ozturk, Sukru; Lopez, Norberto; Wessel, Theda; Poot, Martin; Ippel, P. F.; Groff-Kellermann, Birgit; Hoehn, Holger; Martin, George M.; Kubisch, Christian; Oshima, Junko

    2010-01-01

    Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 11

  6. Genetics and aging; the Werner syndrome as a segmental progeroid syndrome.

    Science.gov (United States)

    Martin, G M

    1985-01-01

    The maximum lifespan potential is a constitutional feature of speciation and must be subject to polygenic controls acting both in the domain of development and in the domain of the maintenance of macromolecular integrity. The enormous genetic heterogeneity that characterizes our own species, the complexities of numerous nature-nurture interactions, and the quantitative and qualitative variations of the senescent phenotype that are observed suggest that precise patterns of aging in each of us may be unique. Patterns of aging may also differ sharply among species (for example, semelparous vs. multiparous mammals). Some potential common denominators, however, allow one to identify progeroid syndromes in man that could lead to the elucidation of important pathways of gene action. (The suffix "-oid" means "like"; it does not mean identity.) Unimodal progeroid syndromes (eg., familial dementia of the Alzheimer type, an autosomal dominant) can help us understand the pathogenesis of a particular aspect of the senescent phenotype of man. Segmental progeroid syndromes (eg. the Werner syndrome, an autosomal recessive) may be relevant to multiple aspects of the senescent phenotype. Some results of research on the Werner syndrome may be interpreted as support for "peripheral" as opposed to "central" theories of aging; they are consistent with the view that gene action in the domain of development (adolescence, in this instance) can set the stage for patterns of aging in the adult; they point to the importance of mesenchymal cell populations in the pathogenesis of age-related disorders; finally, they underscore the role of chromosomal instability, especially in the pathogenesis of neoplasia.

  7. Pyometra and Pregnancy with Herlyn-Werner-Wunderlich Syndrome.

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    Reis, Maria Inês; Vicente, Ana Patrícia; Cominho, Joana; Gomes, Andrea Sousa; Martins, Luísa; Nunes, Filomena

    2016-12-01

    We describe a Herlyn-Werner-Wunderlich syndrome (HWWS) patient with previous history of infertility who got pregnant without treatment and presented a pyometra in the contralateral uterus throughout the gestational period, despite multiple antibiotic treatments. Due to the uterus' congenital anomaly and the possibility of ascending infection with subsequent abortion, this pregnancy was classified as high-risk. We believe that the partial horizontal septum in the vagina may have contributed to the closure of the gravid uterus cervix, thus ensuring that the pregnancy came to term, with an uneventful vaginal delivery.

  8. Association of the rs1346044 Polymorphism of the Werner Syndrome Gene RECQL2 with Increased Risk and Premature Onset of Breast Cancer.

    Science.gov (United States)

    Zins, Karin; Frech, Barbara; Taubenschuss, Eva; Schneeberger, Christian; Abraham, Dietmar; Schreiber, Martin

    2015-12-10

    Like other RECQ helicases, WRN/RECQL2 plays a crucial role in DNA replication and the maintenance of genome stability. Inactivating mutations in RECQL2 lead to Werner syndrome, a rare autosomal disease associated with premature aging and an increased susceptibility to multiple cancer types. We analyzed the association of two coding single-nucleotide polymorphisms in WRN, Cys1367Arg (rs1346044), and Arg834Cys (rs3087425), with the risk, age at onset, and clinical subclasses of breast cancer in a hospital-based case-control study of an Austrian population of 272 breast cancer patients and 254 controls. Here we report that the rare homozygous CC genotype of rs1346044 was associated with an approximately two-fold elevated breast cancer risk. Moreover, patients with the CC genotype exhibited a significantly increased risk of developing breast cancer under the age of 55 in both recessive and log-additive genetic models. CC patients developed breast cancer at a mean age of 55.2 ± 13.3 years and TT patients at 60.2 ± 14.7 years. Consistently, the risk of breast cancer was increased in pre-menopausal patients in the recessive model. These findings suggest that the CC genotype of WRN rs1346044 may contribute to an increased risk and a premature onset of breast cancer.

  9. Gene of Werner's syndrome and its diagnosis%Werner综合征的基因与基因诊断研究进展

    Institute of Scientific and Technical Information of China (English)

    郝顺祖; 钱晖; 王卉放; 刘继林

    2004-01-01

    @@ Werner综合征(Werner's syndrome,WS)是一种罕见的常染色体遗传的退行性疾病.人们对这种罕见的疾病给予了极大的关注,因为WS患者表现的症状是在进入成年后加速老化,WS发病机制的研究有可能对阐明衰老的机制和肿瘤发生的机制有借鉴作用.WS基因于1996年被确定,其后有关此病的研究进展迅速,可望在不久的将来即能在分子水平上阐明此病的发生、发展机制.Werner于1904年首次报道此病后,世界各地报道仅有1 100例,我国尚无WS的报道.考虑现有大部分病例是在日本近亲联姻群体的后代中发现(发生率为1/3 000)[1],估计在中国也有WS病例存在,只是未能得以诊断发现.

  10. Prematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes.

    Science.gov (United States)

    Domínguez-Gerpe, Lourdes; Araújo-Vilar, David

    2008-12-01

    Ageing is thought to be a polygenic and stochastic process in which multiple mechanisms operate at the same time. At the level of the individual organism ageing is associated with a progressive deterioration of health and quality of life, sharing common features such as: alopecia and grey hair, loss of audition, macular degeneration, neurodegeneration, cardiovascular diseases, osteoporosis, cataract formation, type-2 diabetes, lipodystrophies; a generally increased susceptibility to infection, autoimmune disorders and diseases such as cancer; and an impaired ability to cope with stress. Recent studies of mechanisms involved in the ageing process are contributing to the identification of genes involved in longevity. Monogenic heritable disorders causing premature ageing, and animal models have contributed to the understanding of some of the characteristic organism-level features associated with human ageing. Werner syndrome and Hutchinson-Gilford progeria syndrome are the best characterized human disorders. Werner syndrome patients have a median life expectancy of 47 years with clinical conditions from the second decade of life. Hutchinson-Gilford progeria syndrome patients die at a median age of 11-13 years with clinical conditions appearing soon after birth. In both syndromes, alterations in specific genes have been identified, with mutations in the WRN and LMNA genes respectively being the most closely associated with each syndrome. Results from molecular studies strongly suggest an increase in DNA damage and cell senescence as the underlying mechanism of pathological premature ageing in these two human syndromes. The same general mechanism has also been observed in human cells undergoing the normal ageing process. In the present article the molecular mechanisms currently proposed for explaining these two syndromes, which may also partly explain the normal ageing process, are reviewed.

  11. POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome.

    Science.gov (United States)

    Lessel, Davor; Hisama, Fuki M; Szakszon, Katalin; Saha, Bidisha; Sanjuanelo, Alexander Barrios; Salbert, Bonnie A; Steele, Pamela D; Baldwin, Jennifer; Brown, W Ted; Piussan, Charles; Plauchu, Henri; Szilvássy, Judit; Horkay, Edit; Högel, Josef; Martin, George M; Herr, Alan J; Oshima, Junko; Kubisch, Christian

    2015-11-01

    Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few nonclassical cases of WS, another 10%-15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: mandibular hypoplasia, deafness, progeroid features syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with WS. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably underdiagnosed segmental progeroid syndrome.

  12. Chondrosarcoma of the mandibular condyle in a patient with Werner syndrome: a case report.

    Science.gov (United States)

    Goutzanis, Labros; Kalfarentzos, Evagelos F; Petsinis, Vassilis; Papadogeorgakis, Nick

    2013-10-01

    Werner syndrome, also called progeria of the adult and pangeria is a rare autosomal recessive disorder that affects connective tissue throughout the body. It is associated with premature ageing and an increased risk of cancer and other diseases. The mean survival for patients with Werner syndrome is 47 years. Death usually occurs when patients are aged 30-65 years because of atherosclerosis or malignant tumours. The purpose of this paper is to present a patient with Werner syndrome exhibiting a chondrosarcoma of the left temporomandibular joint and ramus. To the best of our knowledge this is the first case, of a Werner syndrome patient with an associated head and neck chondrosarcoma being reported. The diagnostic procedure followed and management of the patient are outlined in the paper as well.

  13. Stochastic simulations of normal aging and Werner's syndrome.

    KAUST Repository

    Qi, Qi

    2014-04-26

    Human cells typically consist of 23 pairs of chromosomes. Telomeres are repetitive sequences of DNA located at the ends of chromosomes. During cell replication, a number of basepairs are lost from the end of the chromosome and this shortening restricts the number of divisions that a cell can complete before it becomes senescent, or non-replicative. In this paper, we use Monte Carlo simulations to form a stochastic model of telomere shortening to investigate how telomere shortening affects normal aging. Using this model, we study various hypotheses for the way in which shortening occurs by comparing their impact on aging at the chromosome and cell levels. We consider different types of length-dependent loss and replication probabilities to describe these processes. After analyzing a simple model for a population of independent chromosomes, we simulate a population of cells in which each cell has 46 chromosomes and the shortest telomere governs the replicative potential of the cell. We generalize these simulations to Werner\\'s syndrome, a condition in which large sections of DNA are removed during cell division and, amongst other conditions, results in rapid aging. Since the mechanisms governing the loss of additional basepairs are not known, we use our model to simulate a variety of possible forms for the rate at which additional telomeres are lost per replication and several expressions for how the probability of cell division depends on telomere length. As well as the evolution of the mean telomere length, we consider the standard deviation and the shape of the distribution. We compare our results with a variety of data from the literature, covering both experimental data and previous models. We find good agreement for the evolution of telomere length when plotted against population doubling.

  14. Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome

    Directory of Open Access Journals (Sweden)

    Mark C. Bagley

    2010-06-01

    Full Text Available Werner syndrome provides a convincing model for aspects of the normal ageing phenotype and may provide a suitable model for therapeutic interventions designed to combat the ageing process. Cultured primary fibroblast cells from Werner syndrome patients provide a powerful model system to study the link between replicative senescence in vitro and in vivo pathophysiology. Genome instability, together with an increased pro-oxidant state, and frequent replication fork stalling, all provide plausible triggers for intracellular stress in Werner syndrome cells, and implicates p38 MAPK signaling in their shortened replicative lifespan. A number of different p38 MAPK inhibitor chemotypes have been prepared rapidly and efficiently using microwave heating techniques for biological study in Werner syndrome cells, including SB203580, VX-745, RO3201195, UR-13756 and BIRB 796, and their selectivity and potency evaluated in this cellular context. Werner syndrome fibroblasts treated with a p38 MAPK inhibitor reveal an unexpected reversal of the accelerated ageing phenotype. Thus the study of p38 inhibition and its effect upon Werner pathophysiology is likely to provide new revelations into the biological mechanisms operating in cellular senescence and human ageing in the future.

  15. New Classification of Herlyn-Werner-Wunderlich Syndrome

    Directory of Open Access Journals (Sweden)

    Lan Zhu

    2015-01-01

    Full Text Available Background: Uterus didelphys and blind hemivagina associated with ipsilateral renal agenesis are collectively known as Herlyn-Werner-Wunderlich syndrome (HWWS. In the literature, the syndrome often appears as a single case report or as a small series. In our study, we reviewed the characteristics of all HWWS patients at Peking Union Medical College Hospital (PUMCH and suggested a new classification for this syndrome because the clinical characteristics differed significantly between the completely and incompletely obstructed vaginal septum. This new classification allows for earlier diagnosis and treatment. Methods: From January 1986 to March 2013, all diagnosed cases of HWWS at PUMCH were reviewed. A retrospective long-term follow-up study of the clinical presentation, surgical prognosis, and pregnancy outcomes was performed. Statistical analyses were performed using SPSS, version 15.0 (IBM, Armonk, NY, USA. Between-group comparisons were performed using the χ2 test, Fisher′s exact test, and the t-test. The significance level for all analyses was set at P < 0.05. Results: The clinical data from 79 patients with HWWS were analyzed until March 31, 2013. According to our newly identified characteristics, we recommend that the syndrome be classified by the complete or incomplete obstruction of the hemivagina as follows: Classification 1, a completely obstructed hemivagina and Classification 2, an incompletely obstructed hemivagina. The clinical details associated with these two types are distinctly different. Conclusions: HWWS patients should be differentiated according to these two classifications. The two classifications could be generalized by gynecologists world-wide.

  16. Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome

    Science.gov (United States)

    Heyn, Holger; Moran, Sebastian; Esteller, Manel

    2013-01-01

    DNA methylation gradiently changes with age and is likely to be involved in aging-related processes with subsequent phenotype changes and increased susceptibility to certain diseases. The Hutchinson-Gilford Progeria (HGP) and Werner Syndrome (WS) are two premature aging diseases showing features of common natural aging early in life. Mutations in the LMNA and WRN genes were associated to disease onset; however, for a subset of patients the underlying causative mechanisms remain elusive. We aimed to evaluate the role of epigenetic alteration on premature aging diseases by performing comprehensive DNA methylation profiling of HGP and WS patients. We observed profound changes in the DNA methylation landscapes of WRN and LMNA mutant patients, which were narrowed down to a set of aging related genes and processes. Although of low overall variance, non-mutant patients revealed differential DNA methylation at distinct loci. Hence, we propose DNA methylation to have an impact on premature aging diseases. PMID:23257959

  17. Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome.

    Science.gov (United States)

    Heyn, Holger; Moran, Sebastian; Esteller, Manel

    2013-01-01

    DNA methylation gradiently changes with age and is likely to be involved in aging-related processes with subsequent phenotype changes and increased susceptibility to certain diseases. The Hutchinson-Gilford Progeria (HGP) and Werner Syndrome (WS) are two premature aging diseases showing features of common natural aging early in life. Mutations in the LMNA and WRN genes were associated to disease onset; however, for a subset of patients the underlying causative mechanisms remain elusive. We aimed to evaluate the role of epigenetic alteration on premature aging diseases by performing comprehensive DNA methylation profiling of HGP and WS patients. We observed profound changes in the DNA methylation landscapes of WRN and LMNA mutant patients, which were narrowed down to a set of aging related genes and processes. Although of low overall variance, non-mutant patients revealed differential DNA methylation at distinct loci. Hence, we propose DNA methylation to have an impact on premature aging diseases.

  18. Werner syndrome: a changing pattern of clinical manifestations in Japan (1917~2008).

    Science.gov (United States)

    Goto, M; Ishikawa, Y; Sugimoto, M; Furuichi, Y

    2013-02-01

    As ~75% of the Werner syndrome (WS) patients recognized between 1904 and 2008 all over the world are of Japanese origin, the most case reports and clinical studies on WS has been published in Japanese journals. Thus, the detailed English-written clinical review on the recent WS case reports has been warranted. Although WS has been characterized by a variety of clinical manifestations mimicking premature aging, the recent longevity and delayed age-associated manifestations observed both from Japanese WS and general population may suggest a common environmental effect on some gene(s) other than WRN and may give us a newer pathophysiological look at WS and also natural aging through the molecular dysfunction of WRN.

  19. 3. Chromosomal instability in B-lymphoblasotoid cell lines from Werner's and Bloom's syndrome patients

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@Werner's syndrome (WS) and Bloom's syndrome (BS) are rare autosomal recessive diseases in which the feature of premature aging and the elevated risk of neoplasia may be associated with genomic instability. To cha-racterize the genomic instability of WS and BS, B-lymphoblastoid cell lines (LCLs) from WS and BS patients were cytogenetically analyzed, comparing to those from healthy donors. Although all

  20. Hydrogen sulfide restores a normal morphological phenotype in Werner syndrome fibroblasts, attenuates oxidative damage and modulates mTOR pathway

    NARCIS (Netherlands)

    Talaei, F.; van Praag, V. M.; Henning, R. H.

    2013-01-01

    Werner syndrome (WS) protein is involved in DNA repair and its truncation causes Werner syndrome, an autosomal recessive genetic disorder with a premature aging phenotype. WRN protein mutation is currently known as the primary cause of WS. In cultured WS fibroblasts, we found an increase in cytosoli

  1. Hydrogen sulfide restores a normal morphological phenotype in Werner syndrome fibroblasts, attenuates oxidative damage and modulates mTOR pathway

    NARCIS (Netherlands)

    Talaei, F.; van Praag, V. M.; Henning, R. H.

    2013-01-01

    Werner syndrome (WS) protein is involved in DNA repair and its truncation causes Werner syndrome, an autosomal recessive genetic disorder with a premature aging phenotype. WRN protein mutation is currently known as the primary cause of WS. In cultured WS fibroblasts, we found an increase in cytosoli

  2. Aortic valve replacement for aortic stenosis with a small aortic annulus in a patient having Werner's syndrome and liver cirrhosis.

    Science.gov (United States)

    Sogawa, M; Kasuya, S; Yamamoto, K; Koshika, M; Oguma, F; Hayashi, J

    2001-12-01

    Werner's syndrome is a rare genetic disease characterized by premature aging and scleroderma-like involvement of the skin. We report a case of aortic valve replacement for severely calcified aortic valve stenosis with a small annulus in a patient suffering from Werner's syndrome and liver cirrhosis

  3. DNA damage accumulation and TRF2 degradation in atypical Werner syndrome fibroblasts with LMNA mutations.

    Science.gov (United States)

    Saha, Bidisha; Zitnik, Galynn; Johnson, Simon; Nguyen, Quyen; Risques, Rosa A; Martin, George M; Oshima, Junko

    2013-01-01

    Segmental progeroid syndromes are groups of disorders with multiple features suggestive of accelerated aging. One subset of adult-onset progeroid syndromes, referred to as atypical Werner syndrome, is caused by mutations in the LMNA gene, which encodes a class of nuclear intermediate filaments, lamin A/C. We previously described rapid telomere attrition and accelerated replicative senescence in cultured fibroblasts overexpressing mutant lamin A. In this study, we investigated the cellular phenotypes associated with accelerated telomere shortening in LMNA mutant primary fibroblasts. In early passage primary fibroblasts with R133L or L140R LMNA mutations, shelterin protein components were already reduced while cells still retained telomere lengths comparable to those of controls. There was a significant inverse correlation between the degree of abnormal nuclear morphology and the level of TRF2, a shelterin subunit, suggesting a potential causal relationship. Stabilization of the telomeres via the introduction of the catalytic subunit of human telomerase, hTERT (human telomerase reverse transcriptase), did not prevent degradation of shelterin components, indicating that reduced TRF2 in LMNA mutants is not mediated by short telomeres. Interestingly, γ-H2AX foci (reflecting double strand DNA damage) in early passage LMNA mutant primary fibroblasts and LMNA mutant hTERT fibroblasts were markedly increased in non-telomeric regions of DNA. Our results raise the possibility that mutant lamin A/C causes global genomic instability with accumulation of non-telomeric DNA damage as an early event, followed by TRF2 degradation and telomere shortening.

  4. Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome.

    OpenAIRE

    Donadille, Bruno; D'Anella, Pascal; Auclair, Martine; Uhrhammer, Nancy; Sorel, Marc; Grigorescu, Romulus; Ouzounian, Sophie; Cambonie, Gilles; Boulot, Pierre; Laforêt, Pascal; Carbonne, Bruno; Christin-Maitre, Sophie; Bignon, Yves-Jean; Vigouroux, Corinne

    2013-01-01

    International audience; BACKGROUND: Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase. METHODS: We analysed the clinical and biological features of two women, aged 32 and...

  5. Werner综合征伴脑膜瘤一例并文献复习%Meningioma arising in Werner syndrome, a case report and literature review

    Institute of Scientific and Technical Information of China (English)

    郝淑煜; 张力伟; 孙彦辉; 辛宇; 吴震; 张俊廷; 王忠诚

    2009-01-01

    Objective To report a case of Werner syndrome with meningioma in cavernous sinus and clivus, and review the relative literatures. Methods A pre-sigmoid sinus approach was performed for the meningioma, and we analyzed the genome sequence of the patient. Results According to her clinical features and result of genetic test of WRN, she was diagnosed as Werner's syndrome. The meningioma was totally removed. Conclusions This is the first case of Werner syndrome with meningioma in Chinese, we should emphasize further study of the associated genes of Werner syndrome and clinical manifestation.%目的 报告1例伴发海绵窦斜坡脑膜瘤的Werner综合征患者并文献复习.方法 通过乙状窦前入路切除肿瘤,并进行相关基因检查.结果 患者衰老面容,双眼白内障,硬皮病样皮肤改变及WRN基因检测结果 ,符合Werner综合征诊断,颅内肿瘤切除效果满意.结论 首次报告了中国人群中伴发脑膜瘤的Werner综合征病例,对Werner综合征相关基因及临床表现仍待进一步研究.

  6. Ethnic-Specific WRN Mutations in South Asian Werner Syndrome Patients: Potential Founder Effect in Patients with Indian or Pakistani Ancestry.

    Science.gov (United States)

    Saha, Bidisha; Lessel, Davor; Nampoothiri, Sheela; Rao, Anuradha S; Hisama, Fuki M; Peter, Dincy; Bennett, Chris; Nürnberg, Gudrun; Nürnberg, Peter; Martin, George M; Kubisch, Christian; Oshima, Junko

    2013-05-01

    Werner syndrome is a rare autosomal recessive disorder characterized by multiple features consistent with accelerated aging. It is caused by mutations in the WRN gene, which encodes a RecQ type helicase. To date, more than 70 disease-causing mutations have been reported. While founder mutations and a corresponding relatively high incidence of WS have been reported in Japan and Sardinia, such mutations have not been previously described among patients of South Asian descent. Here we report two novel WRN mutations in three pedigrees. A homozygous c.561A>G mutation in exon 6 was identified both in a pedigree from Kerala, India and in a British patient of Pakistani ancestry. Although c.561A>G does not alter the corresponding amino acid (p.K187K), it creates a cryptic splice site resulting in a 98bp deletion at the mRNA level (r.557-654del98) followed by a frameshift (p.K187fs). These two cases shared the same haplotype across the WRN gene, and were distinct from another Indian Werner patient with a homozygous stop codon mutation, c.2855 C>A (p.S952*) in exon 24. As the Indian population increases and the awareness of Werner syndrome grows, we anticipate that more cases will be identified with these founder mutations among South Asian Werner syndrome patients.

  7. WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations.

    Science.gov (United States)

    Friedrich, Katrin; Lee, Lin; Leistritz, Dru F; Nürnberg, Gudrun; Saha, Bidisha; Hisama, Fuki M; Eyman, Daniel K; Lessel, Davor; Nürnberg, Peter; Li, Chumei; Garcia-F-Villalta, María J; Kets, Carolien M; Schmidtke, Joerg; Cruz, Vítor Tedim; Van den Akker, Peter C; Boak, Joseph; Peter, Dincy; Compoginis, Goli; Cefle, Kivanc; Ozturk, Sukru; López, Norberto; Wessel, Theda; Poot, Martin; Ippel, P F; Groff-Kellermann, Birgit; Hoehn, Holger; Martin, George M; Kubisch, Christian; Oshima, Junko

    2010-07-01

    Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere.

  8. WRN protein as a novel erythroblast immunohistochemical marker with applications for the diagnosis of Werner syndrome.

    Science.gov (United States)

    Sadahira, Yoshito; Sugihara, Takashi; Fujiwara, Hideyo; Nishimura, Hirotake; Suetsugu, Yoshimasa; Takeshita, Morishige; Okamura, Seiichi; Goto, Makoto

    2015-03-01

    Genetic testing for mutations in the WRN gene is critical for the diagnosis of Werner syndrome (WS); however, these tests cannot be performed in a clinical setting. Nearly all of the WRN mutations result in expression of truncated WRN proteins that are missing the C-terminal nuclear localization signal. We evaluated the use of WRN protein immunohistochemistry for diagnosing WS using paraffin-embedded bone marrow sections. Using a well-defined commercially available polyclonal antibody against the C terminus of WRN, we found that of all the cell types tested, bone marrow erythroid precursors showed the strongest nuclear expression of WRN. Immunohistochemical analysis of bone marrow samples from 120 patients with non-WS hematological disorders (age range, 7 days-90 years) revealed WRN staining of the nuclei of CD71-positive early and late erythroid precursors. Erythroblasts negative for WRN immunostaining were only observed in two patients, both of whom were diagnosed with WS: one with concomitant myelodysplastic syndrome and the other with erythroleukemia with overexpression of TP53. Western blot analysis and immunocytochemistry indicated WRN was localized in the nuclei of the four positive control cell lines from non-WS patients but not in the five cell lines from WS patients, who had three different types of WRN mutations. Thus, immunohistochemical detection of WRN in erythroblasts from bone marrow paraffin sections could be useful in screening of WS cases and worthy of further molecular confirmation.

  9. Expression of Werner and Bloom syndrome genes is differentially regulated by in vitro HIV-1 infection of peripheral blood mononuclear cells.

    Science.gov (United States)

    Bordi, L; Amendola, A; Ciccosanti, F; Abbate, I; Camilloni, G; Capobianchi, M R

    2004-11-01

    In HIV infection, continuous immune activation leads to accelerated ageing of the adaptive immune system, similar to that observed in elderly people. We investigated the expression of WRN and BLM (genes involved in disorders characterized by premature ageing, genomic instability and cancer predisposition) in peripheral blood mononuclear cells (PBMC) activated in vitro with phytohaemagglutinin (PHA) and infected with different HIV-1 strains. The steady state levels of mRNA were analysed by reverse transcription-polymerase chain reaction (RT-PCR), and protein expression was assayed using immunocytochemistry and Western blot techniques. In uninfected PBMC, PHA stimulation induced an increase in BLM mRNA and protein expression, while WRN expression remained virtually unchanged. When PBMC were infected in vitro with a lymphotropic HIV-1 strain, the level of BLM mRNA showed a peak at 24 h of infection, followed by a decline to uninfected culture levels. A similar result failed to be seen using an R5-tropic HIV-1 strain. In accordance with mRNA expression, in HIV-infected cultures PBMC were stained more frequently and more intensely by a BLM-specific antibody as compared to uninfected cultures, staining peaking at 24. Conversely, WRN expression was not modulated by HIV-1. The proportion of cells showing BLM up-regulation, established by immunocytochemical staining, was much greater than the proportion of productively infected PBMC, as established by proviral DNA measurement. This result indicates that BLM up-regulation is probably a result of an indirect bystander cell effect. Activation of the BLM gene in infected PBMC suggests that premature ageing could be a further immunopathogenetic mechanism involved in HIV-induced immunodeficiency, and points to a possible new candidate target for innovative therapeutic intervention.

  10. Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells.

    Science.gov (United States)

    Li, Baomin; Iglesias-Pedraz, Juan Manuel; Chen, Leng-Ying; Yin, Fei; Cadenas, Enrique; Reddy, Sita; Comai, Lucio

    2014-04-01

    The Werner syndrome protein (WRN) is a nuclear protein required for cell growth and proliferation. Loss-of-function mutations in the Werner syndrome gene are associated with the premature onset of age-related diseases. How loss of WRN limits cell proliferation and induces replicative senescence is poorly understood. Here, we show that WRN depletion leads to a striking metabolic shift that coordinately weakens the pathways that generate reducing equivalents for detoxification of reactive oxygen species and increases mitochondrial respiration. In cancer cells, this metabolic shift counteracts the Warburg effect, a defining characteristic of many malignant cells, resulting in altered redox balance and accumulation of oxidative DNA damage that inhibits cell proliferation and induces a senescence-like phenotype. Consistent with these findings, supplementation with antioxidant rescues at least in part cell proliferation and decreases senescence in WRN-knockdown cancer cells. These results demonstrate that WRN plays a critical role in cancer cell proliferation by contributing to the Warburg effect and preventing metabolic stress.

  11. A novel Werner Syndrome mutation: pharmacological treatment by read-through of nonsense mutations and epigenetic therapies

    Science.gov (United States)

    Agrelo, Ruben; Sutz, Miguel Arocena; Setien, Fernando; Aldunate, Fabian; Esteller, Manel; Da Costa, Valeria; Achenbach, Ricardo

    2015-01-01

    Werner Syndrome (WS) is a rare inherited disease characterized by premature aging and increased propensity for cancer. Mutations in the WRN gene can be of several types, including nonsense mutations, leading to a truncated protein form. WRN is a RecQ family member with both helicase and exonuclease activities, and it participates in several cell metabolic pathways, including DNA replication, DNA repair, and telomere maintenance. Here, we reported a novel homozygous WS mutation (c.3767 C > G) in 2 Argentinian brothers, which resulted in a stop codon and a truncated protein (p.S1256X). We also observed increased WRN promoter methylation in the cells of patients and decreased messenger WRN RNA (WRN mRNA) expression. Finally, we showed that the read-through of nonsense mutation pharmacologic treatment with both aminoglycosides (AGs) and ataluren (PTC-124) in these cells restores full-length protein expression and WRN functionality. PMID:25830902

  12. Herlyn Werner Wunderlich Syndrome with Hematocolpos: An Unusual Case Report of Full Diagnostic Approach and Treatment

    Directory of Open Access Journals (Sweden)

    Rohit Bhoil

    2016-05-01

    Full Text Available Herlyn-Werner-Wunderlich (HWW syndrome is an uncommon combined müllerian duct anomalies (MDAs and mesonephric duct malformation of female urogenital tract characterized by uterus didelphys and obstructed hemi-vagina and ipsilateral renal agenesis (OHVIRA syndrome. We present a rare and unusual case of this syndrome in a 19 year-old female who suffered from hypomenorrhoea and abdominal pain. She had an obstructed hemi-vagina on right side which led to marked distention of ipsilateral cervix, while proximal hemi-vagina compressed the contralateral side causing its partial obstruction resulting in hypomenorrhoea. Understanding the imaging findings of this rare condition is important for early diagnosis in order to prevent complications which may lead to infertility.

  13. Síndrome de Werner associada a quadro esclerodermiforme: relato de caso e revisão da literatura Werner's syndrome associated with scleroderma-like syndrome: case report and literature revision

    Directory of Open Access Journals (Sweden)

    Cristiane Kayser

    2008-04-01

    Full Text Available A síndrome de Werner é uma doença autossômica recessiva rara associada a envelhecimento precoce, cujo quadro cutâneo deve ser distinguido daquele encontrado na esclerose sistêmica (ES. Descrevemos aqui o caso de uma paciente de 39 anos de idade, portadora de síndrome de Werner, encaminhada ao nosso serviço com hipótese diagnóstica inicial de ES. A paciente apresentava várias manifestações associadas à síndrome de Werner, incluindo cabelos precocemente grisalhos, voz estridente, baixa estatura, alterações cutâneas esclerodermiformes, diabetes melito, catarata, hipogonadismo, hipotireoidismo e hiperlipidemia. Não apresentava fenômeno de Raynaud, manifestações viscerais típicas da ES, alterações capilaroscópicas periungueais ou auto-anticorpos. O diagnóstico de síndrome de Werner, apesar de raro, deve ser lembrado no diagnóstico diferencial de ES, principalmente na presença de manifestações atípicas e na ausência de alterações típicas da ES.Werner's syndrome is a rare autosomal recessive disease associated with premature ageing. Skin alteration must be distinguished from cutaneous manifestation of systemic sclerosis (SSc. We describe a case of a 39 years old patient with Werner's syndrome admitted with an initial diagnostic hypothesis of SSc. The patient had many characteristic features associated with Werner's syndrome including gray hair, hoarseness, short stature, scleroderma-like skin changes, diabetes mellitus, cataracts, hypogonadism, hypothyroidism, and hyperlipidemia. There was no Raynaud's phenomenon, other typical visceral manifestation of SSc, nailfold capillary alterations or autoantibodies. Werner's syndrome diagnosis notwithstanding rare, should be remember in the differential diagnosis of SSc, mainly in the presence of atypical manifestations and in the absence of typical features of SSc.

  14. The Werner syndrome protein is distinguished from the Bloom syndrome protein by its capacity to tightly bind diverse DNA structures.

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    Kamath-Loeb, Ashwini; Loeb, Lawrence A; Fry, Michael

    2012-01-01

    Loss of Werner syndrome helicase-exonuclease (WRN) or of its homolog Bloom syndrome helicase (BLM) results in different inherited disorders. Whereas Werner syndrome is characterized by premature onset of aging and age-associated diseases, Bloom syndrome involves developmental abnormalities and increased predisposition to diverse malignancies. To identify biochemical differences between WRN and BLM that might contribute to the dissimilar outcomes of their loss, we compared their abilities to unwind and bind in vitro diverse DNA structures. Full-length recombinant WRN and BLM proteins expressed in and purified from Sf9 insect cells unwound to comparable extents and with similar K(m) values partial DNA duplex, splayed arm DNA and G'2 bimolecular quadruplex DNA. However, WRN resolved bubble DNA ∼25-fold more efficiently than BLM. The two enzymes were mainly distinguished by their contrasting abilities to bind DNA. WRN bound partial duplexes, bubble and splayed arm DNA and G'2 bimolecular and G4 four-molecular quadruplexes with dissociation constants of 0.25 to 25 nM. By contrast, BLM formed substantial complexes with only G4 quadruplex DNA while binding only marginally other DNA structures. We raise the possibility that in addition to its enzymatic activities WRN may act as a scaffold for the assembly on DNA of additional DNA processing proteins.

  15. The Werner syndrome protein is distinguished from the Bloom syndrome protein by its capacity to tightly bind diverse DNA structures.

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    Ashwini Kamath-Loeb

    Full Text Available Loss of Werner syndrome helicase-exonuclease (WRN or of its homolog Bloom syndrome helicase (BLM results in different inherited disorders. Whereas Werner syndrome is characterized by premature onset of aging and age-associated diseases, Bloom syndrome involves developmental abnormalities and increased predisposition to diverse malignancies. To identify biochemical differences between WRN and BLM that might contribute to the dissimilar outcomes of their loss, we compared their abilities to unwind and bind in vitro diverse DNA structures. Full-length recombinant WRN and BLM proteins expressed in and purified from Sf9 insect cells unwound to comparable extents and with similar K(m values partial DNA duplex, splayed arm DNA and G'2 bimolecular quadruplex DNA. However, WRN resolved bubble DNA ∼25-fold more efficiently than BLM. The two enzymes were mainly distinguished by their contrasting abilities to bind DNA. WRN bound partial duplexes, bubble and splayed arm DNA and G'2 bimolecular and G4 four-molecular quadruplexes with dissociation constants of 0.25 to 25 nM. By contrast, BLM formed substantial complexes with only G4 quadruplex DNA while binding only marginally other DNA structures. We raise the possibility that in addition to its enzymatic activities WRN may act as a scaffold for the assembly on DNA of additional DNA processing proteins.

  16. The Werner syndrome helicase/exonuclease processes mobile D-loops through branch migration and degradation.

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    Patricia L Opresko

    Full Text Available RecQ DNA helicases are critical for preserving genome integrity. Of the five RecQ family members identified in humans, only the Werner syndrome protein (WRN possesses exonuclease activity. Loss of WRN causes the progeroid disorder Werner syndrome which is marked by cancer predisposition. Cellular evidence indicates that WRN disrupts potentially deleterious intermediates in homologous recombination (HR that arise in genomic and telomeric regions during DNA replication and repair. Precisely how the WRN biochemical activities process these structures is unknown, especially since the DNA unwinding activity is poorly processive. We generated biologically relevant mobile D-loops which mimic the initial DNA strand invasion step in HR to investigate whether WRN biochemical activities can disrupt this joint molecule. We show that WRN helicase alone can promote branch migration through an 84 base pair duplex region to completely displace the invading strand from the D-loop. However, substrate processing is altered in the presence of the WRN exonuclease activity which degrades the invading strand both prior to and after release from the D-loop. Furthermore, telomeric D-loops are more refractory to disruption by WRN, which has implications for tighter regulation of D-loop processing at telomeres. Finally, we show that WRN can recognize and initiate branch migration from both the 5' and 3' ends of the invading strand in the D-loops. These findings led us to propose a novel model for WRN D-loop disruption. Our biochemical results offer an explanation for the cellular studies that indicate both WRN activities function in processing HR intermediates.

  17. Impact of vitamin C on the cardiometabolic and inflammatory profiles of mice lacking a functional Werner syndrome protein helicase.

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    Aumailley, Lucie; Dubois, Marie Julie; Garand, Chantal; Marette, André; Lebel, Michel

    2015-12-01

    Werner syndrome (WS) is a premature aging disorder caused by mutations in a DNA helicase/exonuclease. Mice lacking the helicase domain of this protein exhibit metabolic abnormalities that are reversed by vitamin C. In this study, we used a targeted metabolomic approach to identify serum metabolites significantly altered in young mutant mice treated with or without vitamin C. We also measured several serum inflammatory and cardiometabolic factors. We show that young mutant mice exhibit an increase in serum hydroxyproline and plasminogen activator inhibitor-1 (PAI-1), markers of cardiovascular diseases and inflammation, before they exhibit morphological anomalies in different tissues. We also observed an increase in three very long chain lysophosphatidylcholines underlying peroxisome perturbation. Vitamin C reversed the concentrations of these metabolites and PAI-1 to wild type values. Transcriptomic analyses on the liver of mutant mice revealed a decrease in the expression of genes involved in fatty acid degradation compared to wild type animals. Vitamin C treatment increased the expression of genes involved in glutathione metabolism and the synthesis of unsaturated fatty acids in these mice. These results show that changes at the transcriptomic level concord with the alterations of several serum metabolites in these mice. Finally, we found that a mislocalization of the Wrn mutant protein in the liver endoplasmic reticulum fraction increased oxidative stress in that cellular compartment. Vitamin C reversed this oxidative stress. To conclude, this study provides novel potential predictive cardiometabolic biomarkers in WS that will allow the assessment of the impact of vitamin C on patients with WS.

  18. Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture.

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    Akira Shimamoto

    Full Text Available Werner syndrome (WS is a premature aging disorder characterized by chromosomal instability and cancer predisposition. Mutations in WRN are responsible for the disease and cause telomere dysfunction, resulting in accelerated aging. Recent studies have revealed that cells from WS patients can be successfully reprogrammed into induced pluripotent stem cells (iPSCs. In the present study, we describe the effects of long-term culture on WS iPSCs, which acquired and maintained infinite proliferative potential for self-renewal over 2 years. After long-term cultures, WS iPSCs exhibited stable undifferentiated states and differentiation capacity, and premature upregulation of senescence-associated genes in WS cells was completely suppressed in WS iPSCs despite WRN deficiency. WS iPSCs also showed recapitulation of the phenotypes during differentiation. Furthermore, karyotype analysis indicated that WS iPSCs were stable, and half of the descendant clones had chromosomal profiles that were similar to those of parental cells. These unexpected properties might be achieved by induced expression of endogenous telomerase gene during reprogramming, which trigger telomerase reactivation leading to suppression of both replicative senescence and telomere dysfunction in WS cells. These findings demonstrated that reprogramming suppressed premature senescence phenotypes in WS cells and WS iPSCs could lead to chromosomal stability over the long term. WS iPSCs will provide opportunities to identify affected lineages in WS and to develop a new strategy for the treatment of WS.

  19. Scoliosis in Herlyn-Werner-Wunderlich syndrome: a case report and literature review.

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    Li, Zheng; Yu, Xin; Shen, Jianxiong; Liang, Jinqian

    2014-12-01

    Herlyn-Werner-Wunderlich syndrome (HWWS) is a congenital Müllerian duct anomaly characterized by uterine didelphys, obstructed hemivagina, and ipsilateral renal agenesis. Little is reported about spinal deformity associated with this syndrome. This study presents a case of scoliosis occurring in the setting of HWWS and explores the possible association between the 2 diseases. A previously unreported scoliosis in HWWS is described. The patient is a 12-year-old Chinese female with scoliosis that underwent a posterior correction at thoracic 5-thoracic 12 (T5-T12) levels, using the Moss-SI (Johnson & Johnson, American) spinal system. At 24-month follow-up, the patient was clinically pain free and well balanced. Plain radiographs showed solid spine fusion with no loss of deformity correction. Six months after scoliosis correction surgery, the patient went to our clinics for the treatment of HWWS. She was performed a vaginal septum resection and detected with pyocolpos. Her follow-up was symptom free at the fourth postoperative month. The prevalence of scoliosis among patients with HWWS was 8.57% that is much higher than the incidence of congential scoliosis among general population (1/1000). To the best of our knowledge, this is the first report of HWWS with thoracic scoliosis. During surgery, surgeons and anesthesiologists must pay particular attention to the Müllerian duct anomaly and renal agenesis associated with HWWS. There is a potential association between congenital scoliosis and HWWS.

  20. Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts

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    Terence Davis

    2016-04-01

    Full Text Available Progeroid syndromes show features of accelerated ageing and are used as models for human ageing, of which Werner syndrome (WS is one of the most widely studied. WS fibroblasts show accelerated senescence that may result from p38 MAP kinase activation since it is prevented by the p38 inhibitor SB203580. Thus, small molecule inhibition of p38-signalling may be a therapeutic strategy for WS. To develop this approach issues such as the in vivo toxicity and kinase selectivity of existing p38 inhibitors need to be addressed, so as to strengthen the evidence that p38 itself plays a critical role in mediating the effect of SB203580, and to find an inhibitor suitable for in vivo use. In this work we used a panel of different p38 inhibitors selected for: (1 having been used successfully in vivo in either animal models or human clinical trials; (2 different modes of binding to p38; and (3 different off-target kinase specificity profiles, in order to critically address the role of p38 in the premature senescence seen in WS cells. Our findings confirmed the involvement of p38 in accelerated cell senescence and identified p38 inhibitors suitable for in vivo use in WS, with BIRB 796 the most effective.

  1. Inflammageing assessed by MMP9 in normal Japanese individuals and the patients with Werner syndrome.

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    Goto, Makoto; Chiba, Junji; Matsuura, Masaaki; Iwaki-Egawa, Sachiko; Watanabe, Yasuhiro

    2016-05-01

    Age-associated minor inflammation: inflammageing may explain human ageing mechanism(s). Our previous study reported a significant increase in the serum level of highly sensitive C-reactive protein (hsCRP) with normal ageing and the patients with Werner syndrome (WS). To further study the minor inflammatory condition associated with ageing, another possible ageing biomarker: matrix metalloproteinase-9 (MMP9) was examined in the sera from 217 normal Japanese individuals aged between 1 and 100 years and 41 mutation-proven Japanese WS aged between 32 and 70 years. MMP9 was assayed by ELISA. The serum level of MMP9 was elevated significantly (p normal ageing from both sexes as hsCRP. In contrast to normal ageing, the serum MMP9 level in WS decreased significantly with calendar age (p normal adult population aged between 25 and 70 years (109.1 ± 9.4), nor normal elderly population aged between 71 and 100 years (179.9 ± 16.1). Although both normal ageing and WS were associated with minor inflammation, the inflammatory parameters such as serum MMP9 and hsCRP changed differently between normal ageing and WS. The WS-specific chronic inflammation including skin ulcer and diabetes mellitus may contribute the different behavior of both ageing biomarkers from normal ageing.

  2. Telomerase Protects Werner Syndrome Lineage-Specific Stem Cells from Premature Aging

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    Hoi-Hung Cheung

    2014-04-01

    Full Text Available Werner syndrome (WS patients exhibit premature aging predominantly in mesenchyme-derived tissues, but not in neural lineages, a consequence of telomere dysfunction and accelerated senescence. The cause of this lineage-specific aging remains unknown. Here, we document that reprogramming of WS fibroblasts to pluripotency elongated telomere length and prevented telomere dysfunction. To obtain mechanistic insight into the origin of tissue-specific aging, we differentiated iPSCs to mesenchymal stem cells (MSCs and neural stem/progenitor cells (NPCs. We observed recurrence of premature senescence associated with accelerated telomere attrition and defective synthesis of the lagging strand telomeres in MSCs, but not in NPCs. We postulate this “aging” discrepancy is regulated by telomerase. Expression of hTERT or p53 knockdown ameliorated the accelerated aging phenotypein MSC, whereas inhibition of telomerase sensitized NPCs to DNA damage. Our findings unveil a role for telomerase in the protection of accelerated aging in a specific lineage of stem cells.

  3. Herlyn-Werner-Wunderlich Syndrome Consisting of Uterine Didelphys, Obstructed Hemivagina and Ipsilateral Renal Agenesis in a Newborn

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    Tsung-Hsin Wu

    2012-02-01

    Full Text Available Herlyn-Werner-Wunderlich (HWW syndrome is a rare variant of Müllerian duct anomalies consisting of uterine didelphys, obstructed hemivagina, and ipsilateral renal agenesis. Patients with HWW syndrome are usually asymptomatic until menarche, when they present with acute lower abdominal pain. Here we report a case of a female newborn with right renal agenesis diagnosed during the pregnancy. The patient presented with a protruding mass over the vaginal introitus that was associated with an obstructed hemivagina and uterine didelphys.

  4. Turnover of sulfated glycosaminoglycans in fibroblasts derived from patients with Werner's syndrome

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    Cowles, E.A.; Brauker, J.H.; Anderson, R.L.

    1987-02-01

    Fibroblasts derived from patients with Werner's syndrome (WS) were incubated with radioactive sulfate to study the incorporation of 35S into glycosaminoglycans (GAGs). The accumulation of cell-associated 35S radioactivity in the GAGs of WS fibroblasts was consistently higher than parallel accumulation in normal human fibroblasts, but was substantially less than in fibroblasts derived from patients with Hurler's syndrome (HS). However, when fibroblasts were labeled with 35SO4(2-), trypsinized to remove extracellular and pericellular radioactive GAGs, replated, and chased to follow the fate of the intracellular radioactivity, both WS and normal cells showed a rapid release of the intracellular 35S, while HS cells showed little or no loss of intracellular radioactivity. The radioactivity released from WS and normal cells was of low molecular weight (LMW), eluting from gel filtration columns at the same position as free sulfate. These results establish that WS cells degrade intracellular sulfated GAGs and argue against the hypothesis that a defect in GAG degradation pathways is the basis for the increased level of cell-associated GAGs. Other possible explanations for the increased cell-associated (35S)GAGs in WS cells as compared with normal cells were also considered: increased GAG sulfation; an increase in GAG chain length; an increased rate of GAG synthesis; and a decreased rate of shedding of cell surface proteoglycan into the medium. No difference between normal and WS fibroblasts in any of the above parameters was observed. These results strongly imply that the primary biochemical defect in WS fibroblasts does not involve sulfated GAG metabolism.

  5. Werner Syndrome with Sensorineural Hearing Loss: the First Case Report in China%伴神经性耳聋的Werner综合征1例国内首报

    Institute of Scientific and Technical Information of China (English)

    任军; 刘晓坤; 李新生; 王晓慧; 王官清; 曾抗

    2012-01-01

    目的 探讨Werner综合征的临床表现及诊断,提高对Werner综合征的认识.方法 报告1例伴神经性耳聋的Werner综合征,并进行相关的文献复习,详细分析该病的组织起源、临床表现、鉴别诊断、治疗及预后等,完善患者各系统筛查和实验室检查.结果 各系统筛查结果提示患者多组织发育不良或加速退行性变.其临床表现复杂,伴有神经性耳聋等,但无糖尿病及白内障,临床诊断为伴神经性耳聋Werner综合征.结论 伴神经性耳聋的Werner综合征较为罕见,目前国内未见报道,该病极易误诊,应对Werner综合征相关基因进一步筛查研究.%Objective To identify the clinical spectrum and the clinical diagnostic criteria of werner syndrome. Methods We here reported a novel werner syndrome case. Based on the clinical features of the case and overall review on the related literatures, we aimed to identify the clinical characteristics including involved tissue origin , clinical manifestation, differentiation diagnosis, treatment and prognosis of Werner syndrome. Multiple systems including skin, skeleton, skeletal muscle and adipose tissue were estimated by laboratory investigations. Results The case manifested as the prominent progeroid disorders, multiple system ( skin, skeleton, skeletal muscle and fat) degeneration. The case' s presentation could be classified as a novel Werner syndrome which manifested with sensorineural hearing loss without diabetes mellitus and cataract. Conclusion Werner syndrome is a rare disease which manifested as a wide clinical spectrum. This is the first case of Werner syndrome with sensorineural hearing loss in Chinese. Further study on the associated genes screening will help to elucidate the molecular mechanism.

  6. Competition between the DNA unwinding and strand pairing activities of the Werner and Bloom syndrome proteins

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    Orren David K

    2006-01-01

    Full Text Available Abstract Background The premature aging and cancer-prone Werner and Bloom syndromes are caused by defects in the RecQ helicase enzymes WRN and BLM, respectively. Recently, both WRN and BLM (as well as several other RecQ members have been shown to possess a strand annealing activity in addition to the requisite DNA unwinding activity. Since an annealing function would appear to directly oppose the action of a helicase, we have examined in this study the dynamic equilibrium between unwinding and annealing mediated by either WRN or BLM. Results Our investigation into the competition between annealing and unwinding demonstrates that, under standard reaction conditions, WRN- or BLM-mediated annealing can partially or completely mask unwinding as measured in standard helicase assays. Several strategies were employed to suppress the annealing activity so that the actual strength of WRN- or BLM-dependent unwinding could be more accurately assessed. Interestingly, if a DNA oligomer complementary to one strand of the DNA substrate to be unwound is added during the helicase reaction, both WRN and BLM unwinding is enhanced, presumably by preventing protein-mediated re-annealing. This strategy allowed measurement of WRN-catalyzed unwinding of long (80 base pair duplex regions and fully complementary, blunt-ended duplexes, both of which were otherwise quite refractory to the helicase activity of WRN. Similarly, the addition of trap strand stimulated the ability of BLM to unwind long and blunt-ended duplexes. The stimulatory effect of the human replication protein A (hRPA, the eukaryotic single-stranded DNA binding protein on both WRN- and BLM-dependent unwinding was also re-examined in light of its possible role in preventing re-annealing. Our results show that hRPA influences the outcome of WRN and BLM helicase assays by both inhibiting re-annealing and directly promoting unwinding, with the larger contribution from the latter mechanism. Conclusion These

  7. Competition between the DNA unwinding and strand pairing activities of the Werner and Bloom syndrome proteins.

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    Machwe, Amrita; Lozada, Enerlyn M; Xiao, Liren; Orren, David K

    2006-01-13

    The premature aging and cancer-prone Werner and Bloom syndromes are caused by defects in the RecQ helicase enzymes WRN and BLM, respectively. Recently, both WRN and BLM (as well as several other RecQ members) have been shown to possess a strand annealing activity in addition to the requisite DNA unwinding activity. Since an annealing function would appear to directly oppose the action of a helicase, we have examined in this study the dynamic equilibrium between unwinding and annealing mediated by either WRN or BLM. Our investigation into the competition between annealing and unwinding demonstrates that, under standard reaction conditions, WRN- or BLM-mediated annealing can partially or completely mask unwinding as measured in standard helicase assays. Several strategies were employed to suppress the annealing activity so that the actual strength of WRN- or BLM-dependent unwinding could be more accurately assessed. Interestingly, if a DNA oligomer complementary to one strand of the DNA substrate to be unwound is added during the helicase reaction, both WRN and BLM unwinding is enhanced, presumably by preventing protein-mediated re-annealing. This strategy allowed measurement of WRN-catalyzed unwinding of long (80 base pair) duplex regions and fully complementary, blunt-ended duplexes, both of which were otherwise quite refractory to the helicase activity of WRN. Similarly, the addition of trap strand stimulated the ability of BLM to unwind long and blunt-ended duplexes. The stimulatory effect of the human replication protein A (hRPA, the eukaryotic single-stranded DNA binding protein) on both WRN- and BLM-dependent unwinding was also re-examined in light of its possible role in preventing re-annealing. Our results show that hRPA influences the outcome of WRN and BLM helicase assays by both inhibiting re-annealing and directly promoting unwinding, with the larger contribution from the latter mechanism. These findings indicate that measurements of unwinding by WRN

  8. Interstitial Lung Disease in Werner Syndrome: A Case Report of a 55-Year-Old Male Patient

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    Tiphaine Goletto

    2015-01-01

    Full Text Available Werner syndrome (WS is a progeroid or premature aging syndrome characterized by early onset of age-related pathologies and cancer. The average life expectancy of affected people is 52.8 years and tends to increase. The major causes of death are malignancy and myocardial infarction. Increased telomere attrition and decay are thought to play a causative role in the clinical and pathological manifestations of the disease. Although telomere length, with or without germline mutation, is known to be associated with interstitial lung disease, the latter is not associated with WS. To the best of our knowledge, we report the first case describing a WS patient with fatal ILD. This case suggests that older patients with WS could develop ILD. Clinical outcome of WS patients may thus be improved by counselling them regarding smoking cessation or other exposure and by proposing antifibrotic therapy.

  9. Coronary Artery Disease in a Werner Syndrome-Like Form of Progeria Characterized by Low Levels of Progerin, a Splice Variant of Lamin A

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    Hisama, Fuki M.; Lessel, Davor; Leistritz, Dru; Friedrich, Katrin; McBride, Kim L.; Pastore, Matthew T.; Gottesman, Gary S.; Saha, Bidisha; Martin, George M.; Kubisch, Christian; Oshima, Junko

    2015-01-01

    Classical Hutchinson–Gilford progeria syndrome (HGPS) is caused by LMNA mutations that generate an alternatively spliced form of lamin A, termed progerin. HGPS patients present in early childhood with atherosclerosis and striking features of accelerated aging. We report on two pedigrees of adult-onset coronary artery disease with progeroid features, who were referred to our International Registry of Werner Syndrome (WS) because of clinical features consistent with the diagnosis. No mutations were identified in the WRN gene that is responsible for WS, among these patients. Instead, we found two novel heterozygous mutations at the junction of exon 10 and intron 11 of the LMNA gene. These mutations resulted in the production of progerin at a level substantially lower than that of HGPS. Our findings indicate that LMNA mutations may result in coronary artery disease presenting in the fourth to sixth decades along with short stature and a progeroid appearance resembling WS. The absence of early-onset cataracts in this setting should suggest the diagnosis of progeroid laminopathy. This study illustrates the evolving genotype–phenotype relationship between the amount of progerin produced and the age of onset among the spectrum of restrictive dermopathy, HGPS, and atypical forms of WS. PMID:22065502

  10. Coronary artery disease in a Werner syndrome-like form of progeria characterized by low levels of progerin, a splice variant of lamin A.

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    Hisama, Fuki M; Lessel, Davor; Leistritz, Dru; Friedrich, Katrin; McBride, Kim L; Pastore, Matthew T; Gottesman, Gary S; Saha, Bidisha; Martin, George M; Kubisch, Christian; Oshima, Junko

    2011-12-01

    Classical Hutchinson-Gilford progeria syndrome (HGPS) is caused by LMNA mutations that generate an alternatively spliced form of lamin A, termed progerin. HGPS patients present in early childhood with atherosclerosis and striking features of accelerated aging. We report on two pedigrees of adult-onset coronary artery disease with progeroid features, who were referred to our International Registry of Werner Syndrome (WS) because of clinical features consistent with the diagnosis. No mutations were identified in the WRN gene that is responsible for WS, among these patients. Instead, we found two novel heterozygous mutations at the junction of exon 10 and intron 11 of the LMNA gene. These mutations resulted in the production of progerin at a level substantially lower than that of HGPS. Our findings indicate that LMNA mutations may result in coronary artery disease presenting in the fourth to sixth decades along with short stature and a progeroid appearance resembling WS. The absence of early-onset cataracts in this setting should suggest the diagnosis of progeroid laminopathy. This study illustrates the evolving genotype-phenotype relationship between the amount of progerin produced and the age of onset among the spectrum of restrictive dermopathy, HGPS, and atypical forms of WS.

  11. The effect of RO3201195 and a pyrazolyl ketone P38 MAPK inhibitor library on the proliferation of Werner syndrome cells.

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    Bagley, Mark C; Dwyer, Jessica E; Baashen, Mohammed; Dix, Matthew C; Murziani, Paola G S; Rokicki, Michal J; Kipling, David; Davis, Terence

    2016-01-21

    Microwave-assisted synthesis of the pyrazolyl ketone p38 MAPK inhibitor RO3201195 in 7 steps and 15% overall yield, and the comparison of its effect upon the proliferation of Werner Syndrome cells with a library of pyrazolyl ketones, strengthens the evidence that p38 MAPK inhibition plays a critical role in modulating premature cellular senescence in this progeroid syndrome and the reversal of accelerated ageing observed in vitro on treatment with SB203580.

  12. Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging.

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    Zhang, Weiqi; Li, Jingyi; Suzuki, Keiichiro; Qu, Jing; Wang, Ping; Zhou, Junzhi; Liu, Xiaomeng; Ren, Ruotong; Xu, Xiuling; Ocampo, Alejandro; Yuan, Tingting; Yang, Jiping; Li, Ying; Shi, Liang; Guan, Dee; Pan, Huize; Duan, Shunlei; Ding, Zhichao; Li, Mo; Yi, Fei; Bai, Ruijun; Wang, Yayu; Chen, Chang; Yang, Fuquan; Li, Xiaoyu; Wang, Zimei; Aizawa, Emi; Goebl, April; Soligalla, Rupa Devi; Reddy, Pradeep; Esteban, Concepcion Rodriguez; Tang, Fuchou; Liu, Guang-Hui; Belmonte, Juan Carlos Izpisua

    2015-06-05

    Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.

  13. Werner's syndrome protein is phosphorylated in an ATR/ATM-dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle.

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    Pichierri, Pietro; Rosselli, Filippo; Franchitto, Annapaola

    2003-03-13

    Werner's syndrome (WS) is an autosomal recessive disorder, characterized at the cellular level by genomic instability in the form of variegated translocation mosaicism and extensive deletions. Individuals with WS prematurely develop multiple age-related pathologies and exhibit increased incidence of cancer. WRN, the gene defective in WS, encodes a 160-kDa protein (WRN), which has 3'-5'exonuclease, DNA helicase and DNA-dependent ATPase activities. WRN-defective cells are hypersensitive to certain genotoxic agents that cause replication arrest and/or double-strand breaks at the replication fork, suggesting a pivotal role for WRN in the protection of the integrity of the genoma during the DNA replication process. Here, we show that WRN is phosphorylated through an ATR/ATM dependent pathway in response to replication blockage. However, we provide evidence that WRN phosphorylation is not essential for its subnuclear relocalization after replication arrest. Finally, we show that WRN and ATR colocalize after replication fork arrest, suggesting that WRN and the ATR kinase collaborate to prevent genome instability during the S phase.

  14. The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome

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    Trego, Kelly S.; Chernikova, Sophia B.; Davalos, Albert R.; Perry, J. Jefferson P.; Finger, L. David; Ng, Cliff; Tsai, Miaw-Sheue; Yannone, Steven M.; Tainer, John A.; Campisi, Judith; Cooper, Priscilla K.

    2011-04-20

    XPG is a structure-specific endonuclease required for nucleotide excision repair (NER). XPG incision defects result in the cancer-prone syndrome xeroderma pigmentosum, whereas truncating mutations of XPG cause the severe postnatal progeroid developmental disorder Cockayne syndrome. We show that XPG interacts directly with WRN protein, which is defective in the premature aging disorder Werner syndrome, and that the two proteins undergo similar sub-nuclear redistribution in S-phase and co-localize in nuclear foci. The co-localization was observed in mid- to late-S-phase, when WRN moves from nucleoli to nuclear foci that have been shown to contain protein markers of both stalled replication forks and telomeric proteins. We mapped the interaction between XPG and WRN to the C-terminal domains of each and show that interaction with the C-terminal domain of XPG strongly stimulates WRN helicase activity. WRN also possesses a competing DNA single-strand annealing activity that, combined with unwinding, has been shown to coordinate regression of model replication forks to form Holliday junction/chicken foot intermediate structures. We tested whether XPG stimulated WRN annealing activity and found that XPG itself has intrinsic strand annealing activity that requires the unstructured R- and C-terminal domains, but not the conserved catalytic core or endonuclease activity. Annealing by XPG is cooperative, rather than additive, with WRN annealing. Taken together, our results suggest a novel function for XPG in S-phase that is at least in part carried out coordinately with WRN, and which may contribute to the severity of the phenotypes that occur upon loss of XPG.

  15. Strand exchange of telomeric DNA catalyzed by the Werner syndrome protein (WRN) is specifically stimulated by TRF2.

    Science.gov (United States)

    Edwards, Deanna N; Orren, David K; Machwe, Amrita

    2014-07-01

    Werner syndrome (WS), caused by loss of function of the RecQ helicase WRN, is a hereditary disease characterized by premature aging and elevated cancer incidence. WRN has DNA binding, exonuclease, ATPase, helicase and strand annealing activities, suggesting possible roles in recombination-related processes. Evidence indicates that WRN deficiency causes telomeric abnormalities that likely underlie early onset of aging phenotypes in WS. Furthermore, TRF2, a protein essential for telomere protection, interacts with WRN and influences its basic helicase and exonuclease activities. However, these studies provided little insight into WRN's specific function at telomeres. Here, we explored the possibility that WRN and TRF2 cooperate during telomeric recombination processes. Our results indicate that TRF2, through its interactions with both WRN and telomeric DNA, stimulates WRN-mediated strand exchange specifically between telomeric substrates; TRF2's basic domain is particularly important for this stimulation. Although TRF1 binds telomeric DNA with similar affinity, it has minimal effects on WRN-mediated strand exchange of telomeric DNA. Moreover, TRF2 is displaced from telomeric DNA by WRN, independent of its ATPase and helicase activities. Together, these results suggest that TRF2 and WRN act coordinately during telomeric recombination processes, consistent with certain telomeric abnormalities associated with alteration of WRN function.

  16. Telomeric protein TRF2 protects Holliday junctions with telomeric arms from displacement by the Werner syndrome helicase.

    Science.gov (United States)

    Nora, Gerald J; Buncher, Noah A; Opresko, Patricia L

    2010-07-01

    WRN protein loss causes Werner syndrome (WS), which is characterized by premature aging as well as genomic and telomeric instability. WRN prevents telomere loss, but the telomeric protein complex must regulate WRN activities to prevent aberrant telomere processing. Telomere-binding TRF2 protein inhibits telomere t-loop deletion by blocking Holliday junction (HJ) resolvase cleavage activity, but whether TRF2 also modulates HJ displacement at t-loops is unknown. In this study, we used multiplex fluorophore imaging to track the fate of individual strands of HJ substrates. We report the novel finding that TRF2 inhibits WRN helicase strand displacement of HJs with telomeric repeats in duplex arms, but unwinding of HJs with a telomeric center or lacking telomeric sequence is unaffected. These data, together with results using TRF2 fragments and TRF2 HJ binding assays, indicate that both the TRF2 B- and Myb domains are required to inhibit WRN HJ activity. We propose a novel model whereby simultaneous binding of the TRF2 B-domain to the HJ core and the Myb domain to telomeric arms promote and stabilize HJs in a stacked arm conformation that is unfavorable for unwinding. Our biochemical study provides a mechanistic basis for the cellular findings that TRF2 regulates WRN activity at telomeres.

  17. Werner Syndrome Combined with Meningeoma: Nursing on A Case%Werner综合征伴发脑膜瘤患者一例的护理

    Institute of Scientific and Technical Information of China (English)

    苏继敏; 张秀云; 高红伟; 段宇红; 宋晓东

    2010-01-01

    @@ Werner综合征(Werner syndrome,WS)又称成人早老综合征(adult progeria)、成人早衰老综合征(adult premature aging syndrome),是一种罕见的常染色体隐性遗传性疾病.WS多发于青春期,寿命常在40岁左右,而伴发脑膜瘤的WS病例更为罕见报道,在我国尚无报道.

  18. Telomere-binding Protein TRF2 Binds to and Stimulates the Werner and Bloom Syndrome Helicases

    National Research Council Canada - National Science Library

    Patricia L. Opresko; Cayetano von Kobbe; Jean-Philippe Laine; Jeanine Harrigan; Ian D. Hickson; Vilhelm A. Bohr

    2002-01-01

    .... This interaction is mediated by the RecQ conserved C-terminal region of WRN. In vitro , TRF2 demonstrates high affinity for WRN and for another RecQ family member, the Bloom syndrome protein (BLM...

  19. The Werner and Bloom syndrome proteins help resolve replication blockage by converting (regressed) holliday junctions to functional replication forks.

    Science.gov (United States)

    Machwe, Amrita; Karale, Rajashree; Xu, Xioahua; Liu, Yilun; Orren, David K

    2011-08-16

    Cells cope with blockage of replication fork progression in a manner that allows DNA synthesis to be completed and genomic instability minimized. Models for resolution of blocked replication involve fork regression to form Holliday junction structures. The human RecQ helicases WRN and BLM (deficient in Werner and Bloom syndromes, respectively) are critical for maintaining genomic stability and thought to function in accurate resolution of replication blockage. Consistent with this notion, WRN and BLM localize to sites of blocked replication after certain DNA-damaging treatments and exhibit enhanced activity on replication and recombination intermediates. Here we examine the actions of WRN and BLM on a special Holliday junction substrate reflective of a regressed replication fork. Our results demonstrate that, in reactions requiring ATP hydrolysis, both WRN and BLM convert this Holliday junction substrate primarily to a four-stranded replication fork structure, suggesting they target the Holliday junction to initiate branch migration. In agreement, the Holliday junction binding protein RuvA inhibits the WRN- and BLM-mediated conversion reactions. Importantly, this conversion product is suitable for replication with its leading daughter strand readily extended by DNA polymerases. Furthermore, binding to and conversion of this Holliday junction are optimal at low MgCl(2) concentrations, suggesting that WRN and BLM preferentially act on the square planar (open) conformation of Holliday junctions. Our findings suggest that, subsequent to fork regression events, WRN and/or BLM could re-establish functional replication forks to help overcome fork blockage. Such a function is highly consistent with phenotypes associated with WRN- and BLM-deficient cells.

  20. Metabolic and Phenotypic Differences between Mice Producing a Werner Syndrome Helicase Mutant Protein and Wrn Null Mice.

    Science.gov (United States)

    Aumailley, Lucie; Garand, Chantal; Dubois, Marie Julie; Johnson, F Brad; Marette, André; Lebel, Michel

    2015-01-01

    Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase, WRN. Mice lacking part of the helicase domain of the WRN orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter mean life span. In contrast, mice lacking the entire Wrn protein (i.e. Wrn null mice) do not exhibit a premature aging phenotype. In this study, we used a targeted mass spectrometry-based metabolomic approach to identify serum metabolites that are differentially altered in young Wrn helicase mutant and Wrn null mice. An antibody-based quantification of 43 serum cytokines and markers of cardiovascular disease risk complemented this study. We found that Wrn helicase mutants exhibited elevated and decreased levels, respectively, of the anti-inflammatory cytokine IL-10 and the pro-inflammatory cytokine IL-18. Wrn helicase mutants also exhibited an increase in serum hydroxyproline and plasminogen activator inhibitor-1, markers of extracellular matrix remodeling of the vascular system and inflammation in aging. We also observed an abnormal increase in the ratio of very long chain to short chain lysophosphatidylcholines in the Wrn helicase mutants underlying a peroxisome perturbation in these mice. Remarkably, the Wrn mutant helicase protein was mislocalized to the endoplasmic reticulum and the peroxisomal fractions in liver tissues. Additional analyses with mouse embryonic fibroblasts indicated a severe defect of the autophagy flux in cells derived from Wrn helicase mutants compared to wild type and Wrn null animals. These results indicate that the deleterious effects of the helicase-deficient Wrn protein are mediated by the dysfunction of several cellular organelles.

  1. Metabolic and Phenotypic Differences between Mice Producing a Werner Syndrome Helicase Mutant Protein and Wrn Null Mice.

    Directory of Open Access Journals (Sweden)

    Lucie Aumailley

    Full Text Available Werner syndrome (WS is a premature aging disorder caused by mutations in a RecQ-family DNA helicase, WRN. Mice lacking part of the helicase domain of the WRN orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter mean life span. In contrast, mice lacking the entire Wrn protein (i.e. Wrn null mice do not exhibit a premature aging phenotype. In this study, we used a targeted mass spectrometry-based metabolomic approach to identify serum metabolites that are differentially altered in young Wrn helicase mutant and Wrn null mice. An antibody-based quantification of 43 serum cytokines and markers of cardiovascular disease risk complemented this study. We found that Wrn helicase mutants exhibited elevated and decreased levels, respectively, of the anti-inflammatory cytokine IL-10 and the pro-inflammatory cytokine IL-18. Wrn helicase mutants also exhibited an increase in serum hydroxyproline and plasminogen activator inhibitor-1, markers of extracellular matrix remodeling of the vascular system and inflammation in aging. We also observed an abnormal increase in the ratio of very long chain to short chain lysophosphatidylcholines in the Wrn helicase mutants underlying a peroxisome perturbation in these mice. Remarkably, the Wrn mutant helicase protein was mislocalized to the endoplasmic reticulum and the peroxisomal fractions in liver tissues. Additional analyses with mouse embryonic fibroblasts indicated a severe defect of the autophagy flux in cells derived from Wrn helicase mutants compared to wild type and Wrn null animals. These results indicate that the deleterious effects of the helicase-deficient Wrn protein are mediated by the dysfunction of several cellular organelles.

  2. Herlyn-Werner-Wunderlich Syndrome with Unilateral Hemivaginal Obstruction, Ipsilateral Renal Agenesis, and Contralateral Renal Thin GBM Disease: A Case Report with Radiological Follow Up

    Energy Technology Data Exchange (ETDEWEB)

    Park, Noh Hyuck; Park, Hee Jin; Park, Chan Sup [Myongji Hospital, Kwandong University, Koyang (Korea, Republic of); Park, Sung Il [Bucheon Hospital, Soonchunhyang University, Bucheon (Korea, Republic of)

    2010-08-15

    Herlyn-Werner-Wunderlich syndrome is a rare Mullerian ductal anomaly that is characterized by the presence of a hemivaginal septum, a didelphic uterus and ipsilateral renal agenesis. It is generally difficult to diagnose the uterine malformation before menarche owing to its small size. Therefore, a follow-up study is very important for confirming the uterine malformation in girls with renal agenesis. We report a patient with renal agenesis and microscopic hematuria, who showed symptoms before menarche. A follow-up study eventually revealed uterine didelphys with a hemivaginal obstruction. A biopsy proved that the microscopic hematuria was caused by thin glomerular basement membrane disease of the contralateral kidney

  3. Herlyn-Werner-Wunderlich Syndrome: A Rare Cause of Pelvic Pain and High CA 19-9 Levels in an Adolescent Girl

    Science.gov (United States)

    Unal, Emel; Sonmezer, Murat; Erkol, Hatice Gul; Fitoz, Suat

    2016-01-01

    Herlyn-Werner-Wunderlich (HWW) syndrome is a rare developmental anomaly that includes uterus didelphys with obstructed hemivagina and ipsilateral renal agenesis. A 13-year-old girl presented with chronic abdominal pain. Magnetic resonance imaging revealed uterus didelphys, hematometrocolpos and renal agenesis on the right side with imperforate hymen. Subsequently the patient was found to have Mullerian duct anomalies. CA 19-9 level was high. At laparoscopy combined with vaginoscopy hematocolpos was drained following which she improved clinically and CA 19-9 level returned to normal. PMID:26816677

  4. Investigating the role of c-Jun N-terminal kinases in the proliferation of Werner syndrome fibroblasts using diaminopyridine inhibitors

    Directory of Open Access Journals (Sweden)

    Davis Terence

    2011-12-01

    Full Text Available Abstract Fibroblasts derived from the progeroid Werner syndrome show reduced replicative lifespan and a "stressed" morphology, both alleviated using the MAP kinase inhibitor SB203580. However, interpretation of these data is problematical because although SB203580 has the stress-activated kinases p38 and JNK1/2 as its preferred targets, it does show relatively low overall kinase selectivity. Several lines of data support a role for both p38 and JNK1/2 activation in the control of cellular proliferation and also the pathology of diseases of ageing, including type II diabetes, diseases to which Werner Syndrome individuals are prone, thus making the use of JNK inhibitors attractive as possible therapeutics. We have thus tested the effects of the widely used JNK inhibitor SP600125 on the proliferation and morphology of WS cells. In addition we synthesised and tested two recently described aminopyridine based inhibitors. SP600125 treatment resulted in the cessation of proliferation of WS cells and resulted in a senescent-like cellular phenotype that does not appear to be related to the inhibition of JNK1/2. In contrast, use of the more selective aminopyridine CMPD 6o at concentrations that fully inhibit JNK1/2 had a positive effect on cellular proliferation of immortalised WS cells, but no effect on the replicative lifespan of primary WS fibroblasts. In addition, CMPD 6o corrected the stressed WS cellular morphology. The aminopyridine CMPD 6r, however, had little effect on WS cells. CMDP 6o was also found to be a weak inhibitor of MK2, which may partially explain its effects on WS cells, since MK2 is known to be involved in regulating cellular morphology via HSP27 phosphorylation, and is thought to play a role in cell cycle arrest. These data suggest that total JNK1/2 activity does not play a substantial role in the proliferation control in WS cells.

  5. In Memoriam Werner Callebaut.

    Science.gov (United States)

    Boniolo, Giovanni

    2015-12-01

    The article contains some recollections on Werner Callebaut highlighting his personal character and his role in the community of historians, philosophers and sociologists of the life sciences. Werner Callebaut (1952-2014) was a real European philosopher. He was the Scientific Director of the Konrad Lorenz Institute for Evolution and Cognition Research (KLI, Klosterneuburg, Austria) and the President of the International Society for the History, Philosophy, and Social Studies of Biology.

  6. Werner Albrecht (1924 - 2014)

    CERN Multimedia

    2014-01-01

    Werner Albrecht, one of the very first mechanical designers recruited by CERN, passed away on 28 March. Born and educated in Zurich, where he spent the first years of his professional life, he joined CERN in June 1955.   Thanks to his experience and personality, he soon became the deputy to Frank Blythe, the head of the Synchrocyclotron (SC) technical office. The office, which included a large mechanical workshop, had been created in the light of the development and construction of the SC - the first of CERN’s accelerators. For around 25 years Werner kept this position at Frank’s side while the services under their responsibility evolved to become the natural facility to provide design and development for a large range of apparatus required by experimental physicists. After Frank’s retirement in 1980, Werner became head of the office, maintaining its typical character as an efficient, informal and friendly service. Omega, UA1, Aleph, Opal and Delphi are example...

  7. The Caenorhabditis elegans Werner syndrome protein functions upstream of ATR and ATM in response to DNA replication inhibition and double-strand DNA breaks.

    Directory of Open Access Journals (Sweden)

    Se-Jin Lee

    2010-01-01

    Full Text Available WRN-1 is the Caenorhabditis elegans homolog of the human Werner syndrome protein, a RecQ helicase, mutations of which are associated with premature aging and increased genome instability. Relatively little is known as to how WRN-1 functions in DNA repair and DNA damage signaling. Here, we take advantage of the genetic and cytological approaches in C. elegans to dissect the epistatic relationship of WRN-1 in various DNA damage checkpoint pathways. We found that WRN-1 is required for CHK1 phosphorylation induced by DNA replication inhibition, but not by UV radiation. Furthermore, WRN-1 influences the RPA-1 focus formation, suggesting that WRN-1 functions in the same step or upstream of RPA-1 in the DNA replication checkpoint pathway. In response to ionizing radiation, RPA-1 focus formation and nuclear localization of ATM depend on WRN-1 and MRE-11. We conclude that C. elegans WRN-1 participates in the initial stages of checkpoint activation induced by DNA replication inhibition and ionizing radiation. These functions of WRN-1 in upstream DNA damage signaling are likely to be conserved, but might be cryptic in human systems due to functional redundancy.

  8. Correlations in Werner States

    Institute of Scientific and Technical Information of China (English)

    DONG Li; LUO Shun-Long; XIU Xiao-Ming; LI Nan; GAO Ya-Jun; CHI Feng

    2008-01-01

    Werner states are paradigmatic examples of quantum states and play an innovative role in quantum information theory. In investigating the correlating capability of Werner states, we find the curious phenomenon that quantum correlations, as quantified by the entanglement of formation, may exceed the total correlations, as measured by the quantum mutual information. Consequently, though the entanglement of formation is so widely used in quantifying entanglement, it cannot be interpreted as a consistent measure of quantum correlations per se if we accept the folklore that total correlations are measured (or rather upper bounded) by the quantum mutual information.

  9. Integrated map of the chromosome 8p12-p21 region, a region involved in human cancers and Werner syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Imbert, A.; Chaffanet, M.; Birnbaum, D.; Pebusque, M.J. [INSERM, Marseille (France)] [and others

    1996-02-15

    This article discusses the genetic mapping of the specific region on human chromosome 8, 8p12-p21, and its implications to human hereditary cancers and diseases. The localization of disease genes such as NEFL and FGFR1 are given, accomplished using contigs which span the region of deletion involved in these hereditary diseases. 59 refs., 4 figs., 3 tabs.

  10. Gene expression and DNA repair in progeroid syndromes and human aging.

    Science.gov (United States)

    Kyng, Kasper J; Bohr, Vilhelm A

    2005-11-01

    Human progeroid syndromes are caused by mutations in single genes accelerating some but not all features of normal aging. Most progeroid disorders are linked to defects in genome maintenance, and while it remains unknown if similar processes underlie normal and premature aging, they provide useful models for the study of aging. Altered transcription is speculated to play a causative role in aging, and is involved in the pathology of most if not all progeroid syndromes. Previous studies demonstrate that there is a similar pattern of gene expression changes in primary cells from old and Werner syndrome compared to young suggesting a presence of common cellular aging mechanisms in old and progeria. Here we review the role of transcription in progeroid syndromes and discuss the implications of similar transcription aberrations in normal and premature aging.

  11. An inherited LMNA gene mutation in atypical Progeria syndrome.

    Science.gov (United States)

    Doubaj, Yassamine; De Sandre-Giovannoli, Annachiara; Vera, Esteves-Vieira; Navarro, Claire Laure; Elalaoui, Siham Chafai; Tajir, Mariam; Lévy, Nicolas; Sefiani, Abdelaziz

    2012-11-01

    Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis of HGPS is based on the recognition of common clinical features and detection of the recurrent heterozygous c.1824C>T (p.Gly608Gly) mutation within exon 11 in the Lamin A/C encoding gene (LMNA). Besides "typical HGPS," several "atypical progeria" syndromes (APS) have been described, in a clinical spectrum ranging from mandibuloacral dysplasia to atypical Werner syndrome. These patients's clinical features include progeroid manifestations, such as short stature, prominent nose, premature graying of hair, partial alopecia, skin atrophy, lipodystrophy, skeletal anomalies, such as mandibular hypoplasia and acroosteolyses, and in some cases severe atherosclerosis with metabolic complications. APS are due in several cases to de novo heterozygous LMNA mutations other than the p.Gly608Gly, or due to homozygous BAFN1 mutations in Nestor-Guillermo Progeria syndrome (NGPS). We report here and discuss the observation of a non-consanguineous Moroccan patient presenting with atypical progeria. The molecular studies showed the heterozygous mutation c.412G>A (p.Glu138Lys) of the LMNA gene. This mutation, previously reported as a de novo mutation, was inherited from the apparently healthy father who showed a somatic cell mosaicism.

  12. Loss of Bloom syndrome protein destabilizes human gene cluster architecture.

    Science.gov (United States)

    Killen, Michael W; Stults, Dawn M; Adachi, Noritaka; Hanakahi, Les; Pierce, Andrew J

    2009-09-15

    Bloom syndrome confers strong predisposition to malignancy in multiple tissue types. The Bloom syndrome patient (BLM) protein defective in the disease biochemically functions as a Holliday junction dissolvase and human cells lacking functional BLM show 10-fold elevated rates of sister chromatid exchange. Collectively, these phenomena suggest that dysregulated mitotic recombination drives the genomic instability underpinning the development of cancer in these individuals. Here we use physical analysis of the highly repeated, highly self-similar human ribosomal RNA gene clusters as sentinel biomarkers for dysregulated homologous recombination to demonstrate that loss of BLM protein function causes a striking increase in spontaneous molecular level genomic restructuring. Analysis of single-cell derived sub-clonal populations from wild-type human cell lines shows that gene cluster architecture is ordinarily very faithfully preserved under mitosis, but is so unstable in cell lines derived from BLMs as to make gene cluster architecture in different sub-clonal populations essentially unrecognizable one from another. Human cells defective in a different RecQ helicase, the WRN protein involved in the premature aging Werner syndrome, do not exhibit the gene cluster instability (GCI) phenotype, indicating that the BLM protein specifically, rather than RecQ helicases generally, holds back this recombination-mediated genomic instability. An ataxia-telangiectasia defective cell line also shows elevated rDNA GCI, although not to the extent of BLM defective cells. Genomic restructuring mediated by dysregulated recombination between the abundant low-copy repeats in the human genome may prove to be an important additional mechanism of genomic instability driving the initiation and progression of human cancer.

  13. A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb.

    Science.gov (United States)

    Wieczorek, Dagmar; Pawlik, Barbara; Li, Yun; Akarsu, Nurten A; Caliebe, Almuth; May, Klaus J W; Schweiger, Bernd; Vargas, Fernando R; Balci, Sevim; Gillessen-Kaesbach, Gabriele; Wollnik, Bernd

    2010-01-01

    Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five-fingered hand with absence of thumbs. We show that point mutations of a specific nucleotide within the sonic hedgehog (SHH) regulatory region (ZRS) cause WMS. In a previously unpublished WMS family, we identified the causative G>A transition at position 404 of the ZRS, and in six affected family members of a second WMS family we found a 404G>C mutation of the ZRS. The 404G>A ZRS mutation is known as the "Cuban mutation" of PPD type II (PPD2). Interestingly, the index patient of that family had tibial hypoplasia as well. These data provide the first evidence that WMS is caused by a specific ZRS mutation, which leads to strong ectopic SHH expression. In contrast, we show that complete duplications of the ZRS region lead to type Haas polysyndactyly or triphalangeal thumb-polysyndactyly syndrome, but do not affect lower limb development. We suggest the term "ZRS-associated syndromes" and a clinical subclassification for the continuum of limb malformations caused by different molecular alterations of the ZRS.

  14. Werner's Relevance for Contemporary Developmental Psychology.

    Science.gov (United States)

    Glick, Joseph A.

    1992-01-01

    Considers the contributions of Heinz Werner to developmental psychology and identifies the tensions between Werner's theory and the practices of contemporary developmental psychology. Core issues of Werner's psychology concern: (1) development as heuristic, rather than phenomenon; (2) developmental process analysis; and (3) conceptions of the…

  15. Werner Herzog Tallinnas / Aare Ermel

    Index Scriptorium Estoniae

    Ermel, Aare, 1957-2013

    2002-01-01

    Detsembris toimuvat Pimedate Ööde Filmifestivali laiendatakse ka suvele, et sobivates paikades näidata väärtfilme. Alates 6. juunist näidatakse Katariina kirikus kuuel õhtul algusega kell 22 Werner Herzogi (1942) filme. Režissöörist ja näidatavatest filmidest

  16. Werner Herzog Tallinnas / Aare Ermel

    Index Scriptorium Estoniae

    Ermel, Aare, 1957-2013

    2002-01-01

    Detsembris toimuvat Pimedate Ööde Filmifestivali laiendatakse ka suvele, et sobivates paikades näidata väärtfilme. Alates 6. juunist näidatakse Katariina kirikus kuuel õhtul algusega kell 22 Werner Herzogi (1942) filme. Režissöörist ja näidatavatest filmidest

  17. Werner综合征小鼠模型在早衰与肿瘤研究中的应用%Utilization of Werner syndrome mouse model in studying premature aging and tumor

    Institute of Scientific and Technical Information of China (English)

    贾舒婷; 杨世华; 罗瑛

    2009-01-01

    Werner综合征(Werner syndrome,ws)是一种罕见的人类常染色体隐性遗传疾病,一直以来该病作为研究人类早老综合征的典型病例而受到关注.Werner蛋白(WRN)是Werner综合征中突变的核蛋白,最近的生化及遗传学研究证明WRN在DNA复制,DNA损伤修复以及端粒的维持方面起着重要的作用.文章综述了Wemer综合征的分子遗传学机理及端粒和WRN在Werner综合征发病中的重要作用.通过双敲除Wrn与端粒酶基因建立的小鼠模型忠实地再现了人类Werner综合征,这种Werner综合征小鼠模型因其同时具有早衰与肿瘤表型而在研究人类肿瘤及衰老的相关性中起到的独特作用.

  18. Werner Heisenberg - Life and Work

    CERN Document Server

    2002-01-01

    Werner Heisenberg (centre) with Wolfgang Pauli (left) and Enrico Fermi on Lake Como, September 1927. An exhibition on the life and work of Werner Heisenberg will be on display in the Main Building (Mezzanine) at CERN from 1 - 23 July. The exhibition was produced by the University Archive of Leipzig University (Gerald Wiemers) and the Max-Planck-Institut für Physik in Munich (Helmut Rechenberg) to mark the centenary of Heisenberg's birth in 1901. German theoretical physicist Werner Karl Heisenberg (5 December 1901 - 1 February 1976) was one of the leading scientists of the 20th century. He carried out important work in nuclear and particle physics, but his most significant contribution was to the development of quantum mechanics. He is best known for his uncertainty principle, which restricts the accuracy with which some properties of atoms and particles - such as position and linear momentum - can be determined simultaneously. In 1932 he was awarded the Noble Prize in Physics 'for the creation of q...

  19. Werner Heisenberg - Life and Work

    CERN Multimedia

    2002-01-01

    Werner Heisenberg (centre) with Wolfgang Pauli and Enrico Fermi, 1927. An exhibition on the life and work of Werner Heisenberg will be on display in the Main Building (Mezzanine) at CERN from 1 - 30 July*. German theoretical physicist Werner Karl Heisenberg (1901 - 1976) was one of the leading scientists of the 20th century. Nobel Prize in Physics in 1932, his most significant contribution was to the development of quantum mechanics. He is best known for his uncertainty principle, which restricts the accuracy with which some properties of atoms and particles can be determined simultaneously. Heisenberg was a keen supporter of CERN, and was as the first chairman of CERN's Scientific Policy Committee in October 1954. A related celebration will take place in the TH Amphitheatre (4/3-006), on Thursday 18 July at 16:00. After an introduction from the Director-General Luciano Maiani, his daughter, Barbara Blum, his last postgraduate, Helmut Rechenberg and Valentin Telegdi will evoke memories of the life and work ...

  20. Werner Kienzle (1936 – 2016)

    CERN Document Server

    2016-01-01

    Werner was born in Wiernsheim, a small town in Baden-Württemberg close to Stuttgart. His childhood was profoundly marked by the war and the death of his father on the German eastern front.   Despite life after the war being difficult for his family, he was very successful in his academic studies and earned a fellowship at the University of Göttingen, where he did his PhD in solid-state physics. Werner joined CERN in 1964 as a post-doc fellow and he remained at the Organization for his entire career in experimental particle physics. Concerned and eager for peace in the tense context of the cold war, he was deeply involved in collaboration with Russian colleagues and participated in experiments in Serpukhov from 1968 to 1972. Back at CERN, his work concentrated on the search for experimental evidence of the presence of quarks in hadrons. He was among the main initiators of the NA3 experiment at the SPS that measured the structure functions of the pions: the results indicated a cro...

  1. Werner Heisenberg (1901-1976)

    Science.gov (United States)

    Yang, Chen Ning

    2013-05-01

    Werner Heisenberg was one of the greatest physicists of all times. When he started out as a young research worker, the world of physics was in a very confused and frustrating state, which Abraham Pais has described1 as: It was the spring of hope, it was the winter of despair using Charles Dickens' words in A Tale of Two Cities. People were playing a guessing game: There were from time to time great triumphs in proposing, through sheer intuition, make-shift schemes that amazingly explained some regularities in spectral physics, leading to joy. But invariably such successes would be followed by further work which reveal the inconsistency or inadequacy of the new scheme, leading to despair...

  2. Werner State Structure and Entanglement Classification

    Directory of Open Access Journals (Sweden)

    David W. Lyons

    2012-01-01

    Full Text Available We present applications of the representation theory of Lie groups to the analysis of structure and local unitary classification of Werner states, sometimes called the decoherence-free states, which are states of n quantum bits left unchanged by local transformations that are the same on each particle. We introduce a multiqubit generalization of the singlet state and a construction that assembles these qubits into Werner states.

  3. Werner coordination chemistry and neurodegeneration.

    Science.gov (United States)

    Telpoukhovskaia, Maria A; Orvig, Chris

    2013-02-21

    Neurodegenerative diseases are capturing the world's attention as being the next set of diseases we must tackle collectively. Not only are the patients experiencing gradual cognitive and physical decline in most cases, but these diseases are fatal with no prevention currently available. As these diseases are progressive, providing care and symptom treatment for the ageing population is becoming both a medical and a financial challenge. This review discusses how Werner coordination chemistry plays a role in three diseases - those of Alzheimer's, Parkinson's, and prions. Metal ions are considered to be involved in these diseases in part via their propensity to cause toxic aggregation of proteins. First, the coordination of metal ions, with emphasis on copper(II), to metalloproteins that are hallmarks of these diseases - amyloid β, α-synuclein, and prion, respectively - will be discussed. We will present the current understanding of the metal coordination environments created by the amino acids of these proteins, as well as metal binding affinity. Second, a diverse set of examples of rationally designed metal chelators to outcompete this deleterious binding will be examined based on coordination mode and affinity toward bio-relevant metal ions. Overall, this review will give a general overview of protein and metal chelator coordination environments in neurodegenerative diseases.

  4. Robust and fragile Werner states in the collective dephasing Robust and fragile Werner states in the collective dephasing

    CERN Document Server

    Li, S B; Li, S B; Xu, J B; Li, Shang-Bin; Xu, Jing-Bo; Li, Shang-Bin; Xu, Jing-Bo

    2005-01-01

    We investigate the concurrence and Bell violation of the Werner or Werner-like states in the presence of collective dephasing. It is shown that the Werner and certain kinds of Werner-like states are robust against the collective dephasing, and some kinds of Werner-like states is fragile and becomes completely disentangled in a finite-time. The threshold time of complete disentanglement of the Werner state is given. The influence of external driving field on the finite-time disentanglement of Werner states is discussed. Finally, we present a simple method to control the stationary state entanglement of two qubits. We investigate the concurrence and Bell violation of the Werner or Werner-like states in the presence of collective dephasing. It is shown that the Werner and certain kinds of Werner-like states are robust against the collective dephasing, and some kinds of Werner-like states is fragile and becomes completely disentangled in a finite-time. The threshold time of complete disentanglement of the Werner ...

  5. On Two-Distillable Werner States

    Science.gov (United States)

    Đoković, Dragomir

    2016-06-01

    We consider bipartite mixed states in a $d\\otimes d$ quantum system. We say that $\\rho$ is PPT if its partial transpose $1 \\otimes T (\\rho)$ is positive semidefinite, and otherwise $\\rho$ is NPT. The well-known Werner states are divided into three types: (a) the separable states (the same as the PPT states); (b) the one-distillable states (necessarily NPT); and (c) the NPT states which are not one-distillable. We give several different formulations and provide further evidence for validity of the conjecture that the Werner states of type (c) are not two-distillable.

  6. Richard A. Werners forskning i pengeskabelse

    DEFF Research Database (Denmark)

    2016-01-01

    Hvilken rolle spiller penge i samfundsøkonomien og hvilken rolle burde penge spille i den økonomiske videnskab? Det forsker Richard Werner i. Han er professor i økonomi ved Southampton University i England, og her præsenteres fire dele af hans forskning i penge: (1) Hvad foregår der egentlig i en...

  7. Werner Herzogi üksiklased / Kristiina Davidjants

    Index Scriptorium Estoniae

    Davidjants, Kristiina, 1974-

    2002-01-01

    Detsembris toimuvat Pimedate Ööde Filmifestivali laiendatakse ka suvele, et sobivates paikades näidata väärtfilme. Alates 6. juunist näidatakse Katariina kirikus Werner Herzogi (1942) filme. Lähemalt režissöörist

  8. Werner Herzogi üksiklased / Kristiina Davidjants

    Index Scriptorium Estoniae

    Davidjants, Kristiina, 1974-

    2002-01-01

    Detsembris toimuvat Pimedate Ööde Filmifestivali laiendatakse ka suvele, et sobivates paikades näidata väärtfilme. Alates 6. juunist näidatakse Katariina kirikus Werner Herzogi (1942) filme. Lähemalt režissöörist

  9. An Interview with Werner F. Leopold.

    Science.gov (United States)

    Hakuta, Kenji

    A 1983 interview with Werner F. Leopold (1896-1984), a key figure in the study of bilingualism and child language, is presented. An introductory section gives some background to the interview. The discussion itself reviews Leopold's personal and professional background, work, and writing, and focuses largely on the linguistic development of…

  10. Pleiotropic genes for metabolic syndrome and inflammation

    DEFF Research Database (Denmark)

    Kraja, Aldi T; Chasman, Daniel I; North, Kari E

    2014-01-01

    Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factor...

  11. Rett syndrome: genes, synapses, circuits and therapeutics

    Directory of Open Access Journals (Sweden)

    Abhishek eBanerjee

    2012-05-01

    Full Text Available Development of the nervous system proceeds through a set of complex checkpoints which arise from a combination of sequential gene expression and early neural activity sculpted by the environment. Genetic and environmental insults lead to neurodevelopmental disorders which encompass a large group of diseases that result from anatomical and physiological abnormalities during maturation and development of brain circuits. Rett syndrome (RTT is a postnatal neurological disorder of genetic origin, caused by mutations in the X-linked gene MECP2. It features neuropsychiatric abnormalities like motor dysfunctions and mild to severe cognitive impairment. This review discusses several key questions and attempts to evaluate recently developed animal models, cell-type specific function of MeCP2, defects in neural circuit plasticity and possible therapeutic strategies. Finally, we also discuss how genes, proteins and overlapping signaling pathways affect the molecular etiology of apparently unrelated neuropsychiatric disorders, an understanding of which can offer novel therapeutic strategies.

  12. Bivariate Blending Thiele-Werner's Osculatory Rational Interpolation

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Both the expansive Newton's interpolating polynomial and the Thiele-Werner's interpolation are used to construct a kind of bivariate blending Thiele-Werner's osculatory rational interpolation. A recursive algorithm and its characteristic properties are given. An error estimation is obtained and a numerical example is illustrated.

  13. Frequency of Werner helicase 1367 polymorphism and age-related morbidity in an elderly Brazilian population

    Directory of Open Access Journals (Sweden)

    M.A.C. Smith

    2005-07-01

    Full Text Available Werner syndrome (WS is a premature aging disease caused by a mutation in the WRN gene. The gene was identified in 1996 and its product acts as a DNA helicase and exonuclease. Some specific WRN polymorphic variants were associated with increased risk for cardiovascular diseases. The identification of genetic polymorphisms as risk factors for complex diseases affecting older people can improve their prevention, diagnosis and prognosis. We investigated WRN codon 1367 polymorphism in 383 residents in a district of the city of São Paulo, who were enrolled in an Elderly Brazilian Longitudinal Study. Their mean age was 79.70 ± 5.32 years, ranging from 67 to 97. This population was composed of 262 females (68.4% and 121 males (31.6% of European (89.2%, Japanese (3.3%, Middle Eastern (1.81%, and mixed and/or other origins (5.7%. There are no studies concerning this polymorphism in Brazilian population. These subjects were evaluated clinically every two years. The major health problems and morbidities affecting this cohort were cardiovascular diseases (21.7%, hypertension (83.7%, diabetes (63.3%, obesity (41.23%, dementia (8.0%, depression (20.0%, and neoplasia (10.8%. Their prevalence is similar to some urban elderly Brazilian samples. DNA was isolated from blood cells, amplified by PCR and digested with PmaCI. Allele frequencies were 0.788 for the cysteine and 0.211 for the arginine. Genotype distributions were within that expected for the Hardy-Weinberg equilibrium. Female gender was associated with hypertension and obesity. Logistic regression analysis did not detect significant association between the polymorphism and morbidity. These findings confirm those from Europeans and differ from Japanese population.

  14. The Werner Protein Acts as a Coactivator of Nuclear Factor κB (NF-κB) on HIV-1 and Interleukin-8 (IL-8) Promoters.

    Science.gov (United States)

    Mizutani, Taketoshi; Ishizaka, Aya; Furuichi, Yasuhiro

    2015-07-24

    The Werner syndrome helicase (WRN) plays a role in maintaining genomic stability. The lack of WRN results in Werner syndrome, a rare autosomal recessive genetic disorder, which causes premature aging accompanied by many complications such as rare forms of cancer and type 2 diabetes. However, the underlying mechanisms of these complications, arising due to the loss of WRN, are poorly understood. In this study, we demonstrated the function of WRN in transcriptional regulation of NF-κB targets. WRN physically interacts via its RecQ C-terminal (RQC) domain with the Rel homology domain of both the RelA (p65) and the p50 subunits of NF-κB. In the steady state, WRN is recruited to HIV-1 long terminal repeat (LTR), a typical NF-κB-responsive promoter, as well as the p50/p50 homodimer, in an NF-κB site-dependent manner. The amount of WRN on LTR increased along with the transactivating RelA/p50 heterodimer in response to TNF-α stimulation. Further, a knockdown of WRN reduced the transactivation of LTR in exogenous RelA/p50-introduced or TNF-α-stimulated cells. Additionally, knockdown of WRN reduced TNF-α stimulation-induced activation of the endogenous promoter of IL-8, an NF-κB-responsive gene, and WRN increased its association with the IL-8 promoter region together with RelA/p50 after TNF-α stimulation. In conjunction with studies that have shown NF-κB to be a key regulator of aging and inflammation, our results indicate a novel role of WRN in transcriptional regulation. Along with NF-κB, the loss of WRN is expected to result in incorrect regulation of downstream targets and leads to immune abnormalities and homeostatic disruption.

  15. Behavior of Werner states under relativistic boosts

    Science.gov (United States)

    Palge, Veiko; Dunningham, Jacob

    2015-12-01

    We study the structure of maps that Lorentz boosts induce on the spin degree of freedom of a system consisting of two massive spin- 1 / 2 particles. We consider the case where the spin state is described by the Werner state and the momenta are discrete. Transformations on the spins are systematically investigated in various boost scenarios by calculating the orbit and concurrence of the bipartite spin state with different kinds of product and entangled momenta. We confirm the general conclusion that Lorentz boosts cause non-trivial behavior of bipartite spin entanglement. Visualization of the evolution of the spin state is shown to be valuable in explaining the pattern of concurrence. The idealized model provides a basis of explanation in terms of which phenomena in systems involving continuous momenta can be understood.

  16. Reflections on My Werner H. Kirsten Student Internship | Poster

    Science.gov (United States)

    By Nathalie Walker, Guest Writer Editor’s note: This article represents one student’s perspective on her experiences as a Werner H. Kirsten student intern. Failure isn’t just a possibility, it is a certainty; yet failure is what leads you to success. Above all else, that is what I will retain from my experience in the Werner H. Kirsten Student Intern Program (WHK SIP).

  17. Reflections on My Werner H. Kirsten Student Internship | Poster

    Science.gov (United States)

    By Nathalie Walker, Guest Writer Editor’s note: This article represents one student’s perspective on her experiences as a Werner H. Kirsten student intern. Failure isn’t just a possibility, it is a certainty; yet failure is what leads you to success. Above all else, that is what I will retain from my experience in the Werner H. Kirsten Student Intern Program (WHK SIP).

  18. Pleiotropic genes for metabolic syndrome and inflammation

    Science.gov (United States)

    Kraja, Aldi T.; Chasman, Daniel I.; North, Kari E.; Reiner, Alexander P.; Yanek, Lisa R.; Kilpeläinen, Tuomas O.; Smith, Jennifer A.; Dehghan, Abbas; Dupuis, Josée; Johnson, Andrew D.; Feitosa, Mary F.; Tekola-Ayele, Fasil; Chu, Audrey Y.; Nolte, Ilja M.; Dastani, Zari; Morris, Andrew; Pendergrass, Sarah A.; Sun, Yan V.; Ritchie, Marylyn D.; Vaez, Ahmad; Lin, Honghuang; Ligthart, Symen; Marullo, Letizia; Rohde, Rebecca; Shao, Yaming; Ziegler, Mark A.; Im, Hae Kyung; Schnabel, Renate B.; Jørgensen, Torben; Jørgensen, Marit E.; Hansen, Torben; Pedersen, Oluf; Stolk, Ronald P.; Snieder, Harold; Hofman, Albert; Uitterlinden, Andre G.; Franco, Oscar H.; Ikram, M. Arfan; Richards, J. Brent; Rotimi, Charles; Wilson, James G.; Lange, Leslie; Ganesh, Santhi K.; Nalls, Mike; Rasmussen-Torvik, Laura J.; Pankow, James S.; Coresh, Josef; Tang, Weihong; Kao, W.H. Linda; Boerwinkle, Eric; Morrison, Alanna C.; Ridker, Paul M.; Becker, Diane M.; Rotter, Jerome I.; Kardia, Sharon L.R.; Loos, Ruth J.F.; Larson, Martin G.; Hsu, Yi-Hsiang; Province, Michael A.; Tracy, Russell; Voight, Benjamin F.; Vaidya, Dhananjay; O’Donnell, Christopher; Benjamin, Emelia J.; Alizadeh, Behrooz Z.; Prokopenko, Inga; Meigs, James B.; Borecki, Ingrid B.

    2014-01-01

    Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic

  19. Accelerated aging syndromes, are they relevant to normal human aging?

    Science.gov (United States)

    Dreesen, Oliver; Stewart, Colin L

    2011-09-01

    Hutchinson-Gilford Progeria (HGPS) and Werner syndromes are diseases that clinically resemble some aspects of accelerated aging. HGPS is caused by mutations in theLMNA gene resulting in post-translational processing defects that trigger Progeria in children. Werner syndrome, arising from mutations in the WRN helicase gene, causes premature aging in young adults. What are the molecular mechanism(s) underlying these disorders and what aspects of the diseases resemble physiological human aging? Much of what we know stems from the study of patient derived fibroblasts with both mutations resulting in increased DNA damage, primarily at telomeres. However, in vivo patients with Werner's develop arteriosclerosis, among other pathologies. In HGPS patients, including iPS derived cells from HGPS patients, as well as some mouse models for Progeria, vascular smooth muscle (VSM) appears to be among the most severely affected tissues. Defective Lamin processing, associated with DNA damage, is present in VSM from old individuals, indicating processing defects may be a factor in normal aging. Whether persistent DNA damage, particularly at telomeres, is the root cause for these pathologies remains to be established, since not all progeroid Lmna mutations result in DNA damage and genome instability.

  20. Diverse growth hormone receptor gene mutations in Laron syndrome.

    OpenAIRE

    Berg, M.A.; Argente, J.; Chernausek, S; Gracia, R.; Guevara-Aguirre, J; Hopp, M; Pérez-Jurado, L; Rosenbloom, A; Toledo,S.P.; Francke, U.

    1993-01-01

    To better understand the molecular genetic basis and genetic epidemiology of Laron syndrome (growth-hormone insensitivity syndrome), we analyzed the growth-hormone receptor (GHR) genes of seven unrelated affected individuals from the United States, South America, Europe, and Africa. We amplified all nine GHR gene exons and splice junctions from these individuals by PCR and screened the products for mutations by using denaturing gradient gel electrophoresis (DGGE). We identified a single GHR g...

  1. ADAMTS-13 gene expression in antiphospholipid syndrome

    Directory of Open Access Journals (Sweden)

    Veysel Sabri Hançer

    2011-09-01

    Full Text Available Antiphospholipid syndrome (APS is an autoimmune disorder characterized by recurrent thrombosis and fetal mortality. Thrombotic microangiopathy (TMA is an important histological finding in catastrophic APS (CAPS and in APS patients with nephropathy. Analysis of familial thrombotic thrombocytopenic purpura patients showed that there are mutations in the ADAMTS-13 gene that lead to functional defects in the ADAMTS-13 enzyme. The aim of this study was to investigate the prevalence of the aforementioned mutations in APS, as well as to evaluate the level and activity of the ADAMTS-13 enzyme in patients with APS. C365del, Q449stop codon, P475S, and C508Y mutations were analyzed in APS patients. Transcriptions were analyzed using real-time PCR, and the level and activity of ADAMTS-13 were analyzed via fluorogenic assay. None of the mutations tested were present in the patient or control groups. The level of ADAMTS-13 mRNA in the patient group was 50% lower than that in the control group. Although a significant difference in ADAMTS-13 activity was not observed between the patient and control groups, a significant association was observed with the level of ADAMTS-13 (p<0.0001. The level and activity of ADAMTS-13 were not associated with thrombotic complications, thrombocytopenia, or pregnancy complications in the patients with APS.

  2. Werner Sombart and his reception in Italy

    Directory of Open Access Journals (Sweden)

    Simona Pisanelli

    2015-03-01

    Full Text Available This article intends to focus on the difficulty encountered by Werner Sombart’s works in gaining a hearing in various Italian intellectual circuits. As is well known, Sombart belonged to the German Historical School of economics, sharing with other scholars of that school the same problems in getting his work known in Italy. Our aim is to explain the reason for this hostile reception. First of all, we will analyze the factors which generally hindered the spread of the German Historical School in Italy, recognizing in economists like Francesco Ferrara, Idealists like Benedetto Croce and Marxists like Antonio Labriola some of its strongest opponents. We will dwell on the cases of Gustav Schmoller and Max Weber, in order to give two representative examples of the slow and complicated Italian reception of methodological approaches and analytical perspectives which characterized the scientific experience of the German Historical School. Secondly, we will try to show why Sombart was even less appreciated than other German social scientists, giving the reasons that attracted severe criticism from economists, economic historians and sociologists towards his interdisciplinary approach in the analysis of modern capitalism. Finally, we will show the reasons of the contemporary rediscovery of Sombart and of his works.

  3. Genes and Disease: Prader-Willi Syndrome

    Science.gov (United States)

    ... MD): National Center for Biotechnology Information (US); 1998-. Genes and Disease [Internet]. Show details National Center for ... 45K) PDF version of this title (3.8M) Gene sequence Genome view see gene locations Entrez Gene ...

  4. A Two-Party Probabilistic Communication Complexity Scenario via Werner States

    Institute of Scientific and Technical Information of China (English)

    XUE Peng; LI Chuan-Feng; GUO Guang-Can

    2001-01-01

    We propose a probabilistic two-party communication complexity scenario with a prior Werner state and analyse the communication abilities of quantum correlations (entanglements) and classical correlations. This process can be used as an entanglement monotone of Werner states.

  5. Variant of Rett syndrome and CDKL5 gene

    DEFF Research Database (Denmark)

    Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt;

    2012-01-01

    UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have b...

  6. Syndrome to gene (S2G): in-silico identification of candidate genes for human diseases.

    Science.gov (United States)

    Gefen, Avitan; Cohen, Raphael; Birk, Ohad S

    2010-03-01

    The identification of genomic loci associated with human genetic syndromes has been significantly facilitated through the generation of high density SNP arrays. However, optimal selection of candidate genes from within such loci is still a tedious labor-intensive bottleneck. Syndrome to Gene (S2G) is based on novel algorithms which allow an efficient search for candidate genes in a genomic locus, using known genes whose defects cause phenotypically similar syndromes. S2G (http://fohs.bgu.ac.il/s2g/index.html) includes two components: a phenotype Online Mendelian Inheritance in Man (OMIM)-based search engine that alleviates many of the problems in the existing OMIM search engine (negation phrases, overlapping terms, etc.). The second component is a gene prioritizing engine that uses a novel algorithm to integrate information from 18 databases. When the detailed phenotype of a syndrome is inserted to the web-based software, S2G offers a complete improved search of the OMIM database for similar syndromes. The software then prioritizes a list of genes from within a genomic locus, based on their association with genes whose defects are known to underlie similar clinical syndromes. We demonstrate that in all 30 cases of novel disease genes identified in the past year, the disease gene was within the top 20% of candidate genes predicted by S2G, and in most cases--within the top 10%. Thus, S2G provides clinicians with an efficient tool for diagnosis and researchers with a candidate gene prediction tool based on phenotypic data and a wide range of gene data resources. S2G can also serve in studies of polygenic diseases, and in finding interacting molecules for any gene of choice.

  7. Rare and unusual endocrine cancer syndromes with mutated genes.

    Science.gov (United States)

    Lodish, Maya B; Stratakis, Constantine A

    2010-12-01

    The study of a number of rare familial syndromes associated with endocrine tumor development has led to the identification of genes involved in the development of these tumors. Major advances have expanded our understanding of the pathophysiology of these rare endocrine tumors, resulting in the elucidation of causative genes in rare familial diseases and a better understanding of the signaling pathways implicated in endocrine cancers. Recognition of the familial syndrome associated with a particular patient's endocrine tumor has important implications in terms of prognosis, screening of family members, and screening for associated conditions.

  8. Marfan syndrome: from gene to therapy

    NARCIS (Netherlands)

    Bolar, N.; Laer, L. van; Loeys, B.L.

    2012-01-01

    PURPOSE OF REVIEW: Although historically Marfan syndrome (MFS) has always been considered as a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1, the study of Marfan mouse models and Marfan-related conditions has shifted our current understanding to a patho

  9. Braddock-Carey syndrome: A 21q22 contiguous gene syndrome encompassing RUNX1.

    Science.gov (United States)

    Braddock, Stephen R; South, Sarah T; Schiffman, Joshua D; Longhurst, Maria; Rowe, Leslie R; Carey, John C

    2016-10-01

    In 1994, Braddock and Carey first reported two unrelated girls with a new multiple malformation syndrome. The primary features included Pierre Robin sequence, persistent neonatal-onset thrombocytopenia, agenesis of the corpus callosum, a distinctive facies, enamel hypoplasia, and severe developmental delay. Since that time, there have been multiple other reported patients with a similar phenotype. In addition, several reports of thrombocytopenia and developmental delay have been documented in association with deletions in the Down syndrome critical region at 21q22. The similarity of the reported cases with deletions involving 21q22 with the clinical presentation of the two patients with Braddock-Carey syndrome resulted in a reinvestigation of the genetic etiology of these two patients 20 years after the original study. This investigation provides evidence that the etiology of this and other "Fanconi-like" disorders represent a newly recognized contiguous gene deletion syndrome involving 21q22 and specifically, the RUNX1 gene. © 2016 Wiley Periodicals, Inc.

  10. Candidate gene association studies in syndromic and non-syndromic cleft lip and palate

    Energy Technology Data Exchange (ETDEWEB)

    Daack-Hirsch, S.; Basart, A.; Frischmeyer, P. [Univ. of Iowa, IA (United States)] [and others

    1994-09-01

    Using ongoing case ascertainment through a birth defects registry, we have collected 219 nuclear families with non-syndromic cleft lip and/or palate and 111 families with a collection of syndromic forms. Syndromic cases include 24 with recognized forms and 72 with unrecognized syndromes. Candidate gene studies as well as genome-wide searches for evidence of microdeletions and isodisomy are currently being carried out. Candidate gene association studies, to date, have made use of PCR-based polymorphisms for TGFA, MSX1, CLPG13 (a CA repeat associated with a human homologue of a locus that results in craniofacial dysmorphogenesis in the mouse) and an STRP found in a Van der Woude syndrome microdeletion. Control tetranucleotide repeats, which insure that population-based differences are not responsible for any observed associations, are also tested. Studies of the syndromic cases have included the same list of candidate genes searching for evidence of microdeletions and a genome-wide search using tri- and tetranucleotide polymorphic markers to search for isodisomy or structural rearrangements. Significant associations have previously been identified for TGFA, and, in this report, identified for MSX1 and nonsyndromic cleft palate only (p = 0.04, uncorrected). Preliminary results of the genome-wide scan for isodisomy has returned no true positives and there has been no evidence for microdeletion cases.

  11. The Change-Over of Yin-yang and Gene Regulation in Kidney Deficiency Syndromes

    Institute of Scientific and Technical Information of China (English)

    DONG Fei-xia; HE Li-qun

    2009-01-01

    The present paper studies gene regulation in kidney deficiency syndromes from the simple Nephrotic Syndrome and with the principle of positive-negative regulation to control the change-over ofyin-yang, the modern molecular biological techniques can be used, such as gene chip, representational difference analysis (RDA) and gene sequence analysis, so as to investigate the inner relationship between the genes and kidney deficiency syndromes and prove the effect given by these genes on the pathophysiological status of change-over ofyin-yang in kidney deficiency syndromes.This philosophical approach and method can also be adopted for studies of the related genes in other TCM syndromes.

  12. Fragile X Syndrome--From Genes to Cognition

    Science.gov (United States)

    Schneider, A.; Hagerman, R. J.; Hessl, D.

    2009-01-01

    Fragile X syndrome (FXS), a single gene disorder with an expanded CGG allele on the X chromosome, is the most common form of inherited cognitive impairment. The cognitive deficit ranges from mild learning disabilities to severe intellectual disability. The phenotype includes hyperactivity, short attention span, emotional problems including…

  13. Single Gene and Syndromic Causes of Obesity: Illustrative Examples.

    Science.gov (United States)

    Butler, Merlin G

    2016-01-01

    Obesity is a significant health problem in westernized societies, particularly in the United States where it has reached epidemic proportions in both adults and children. The prevalence of childhood obesity has doubled in the past 30 years. The causation is complex with multiple sources, including an obesity promoting environment with plentiful highly dense food sources and overall decreased physical activity noted for much of the general population, but genetic factors clearly play a role. Advances in genetic technology using candidate gene approaches, genome-wide association studies, structural and expression microarrays, and next generation sequencing have led to the discovery of hundreds of genes recognized as contributing to obesity. Polygenic and monogenic causes of obesity are now recognized including dozens of examples of syndromic obesity with Prader-Willi syndrome, as a classical example and recognized as the most common known cause of life-threatening obesity. Genetic factors playing a role in the causation of obesity will be discussed along with the growing evidence of single genes and the continuum between monogenic and polygenic obesity. The clinical and genetic aspects of four classical but rare obesity-related syndromes (ie, Prader-Willi, Alström, fragile X, and Albright hereditary osteodystrophy) will be described and illustrated in this review of single gene and syndromic causes of obesity. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Fragile X Syndrome--From Genes to Cognition

    Science.gov (United States)

    Schneider, A.; Hagerman, R. J.; Hessl, D.

    2009-01-01

    Fragile X syndrome (FXS), a single gene disorder with an expanded CGG allele on the X chromosome, is the most common form of inherited cognitive impairment. The cognitive deficit ranges from mild learning disabilities to severe intellectual disability. The phenotype includes hyperactivity, short attention span, emotional problems including…

  15. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies.

    Science.gov (United States)

    Urdinguio, Rocio G; Sanchez-Mut, Jose V; Esteller, Manel

    2009-11-01

    Epigenetic mechanisms such as DNA methylation and modifications to histone proteins regulate high-order DNA structure and gene expression. Aberrant epigenetic mechanisms are involved in the development of many diseases, including cancer. The neurological disorder most intensely studied with regard to epigenetic changes is Rett syndrome; patients with Rett syndrome have neurodevelopmental defects associated with mutations in MeCP2, which encodes the methyl CpG binding protein 2, that binds to methylated DNA. Other mental retardation disorders are also linked to the disruption of genes involved in epigenetic mechanisms; such disorders include alpha thalassaemia/mental retardation X-linked syndrome, Rubinstein-Taybi syndrome, and Coffin-Lowry syndrome. Moreover, aberrant DNA methylation and histone modification profiles of discrete DNA sequences, and those at a genome-wide level, have just begun to be described for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, and in other neurological disorders such as multiple sclerosis, epilepsy, and amyotrophic lateral sclerosis. In this Review, we describe epigenetic changes present in neurological diseases and discuss the therapeutic potential of epigenetic drugs, such as histone deacetylase inhibitors.

  16. A Marfan syndrome gene expression phenotype in cultured skin fibroblasts

    Directory of Open Access Journals (Sweden)

    Emond Mary

    2007-09-01

    Full Text Available Abstract Background Marfan syndrome (MFS is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms. Results We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR. Conclusion Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value -6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status. An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater.

  17. A Marfan syndrome gene expression phenotype in cultured skin fibroblasts

    Science.gov (United States)

    Yao, Zizhen; Jaeger, Jochen C; Ruzzo, Walter L; Morale, Cecile Z; Emond, Mary; Francke, Uta; Milewicz, Dianna M; Schwartz, Stephen M; Mulvihill, Eileen R

    2007-01-01

    Background Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms. Results We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR. Conclusion Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value < 3 × 10-6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status). An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater. PMID:17850668

  18. Diverse growth hormone receptor gene mutations in Laron syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Berg, M.A.; Francke, U. (Stanford Univ. School of Medicine, CA (United States)); Gracia, R.; Rosenbloom, A.; Toledo, S.P.A. (Univ. Autonoma, Madrid (Spain)); Chernausek, S. (Children' s Hospital Medical Center, Cincinnati, OH (United States)); Guevara-Aguirre, J. (Institute of Endocrinology, Metabolism, and Reproduction, Quito (Ecuador)); Hopp, M. (Univ. of Witwatersrand, Johannesburg (South Africa)); Rosenbloom, A.; Argente, J. (Univ. of Florida, Gainesville (United States)); Toledo, S.P.A. (Univ. of Sao Paulo (Brazil))

    1993-05-01

    To better understand the molecular genetic basis and genetic epidemiology of Laron syndrome (growth-hormone insensitivity syndrome), the authors analysed the growth-hormone receptor (GHR) genes of seven unrelated affected individuals from the United States, South America, Europe, and Africa. They amplified all nine GHR gene exons and splice junctions from these individuals by PCR and screened the products for mutations by using denaturing gradient gel electrophoresis (DGGE). They identified a single GHR gene fragment with abnormal DGGE results for each affected individual, sequenced this fragment, and, in each case, identified a mutation likely to cause Laron syndrome, including two nonsense mutations (R43X and R217X), two splice-junction mutations, (189-1 G to T and 71+1 G to A), and two frameshift mutations (46 del TT and 230 del TA or AT). Only one of these mutations, R43X, has been previously reported. Using haplotype analysis, they determined that this mutation, which involves a CpG dinucleotide hot spot, likely arose as a separate event in this case, relative to the two prior reports of R43X. Aside from R43X, the mutations identified are unique to patients from particular geographic regions. Ten GHR gene mutations have now been described in this disorder. The authors conclude that Laron syndrome is caused by diverse GHR gene mutations, including deletions, RNA processing defects, translational stop codons, and missense codons. All the identified mutations involve the extracellular domain of the receptor, and most are unique to particular families or geographic areas. 35 refs., 3 figs., 1 tab.

  19. Werner Herzog - saksa kino atleet ja aadlik / Mart Rummo

    Index Scriptorium Estoniae

    Rummo, Mart

    2002-01-01

    Alates 6. juunist näidatakse Katariina kirikus kuuel õhtul algusega kell 22 Werner Herzogi (1942) filme. Väljavõtteid W. Herzogi poolt 1999. aastal Cannes'i festivali järel antud intervjuust, kus juttu ka režissööri suhetest näitleja Klaus Kinskiga, millest kõneleb ka Tallinnas näidatav "Minu armas vaenlane"

  20. Werner Herzog - saksa kino atleet ja aadlik / Mart Rummo

    Index Scriptorium Estoniae

    Rummo, Mart

    2002-01-01

    Alates 6. juunist näidatakse Katariina kirikus kuuel õhtul algusega kell 22 Werner Herzogi (1942) filme. Väljavõtteid W. Herzogi poolt 1999. aastal Cannes'i festivali järel antud intervjuust, kus juttu ka režissööri suhetest näitleja Klaus Kinskiga, millest kõneleb ka Tallinnas näidatav "Minu armas vaenlane"

  1. Werner's Measure on Self-Avoiding Loops and Welding

    Science.gov (United States)

    Chavez, Angel; Pickrell, Doug

    2014-08-01

    Werner's conformally invariant family of measures on self-avoiding loops on Riemann surfaces is determined by a single measure μ_0 on self-avoiding loops in C setminus{0} which surround 0. Our first major objective is to show that the measure μ_0 is infinitesimally invariant with respect to conformal vector fields (essentially the Virasoro algebra of conformal field theory). This makes essential use of classical variational formulas of Duren and Schiffer, which we recast in representation theoretic terms for efficient computation. We secondly show how these formulas can be used to calculate (in principle, and sometimes explicitly) quantities (such as moments for coefficients of univalent functions) associated to the conformal welding for a self-avoiding loop. This gives an alternate proof of the uniqueness of Werner's measure. We also attempt to use these variational formulas to derive a differential equation for the (Laplace transform of) the ''diagonal distribution'' for the conformal welding associated to a loop; this generalizes in a suggestive way to a deformation of Werner's measure conjectured to exist by Kontsevich and Suhov (a basic inspiration for this paper).

  2. The Mitochondrial Aminoacyl tRNA Synthetases: Genes and Syndromes

    OpenAIRE

    2014-01-01

    Mitochondrial respiratory chain (RC) disorders are a group of genetically and clinically heterogeneous diseases. This is because protein components of the RC are encoded by both mitochondrial and nuclear genomes and are essential in all cells. In addition, the biogenesis and maintenance of mitochondria, including mitochondrial DNA (mtDNA) replication, transcription, and translation, require nuclear-encoded genes. In the past decade, a growing number of syndromes associated with dysfunction of...

  3. RENIN ANGIOTENSIN SYSTEM GENE POLYMORPHISMS IN CHILDREN WITH NEPHROTIC SYNDROM

    Directory of Open Access Journals (Sweden)

    Zh.P. Sharnova

    2006-01-01

    Full Text Available To investigate the role of the reninangiotensin system genes polymorphisms in develop and progression of nephrotic syndrom (NS in children we determined the genotypes of angiotensin converting enzyme (ACE, angiotensinogen (AGT and angiotensin ii receptor (ATII-R of 1 type in 80 russian children with ns including and 15 children with chronic renal failure (CRF. Genotype frequencies did not differ between patients with ns and controls (n = 165. The distribution of ace, AGT and ATII-R 1 type genotypes was similar among ns sub groups, such as focal segmental glomerulosclerosis (FSGS (n = 18, steroid-sensitive nephrotic syndrome (n = 32, nephrotic syndrome with hypertension and hemoturia (n = 22 and with control group. When ns subjects with CRF (n = 15 were compared with control, the prevalence of ace DD genotype was significantly higher (47% VS 21%; χ2 = 4,44; p < 0,05. Our results indicate that the DD genotype ace may be a factor of risk for the dеvеlopment of progressive renal impairment in the children with nephrotic syndrome. The analysis of treatment's effect with inhibitor of ace in groups patients with steroid resistant NS (SRNS demonstrated decreasing of renoprotective effect of this drugs in patients with id and dd genotypes com? Pared with ii genotype: the degree of blood pressure, proteinuria and the rate of glomerular filtration decrease was significantly lower (55,46 ± 9,25 VS 92,74 ± 25; р < 0,05 in these patients.Key words: nephrotic syndrom, chronic renal failure, polymorphism of genes, renin-angiotensin system.

  4. Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects.

    NARCIS (Netherlands)

    Weemaes, C.M.R.; Tol, M.J. van; Wang, J.; Ostaijen-ten Dam, M.M. van; Eggermond, M.C. van; Thijssen, P.E.; Aytekin, C.; Brunetti-Pierri, N.; Burg, M. van der; aham Davies, E. Gr; Ferster, A.; Furthner, D.; Gimelli, G.; Gennery, A.; Kloeckener-Gruissem, B.; Meyn, S.; Powell, C.; Reisli, I.; Schuetz, C.; Schulz, A.; Shugar, A.; Elsen, P.J. van den; Maarel, S.M. van der

    2013-01-01

    Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome

  5. Non-syndromic retinal ciliopathies: translating gene discovery into therapy.

    Science.gov (United States)

    Estrada-Cuzcano, Alejandro; Roepman, Ronald; Cremers, Frans P M; den Hollander, Anneke I; Mans, Dorus A

    2012-10-15

    Homozygosity mapping and exome sequencing have accelerated the discovery of gene mutations and modifier alleles implicated in inherited retinal degeneration in humans. To date, 158 genes have been found to be mutated in individuals with retinal dystrophies. Approximately one-third of the gene defects underlying retinal degeneration affect the structure and/or function of the 'connecting cilium' in photoreceptors. This structure corresponds to the transition zone of a prototypic cilium, a region with increasing relevance for ciliary homeostasis. The connecting cilium connects the inner and outer segments of the photoreceptor, mediating bi-directional transport of phototransducing proteins required for vision. In fact, the outer segment, connecting cilium and associated basal body, forms a highly specialized sensory cilium, fully dedicated to photoreception and subsequent signal transduction to the brain. At least 21 genes that encode ciliary proteins are implicated in non-syndromic retinal dystrophies such as cone dystrophy, cone-rod dystrophy, Leber congenital amaurosis (LCA), macular degeneration or retinitis pigmentosa (RP). The generation and characterization of vertebrate retinal ciliopathy animal models have revealed insights into the molecular disease mechanism which are indispensable for the development and evaluation of therapeutic strategies. Gene augmentation therapy has proven to be safe and successful in restoring long-term sight in mice, dogs and humans suffering from LCA or RP. Here, we present a comprehensive overview of the genes, mutations and modifier alleles involved in non-syndromic retinal ciliopathies, review the progress in dissecting the associated retinal disease mechanisms and evaluate gene augmentation approaches to antagonize retinal degeneration in these ciliopathies.

  6. Sjogren Syndrome-Gene Therapy and its Prospective

    Directory of Open Access Journals (Sweden)

    R Rahpeyma

    2003-02-01

    Full Text Available Sjogren syndrome is one of the autoimmune diseases which is characterized by lymphocytic infiltration to exocrine glands and causes keratoconjunctivitis sicca and xerostomia. Today, a large population, with a majority of women over 40, suffer from this disease and have several complications regarding oral health and reduced life quality such as severe dental caries, painful eyes, olfactory and gustatory deficiency, speech, mastication and swallowing discomforts. Unfortunately, these patients do not respond to the conventional therapies. Nowadays in medical world, which its target is basic therapy and not symptomatic one, several gene therapy approaches, have gained importance in treatment of this apparently incurable diseases. Due to the facts that this disease is the second prevelant autoimmune disease, after rheumatoid arthritis, and the conventional therapies of the disease are all relative and symptomatic, researchers have insisted on the basic and causative therapy through gene transfer more than before. In the Present article, through reviewing 58 references containing recent scientific and investigatory findings it has been tried, to consider the pathogenesis and conventional therapies of this syndrome. Another purpose of this study was to investigate several and potentially very effective gene transfer systems and different theraputic genes (mainly membrane water channels, ione transporter molecules, transcription factors, antifungal proteins and free radical scavengers.

  7. [From gene to disease; the nail-patella syndrome and the LMX1B gene

    NARCIS (Netherlands)

    Bongers, M.H.F.; Knoers, N.V.A.M.

    2003-01-01

    Nail-patella syndrome (NPS) is an autosomal dominant hereditary disorder characterised by nail dysplasia, patellar apoplasia/hypoplasia, iliac horns, elbow dysplasia, and frequently primary open angle glaucoma and progressive nephropathy. The gene underlying NPS, LMX1B on chromosome 9q34.1, is a

  8. An Engineered Endomorphin-2 Gene for Morphine Withdrawal Syndrome

    Science.gov (United States)

    Wu, Fei-xiang; He, Yan; Di, Hui-ting; Sun, Yu-ming; Pan, Rui-rui; Yu, Wei-feng; Liu, Renyu

    2016-01-01

    An optimal therapeutics to manage opioid withdrawal syndrome is desired for opioid addiction treatment. Down-regulation of endogenous endomorphin-2 (EM2) level in the central nervous system after continuous morphine exposure was observed, which suggested that increase of EM2 could be an alternative novel method for opioid dependence. As a short peptide, the short half-life of EM2 limits its clinical usage through conventional administration. In the present study, we engineered an EM2 gene using a signal peptide of mouse growth factor for an out-secretory expression of EM2 and an adenovirus as a vector, which ultimately sustained the release of EM-2. After administration of the adenovirus in central nervous system, a sustained increase of EM2 level in the cerebral spinal fluid (CSF) was observed along with a reduction of morphine withdrawal syndrome. These findings suggest that the engineered EM2 gene delivered to the central nervous system could be a novel therapeutics for withdrawal syndrome in opioid dependent subjects. PMID:27003293

  9. A novel PTEN gene promoter mutation and untypical Cowden syndrome

    Institute of Scientific and Technical Information of China (English)

    Chen Liu; Guangbing Li; Rongrong Chen; Xiaobo Yang; Xue Zhao; Haitao Zhao

    2013-01-01

    Cowden syndrome (CS),an autosomal dominant disorder,is one of a spectrum of clinical disorders that have been linked to germline mutations in the phosphatase and tensin homolog (PTEN) gene.Although 70-80% of patients with CS have an identifiable germline PTEN mutation,the clinical diagnosis presents many challenges because of the phenotypic and genotypic variations.In the present study,we sequenced the exons and the promoter of PTEN gene,mutations and variations in the promoter and exons were identified,and a PTEN protein expression negative region was determined by immunohistochemistry (IHC).In conclusion,a novel promoter mutation we found in PTEN gene may turn off PTEN protein expression occasionally,leading to the disorder of PTEN and untypical CS manifestations.

  10. Werner complex deficiency in cells disrupts the Nuclear Pore Complex and the distribution of lamin B1.

    Science.gov (United States)

    Li, Zhi; Zhu, Yizhou; Zhai, Yujia; R Castroagudin, Michelle; Bao, Yifei; White, Tommy E; Glavy, Joseph S

    2013-12-01

    From the surrounding shell to the inner machinery, nuclear proteins provide the functional plasticity of the nucleus. This study highlights the nuclear association of Pore membrane (POM) protein NDC1 and Werner protein (WRN), a RecQ helicase responsible for the DNA instability progeria disorder, Werner Syndrome. In our previous publication, we connected the DNA damage sensor Werner's Helicase Interacting Protein (WHIP), a binding partner of WRN, to the NPC. Here, we confirm the association of the WRN/WHIP complex and NDC1. In established WRN/WHIP knockout cell lines, we further demonstrate the interdependence of WRN/WHIP and Nucleoporins (Nups). These changes do not completely abrogate the barrier of the Nuclear Envelope (NE) but do affect the distribution of FG Nups and the RAN gradient, which are necessary for nuclear transport. Evidence from WRN/WHIP knockout cell lines demonstrates changes in the processing and nucleolar localization of lamin B1. The appearance of "RAN holes" void of RAN corresponds to regions within the nucleolus filled with condensed pools of lamin B1. From WRN/WHIP knockout cell line extracts, we found three forms of lamin B1 that correspond to mature holoprotein and two potential post-translationally modified forms of the protein. Upon treatment with topoisomerase inhibitors lamin B1 cleavage occurs only in WRN/WHIP knockout cells. Our data suggest the link of the NDC1 and WRN as one facet of the network between the nuclear periphery and genome stability. Loss of WRN complex leads to multiple alterations at the NPC and the nucleolus.

  11. Experimental preparation of Werner state via spontaneous parametric down-conversion

    CERN Document Server

    Zhang, Y S; Li, C F; Guo, G C; Zhang, Yong-Sheng; Huang, Yun-Feng; Li, Chuan-Feng; Guo, Guang-Can

    2002-01-01

    We present an experiment of preparing Werner state via spontaneous parametric down-conversion and controlled decoherence of photons in this paper. In this experiment two independent BBO (beta-barium borate) crystals are used to produce down-conversion light beams, which are mixed to prepare Werner state.

  12. Nye lektioner i kærlighedens teologi: Werner G. Jeanrond: Kærlighedens teologi

    DEFF Research Database (Denmark)

    Pallesen, Carsten

    2012-01-01

    Anmeldelse af Werner G. Jeanrond, Kærlighedens teologi, Frederiksberg: Aros Forlag 2012 (oversat fra engelsk A Theology of Love, London: T&T Clark 2010)......Anmeldelse af Werner G. Jeanrond, Kærlighedens teologi, Frederiksberg: Aros Forlag 2012 (oversat fra engelsk A Theology of Love, London: T&T Clark 2010)...

  13. Bayesian Nash equilibria using extended Werner-like states

    Science.gov (United States)

    Alid-Vaccarezza, M.; Soto, M. E.

    2016-10-01

    We study quantum strategies in games of incomplete information using a formalism of game theory based on multi-sector probability matrix. We analyze an extension of the well-known game of Battle of Sexes using an extended Werner-like state focusing in how its mixedness and entanglement affect the Bayesian Nash payoffs of the player. It is shown that entanglement is needed to outperform classical payoffs but not all entangled states are useful due to the presence of mixedness. A threshold for the mixedness parameter and the minimum entanglement value were found.

  14. 心导管术创始人Werner Forssmann

    Institute of Scientific and Technical Information of China (English)

    周白瑜

    2009-01-01

    @@ Werner Theodor Otto Forssmann教授(1904-1979年,图1),德国人,因发明心导管术获得1956年诺贝尔生理学和医学奖.Forssmann教授毕业于柏林大学医学部,实习期间在Georg Klemperer教授的指导下进行临床实习,师从Rudolph Fick教授学习解削.1929年在柏林市内的Eberswalde医院进行外科实习.

  15. Depletion of mtDNA: syndromes and genes.

    Science.gov (United States)

    Alberio, Simona; Mineri, Rossana; Tiranti, Valeria; Zeviani, Massimo

    2007-01-01

    Maintenance of mitochondrial DNA (mtDNA) requires the concerted activity of several nuclear-encoded factors that participate in its replication, being part of the mitochondrial replisome or ensuring the balanced supply of dNTPs to mitochondria. In the past decade, a growing number of syndromes associated with dysfunction due to tissue-specific depletion of mtDNA (MDS) have been reported. This article reviews the current knowledge of the genes responsible for these disorders, the impact of different mutations in the epidemiology of MDS and their role in the pathogenic mechanisms underlying the different clinical presentations.

  16. The Mitochondrial Aminoacyl tRNA Synthetases: Genes and Syndromes.

    Science.gov (United States)

    Diodato, Daria; Ghezzi, Daniele; Tiranti, Valeria

    2014-01-01

    Mitochondrial respiratory chain (RC) disorders are a group of genetically and clinically heterogeneous diseases. This is because protein components of the RC are encoded by both mitochondrial and nuclear genomes and are essential in all cells. In addition, the biogenesis and maintenance of mitochondria, including mitochondrial DNA (mtDNA) replication, transcription, and translation, require nuclear-encoded genes. In the past decade, a growing number of syndromes associated with dysfunction of mtDNA translation have been reported. This paper reviews the current knowledge of mutations affecting mitochondrial aminoacyl tRNAs synthetases and their role in the pathogenic mechanisms underlying the different clinical presentations.

  17. The Mitochondrial Aminoacyl tRNA Synthetases: Genes and Syndromes

    Directory of Open Access Journals (Sweden)

    Daria Diodato

    2014-01-01

    Full Text Available Mitochondrial respiratory chain (RC disorders are a group of genetically and clinically heterogeneous diseases. This is because protein components of the RC are encoded by both mitochondrial and nuclear genomes and are essential in all cells. In addition, the biogenesis and maintenance of mitochondria, including mitochondrial DNA (mtDNA replication, transcription, and translation, require nuclear-encoded genes. In the past decade, a growing number of syndromes associated with dysfunction of mtDNA translation have been reported. This paper reviews the current knowledge of mutations affecting mitochondrial aminoacyl tRNAs synthetases and their role in the pathogenic mechanisms underlying the different clinical presentations.

  18. Atypical haemolytic uraemic syndrome associated with a hybrid complement gene.

    Directory of Open Access Journals (Sweden)

    Julian P Venables

    2006-10-01

    Full Text Available BACKGROUND: Sequence analysis of the regulators of complement activation (RCA cluster of genes at chromosome position 1q32 shows evidence of several large genomic duplications. These duplications have resulted in a high degree of sequence identity between the gene for factor H (CFH and the genes for the five factor H-related proteins (CFHL1-5; aliases CFHR1-5. CFH mutations have been described in association with atypical haemolytic uraemic syndrome (aHUS. The majority of the mutations are missense changes that cluster in the C-terminal region and impair the ability of factor H to regulate surface-bound C3b. Some have arisen as a result of gene conversion between CFH and CFHL1. In this study we tested the hypothesis that nonallelic homologous recombination between low-copy repeats in the RCA cluster could result in the formation of a hybrid CFH/CFHL1 gene that predisposes to the development of aHUS. METHODS AND FINDINGS: In a family with many cases of aHUS that segregate with the RCA cluster we used cDNA analysis, gene sequencing, and Southern blotting to show that affected individuals carry a heterozygous CFH/CFHL1 hybrid gene in which exons 1-21 are derived from CFH and exons 22/23 from CFHL1. This hybrid encodes a protein product identical to a functionally significant CFH mutant (c.3572C>T, S1191L and c.3590T>C, V1197A that has been previously described in association with aHUS. CONCLUSIONS: CFH mutation screening is recommended in all aHUS patients prior to renal transplantation because of the high risk of disease recurrence post-transplant in those known to have a CFH mutation. Because of our finding it will be necessary to implement additional screening strategies that will detect a hybrid CFH/CFHL1 gene.

  19. In silico Analysis of Candidate Genes Involved in Sanfilippo Syndrome

    Directory of Open Access Journals (Sweden)

    Mehreen Zaka

    2015-04-01

    Full Text Available Sanfilippo syndrome is an autosomal recessive lysosomal storage disorder, caused by the deficiency of enzymes that play an important role in degradation of glycosaminoglycans and also called mucopolysaccharidosis III. Mucopolysaccharidosis is genetic disorder. Here, we searched the candidate genes for Sanfilippo syndrome by using BLAST with the query sequence. As no suitable homology was found against the query sequence we moved towards threading approach. The threading approach was carried out by employing online CPH models and LOMETS tools. Through present research, domains of the proteins were predicted by utilizing the Domain Sweep tools, GNS and two domains were reported. Motif search reported the maximum number of motifs for Type D protein as compared to other types. All four proteins were totally soluble proteins and no transmembrane domains were found. In future, these results and predicted 3D structures can be used for the molecular docking studies, binding activities and protein-protein interactions for all the four types of Sanfilippo syndrome.

  20. Three new BLM gene mutations associated with Bloom syndrome.

    Science.gov (United States)

    Amor-Guéret, Mounira; Dubois-d'Enghien, Catherine; Laugé, Anthony; Onclercq-Delic, Rosine; Barakat, Abdelhamid; Chadli, Elbekkay; Bousfiha, Ahmed Aziz; Benjelloun, Meriem; Flori, Elisabeth; Doray, Bérénice; Laugel, Vincent; Lourenço, Maria Teresa; Gonçalves, Rui; Sousa, Silvia; Couturier, Jérôme; Stoppa-Lyonnet, Dominique

    2008-06-01

    Bloom's syndrome (BS) is a rare autosomal recessive disease predisposing patients to all types of cancers affecting the general population. BS cells display a high level of genetic instability, including a 10-fold increase in the rate of sister chromatid exchanges, currently the only objective criterion for BS diagnosis. We have developed a method for screening the BLM gene for mutations based on direct genomic DNA sequencing. A questionnaire based on clinical information, cytogenetic features, and family history was addressed to physicians prescribing BS genetic screening, with the aim of confirming or guiding diagnosis. We report here four BLM gene mutations, three of which have not been described before. Three of the mutations are frameshift mutations, and the fourth is a nonsense mutation. All these mutations introduce a stop codon, and may therefore be considered to have deleterious biological effect. This approach should make it possible to identify new mutations and to correlate them with clinical information.

  1. A novel mutation of the fibrillin-1 gene in a newborn with severe Marfan syndrome.

    Science.gov (United States)

    Kochilas, L; Gundogan, F; Atalay, M; Bliss, J M; Vatta, M; Pena, L S; Abuelo, D

    2008-04-01

    Marfan syndrome in the neonatal age represents a severe early and commonly lethal manifestation of Marfan syndrome, which is caused by mutations in the gene encoding fibrillin-1 (FBN1). Here, we report a newborn with severe Marfan syndrome and a novel mutation involving cysteine substitution within one of the epidermal growth factor-like domains of FBN1.

  2. Amniotic fluid RNA gene expression profiling provides insights into the phenotype of Turner syndrome.

    Science.gov (United States)

    Massingham, Lauren J; Johnson, Kirby L; Scholl, Thomas M; Slonim, Donna K; Wick, Heather C; Bianchi, Diana W

    2014-09-01

    Turner syndrome is a sex chromosome aneuploidy with characteristic malformations. Amniotic fluid, a complex biological material, could contribute to the understanding of Turner syndrome pathogenesis. In this pilot study, global gene expression analysis of cell-free RNA in amniotic fluid supernatant was utilized to identify specific genes/organ systems that may play a role in Turner syndrome pathophysiology. Cell-free RNA from amniotic fluid of five mid-trimester Turner syndrome fetuses and five euploid female fetuses matched for gestational age was extracted, amplified, and hybridized onto Affymetrix(®) U133 Plus 2.0 arrays. Significantly differentially regulated genes were identified using paired t tests. Biological interpretation was performed using Ingenuity Pathway Analysis and BioGPS gene expression atlas. There were 470 statistically significantly differentially expressed genes identified. They were widely distributed across the genome. XIST was significantly down-regulated (p Turner syndrome transcriptome from other aneuploidies we previously studied. Manual curation of the differentially expressed gene list identified genes of possible pathologic significance, including NFATC3, IGFBP5, and LDLR. Transcriptomic differences in the amniotic fluid of Turner syndrome fetuses are due to genome-wide dysregulation. The hematologic/immune system differences may play a role in early-onset autoimmune dysfunction. Other genes identified with possible pathologic significance are associated with cardiac and skeletal systems, which are known to be affected in females with Turner syndrome. The discovery-driven approach described here may be useful in elucidating novel mechanisms of disease in Turner syndrome.

  3. [Polymorphism of connexin 40 gene-- a novel genetic marker of the sick sinus node syndrome].

    Science.gov (United States)

    Chernova, A A; Nikulina, S Iu; Shul'man, V A; Kukushkina, T S; Voevoda, M I; Maksimov, V N

    2011-01-01

    In this work we have demonstrated for the first time on the clinico-genetic material association between hereditary sick sinus node syndrome and connexin 40 gene polymorphism. We have revealed that heterozygous variant of connexin 40 gene variant is more frequent among patients with sick sinus node syndrome and their healthy relatives than in persons of control group.

  4. Partial duplications of the ATRX gene cause the ATR-X syndrome.

    Science.gov (United States)

    Thienpont, Bernard; de Ravel, Thomy; Van Esch, Hilde; Van Schoubroeck, Dominique; Moerman, Philippe; Vermeesch, Joris Robert; Fryns, Jean-Pierre; Froyen, Guy; Lacoste, Caroline; Badens, Catherine; Devriendt, Koen

    2007-10-01

    ATR-X syndrome is a rare syndromic X-linked mental retardation disorder. We report that some of the patients suspected of ATR-X carry large intragenic duplications in the ATRX gene, leading to an absence of ATRX mRNA and of the protein. These findings underscore the need for including quantitative analyses to mutation analysis of the ATRX gene.

  5. Deletions of the elastin gene in Williams Syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Greenberg, F.; Nickerson, E.; McCaskill, C. [Baylor College of Medicine, Houston, TX (United States)] [and others

    1994-09-01

    To investigate deletions in the elastin gene in patients with Williams Syndrome (WS), we screened 37 patients and their parents for deletions in the elastin gene by both fluorescence in situ hybridization (FISH) using cosmid cELN272 containing the 5{prime} end of the elastin gene and by polymerase chain reaction (PCR) using a primer pair which amplifies intron 17 in the elastin gene, producing a polymorphic amplification product. Thirty-two patients have been investigated by both the FISH and PCR techniques, one patient was studied only by PCR, and 4 patients were studied only by FISH. Overall, 34 of 37 patients (92%) were deleted for the elastin gene. Using the PCR marker, 14 patients were informative and 12 were shown to be deleted [maternal (n=5) and paternal (n=7)]. Using cosmid cELN272, 33 of 36 patients demonstrated a deletion of chromosome 7q11.23. In one family, both the mother and daughter were deleted due to an apparently de novo deletion arising in the mother. Three patients were not deleted using the elastin cosmid; 2 of these patients have classic WS. Another non-deleted patient has the typical facial features and hypercalcemia but normal intelligence. These three patients will be important in delineating the critical region(s) responsible for the facial features, hypercalcemia, mental retardation and supravalvular aortic stenosis (SVAS). There was not an absolute correlation between deletions in elastin and SVAS, although these individuals may be at risk for other cardiovascular complications such as hypertention. Since the majority of WS patients are deleted for a portion of the elastin gene, most likely this marker will be an important diagnostic tool, although more patients will need to be studied. Those patients who are not deleted but clinically have WS will be missed using only this one marker. Expansion of the critical region to other loci and identification of additional markers will be essential for identifying all patients with WS.

  6. Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes

    Science.gov (United States)

    Gerstung, Moritz; Pellagatti, Andrea; Malcovati, Luca; Giagounidis, Aristoteles; Porta, Matteo G Della; Jädersten, Martin; Dolatshad, Hamid; Verma, Amit; Cross, Nicholas C. P.; Vyas, Paresh; Killick, Sally; Hellström-Lindberg, Eva; Cazzola, Mario; Papaemmanuil, Elli; Campbell, Peter J.; Boultwood, Jacqueline

    2015-01-01

    Cancer is a genetic disease, but two patients rarely have identical genotypes. Similarly, patients differ in their clinicopathological parameters, but how genotypic and phenotypic heterogeneity are interconnected is not well understood. Here we build statistical models to disentangle the effect of 12 recurrently mutated genes and 4 cytogenetic alterations on gene expression, diagnostic clinical variables and outcome in 124 patients with myelodysplastic syndromes. Overall, one or more genetic lesions correlate with expression levels of ~20% of all genes, explaining 20–65% of observed expression variability. Differential expression patterns vary between mutations and reflect the underlying biology, such as aberrant polycomb repression for ASXL1 and EZH2 mutations or perturbed gene dosage for copy-number changes. In predicting survival, genomic, transcriptomic and diagnostic clinical variables all have utility, with the largest contribution from the transcriptome. Similar observations are made on the TCGA acute myeloid leukaemia cohort, confirming the general trends reported here. PMID:25574665

  7. Gene-level integrated metric of negative selection (GIMS prioritizes candidate genes for nephrotic syndrome.

    Directory of Open Access Journals (Sweden)

    Matthew G Sampson

    Full Text Available Nephrotic syndrome (NS gene discovery efforts are now occurring in small kindreds and cohorts of sporadic cases. Power to identify causal variants in these groups beyond a statistical significance threshold is challenging due to small sample size and/or lack of family information. There is a need to develop novel methods to identify NS-associated variants. One way to determine putative functional relevance of a gene is to measure its strength of negative selection, as variants in genes under strong negative selection are more likely to be deleterious. We created a gene-level, integrated metric of negative selection (GIMS score for 20,079 genes by combining multiple comparative genomics and population genetics measures. To understand the utility of GIMS for NS gene discovery, we examined this score in a diverse set of NS-relevant gene sets. These included genes known to cause monogenic forms of NS in humans as well as genes expressed in the cells of the glomerulus and, particularly, the podocyte. We found strong negative selection in the following NS-relevant gene sets: (1 autosomal-dominant Mendelian focal segmental glomerulosclerosis (FSGS genes (p = 0.03 compared to reference, (2 glomerular expressed genes (p = 4×10(-23, and (3 predicted podocyte genes (p = 3×10(-9. Eight genes causing autosomal dominant forms of FSGS had a stronger combined score of negative selection and podocyte enrichment as compared to all other genes (p = 1 x 10(-3. As a whole, recessive FSGS genes were not enriched for negative selection. Thus, we also created a transcript-level, integrated metric of negative selection (TIMS to quantify negative selection on an isoform level. These revealed transcripts of known autosomal recessive disease-causing genes that were nonetheless under strong selection. We suggest that a filtering strategy that includes measuring negative selection on a gene or isoform level could aid in identifying NS-related genes. Our GIMS and TIMS

  8. Gene-level integrated metric of negative selection (GIMS) prioritizes candidate genes for nephrotic syndrome.

    Science.gov (United States)

    Sampson, Matthew G; Gillies, Christopher E; Ju, Wenjun; Kretzler, Matthias; Kang, Hyun Min

    2013-01-01

    Nephrotic syndrome (NS) gene discovery efforts are now occurring in small kindreds and cohorts of sporadic cases. Power to identify causal variants in these groups beyond a statistical significance threshold is challenging due to small sample size and/or lack of family information. There is a need to develop novel methods to identify NS-associated variants. One way to determine putative functional relevance of a gene is to measure its strength of negative selection, as variants in genes under strong negative selection are more likely to be deleterious. We created a gene-level, integrated metric of negative selection (GIMS) score for 20,079 genes by combining multiple comparative genomics and population genetics measures. To understand the utility of GIMS for NS gene discovery, we examined this score in a diverse set of NS-relevant gene sets. These included genes known to cause monogenic forms of NS in humans as well as genes expressed in the cells of the glomerulus and, particularly, the podocyte. We found strong negative selection in the following NS-relevant gene sets: (1) autosomal-dominant Mendelian focal segmental glomerulosclerosis (FSGS) genes (p = 0.03 compared to reference), (2) glomerular expressed genes (p = 4×10(-23)), and (3) predicted podocyte genes (p = 3×10(-9)). Eight genes causing autosomal dominant forms of FSGS had a stronger combined score of negative selection and podocyte enrichment as compared to all other genes (p = 1 x 10(-3)). As a whole, recessive FSGS genes were not enriched for negative selection. Thus, we also created a transcript-level, integrated metric of negative selection (TIMS) to quantify negative selection on an isoform level. These revealed transcripts of known autosomal recessive disease-causing genes that were nonetheless under strong selection. We suggest that a filtering strategy that includes measuring negative selection on a gene or isoform level could aid in identifying NS-related genes. Our GIMS and TIMS scores are

  9. Spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome

    Institute of Scientific and Technical Information of China (English)

    Tony M.F. Tong; Edgar W.L. Hau; Ivan F.M. Lo; Daniel H.C. Chan; Stephen T.S. Lam

    2005-01-01

    Background Sotos syndrome is an overgrowth syndrome with characteristic facial gestalt and mental retardation of variable severity. Haploinsufficiency of the NSD1 gene has been implicated as the major cause of Sotos syndrome, with a predominance of microdeletions reported in Japanese patients. This study was conducted to investigate into the spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome. Methods Thirty-six Chinese patients with Sotos syndrome and two patients with Weaver syndrome were subject to molecular testing. Results NSD1 gene mutations were detected in 26 (72%) Sotos patients. Microdeletion was found in only 3 patients, while the other 23 had point mutations (6 frameshift, 8 nonsense, 2 spice site, and 7 missense). Of these, 19 mutations were never reported. NSD1 gene mutations were not found in the two patients with Weaver syndrome. Conclusions Most cases of Sotos syndrome are caused by NSD1 gene defects, but the spectrum of mutations is different from that of Japanese patients. Genotype-phenotype correlation showed that patients with microdeletions might be more prone to congenital heart disease but less likely to have somatic overgrowth. The two patients with Weaver syndrome were not found to have NSD1 gene mutations, but the number was too small for any conclusion to be drawn.

  10. On the Work of the German-American Artist Werner Klotz

    DEFF Research Database (Denmark)

    Kacunko, Slavko

    2010-01-01

    A closer look is a must if we want to begin to appreciate the reflecting material and reflexive effect of German-American artist Werner Klotz’s array of Wahrnehmungsinstrumenten – his Instruments of Perception from today’s standpoint, better still one taken a step aside from the exploding Art...... as it was interesting then, to observe how in Werner Klotz’s oeuvre, following an artistic logic, they entered into a symbiosis with the closed-circuit video installations but have ultimately left that stage to today’s world-wide Public Art. Especially in his current public installations and projects, Werner Klotz...

  11. The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.

    Science.gov (United States)

    Baala, Lekbir; Romano, Stephane; Khaddour, Rana; Saunier, Sophie; Smith, Ursula M; Audollent, Sophie; Ozilou, Catherine; Faivre, Laurence; Laurent, Nicole; Foliguet, Bernard; Munnich, Arnold; Lyonnet, Stanislas; Salomon, Remi; Encha-Razavi, Ferechte; Gubler, Marie-Claire; Boddaert, Nathalie; de Lonlay, Pascale; Johnson, Colin A; Vekemans, Michel; Antignac, Corinne; Attie-Bitach, Tania

    2007-01-01

    Joubert syndrome (JS) is an autosomal recessive disorder characterized by cerebellar vermis hypoplasia associated with hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The association of retinal dystrophy and renal anomalies defines JS type B. JS is a genetically heterogeneous condition with mutations in two genes, AHI1 and CEP290, identified to date. In addition, NPHP1 deletions identical to those that cause juvenile nephronophthisis have been identified in a subset of patients with a mild form of cerebellar and brainstem anomaly. Occipital encephalocele and/or polydactyly have occasionally been reported in some patients with JS, and these phenotypic features can also be observed in Meckel-Gruber syndrome (MKS). 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. Since there is obvious phenotypic overlap between JS and MKS, we hypothesized that mutations in the recently identified MKS genes, MKS1 on chromosome 17q and MKS3 on 8q, may be a cause of JS. After mutation analysis of MKS1 and MKS3 in a series of patients with JS (n=22), we identified MKS3 mutations in four patients with JS, thus defining MKS3 as the sixth JS locus (JBTS6). No MKS1 mutations were identified in this series, suggesting that the allelism is restricted to MKS3.

  12. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients.

    Directory of Open Access Journals (Sweden)

    Anne M L Jansen

    Full Text Available Lynch Syndrome (LS is caused by pathogenic germline variants in one of the mismatch repair (MMR genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history.Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants.Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG. Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29% cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32% with one pathogenic somatic variant (n = 8 or one VUS predicted to be pathogenic (n = 1.This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%. In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes.

  13. Widespread DNA hypomethylation and differential gene expression in Turner syndrome

    Science.gov (United States)

    Trolle, Christian; Nielsen, Morten Muhlig; Skakkebæk, Anne; Lamy, Philippe; Vang, Søren; Hedegaard, Jakob; Nordentoft, Iver; Ørntoft, Torben Falck; Pedersen, Jakob Skou; Gravholt, Claus Højbjerg

    2016-01-01

    Adults with 45,X monosomy (Turner syndrome) reflect a surviving minority since more than 99% of fetuses with 45,X monosomy die in utero. In adulthood 45,X monosomy is associated with increased morbidity and mortality, although strikingly heterogeneous with some individuals left untouched while others suffer from cardiovascular disease, autoimmune disease and infertility. The present study investigates the leukocyte DNAmethylation profile by using the 450K-Illumina Infinium assay and the leukocyte RNA-expression profile in 45,X monosomy compared with karyotypically normal female and male controls. We present results illustrating that genome wide X-chromosome RNA-expression profile, autosomal DNA-methylation profile, and the X-chromosome methylation profile clearly distinguish Turner syndrome from controls. Our results reveal genome wide hypomethylation with most differentially methylated positions showing a medium level of methylation. Contrary to previous studies, applying a single loci specific analysis at well-defined DNA loci, our results indicate that the hypomethylation extend to repetitive elements. We describe novel candidate genes that could be involved in comorbidity in TS and explain congenital urinary malformations (PRKX), premature ovarian failure (KDM6A), and aortic aneurysm formation (ZFYVE9 and TIMP1). PMID:27687697

  14. Quantum Errors and Disturbances: Response to Busch, Lahti and Werner

    Directory of Open Access Journals (Sweden)

    David Marcus Appleby

    2016-05-01

    Full Text Available Busch, Lahti and Werner (BLW have recently criticized the operator approach to the description of quantum errors and disturbances. Their criticisms are justified to the extent that the physical meaning of the operator definitions has not hitherto been adequately explained. We rectify that omission. We then examine BLW’s criticisms in the light of our analysis. We argue that, although the BLW approach favour (based on the Wasserstein two-deviation has its uses, there are important physical situations where an operator approach is preferable. We also discuss the reason why the error-disturbance relation is still giving rise to controversies almost a century after Heisenberg first stated his microscope argument. We argue that the source of the difficulties is the problem of interpretation, which is not so wholly disconnected from experimental practicalities as is sometimes supposed.

  15. Quantum Errors and Disturbances: Response to Busch, Lahti and Werner

    Science.gov (United States)

    Appleby, David

    2016-05-01

    Busch, Lahti and Werner (BLW) have recently criticized the operator approach to the description of quantum errors and disturbances. Their criticisms are justified to the extent that the physical meaning of the operator definitions has not hitherto been adequately explained. We rectify that omission. We then examine BLW's criticisms in the light of our analysis. We argue that, although the approach BLW favour (based on the Wasserstein 2-deviation) has its uses, there are important physical situations where an operator approach is preferable. We also discuss the reason why the error-disturbance relation is still giving rise to controversies almost a century after Heisenberg first stated his microscope argument. We argue that the source of the difficulties is the problem of interpretation, which is not so wholly disconnected from experimental practicalities as is sometimes supposed.

  16. Angelman syndrome due to a novel splicing mutation of the UBE3A gene.

    Science.gov (United States)

    Sartori, Stefano; Anesi, Laura; Polli, Roberta; Toldo, Irene; Casarin, Alberto; Drigo, Paola; Murgia, Alessandra

    2008-08-01

    Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, absence of speech, seizures, abnormal electroencephalography (EEG), and happy disposition. The syndrome results from lack of function of the maternal copy of the UBE3A gene on the imprinted Prader-Willi/Angelman syndrome critical region; it is caused by large deletions, paternal uniparental disomy, imprinting center defects or UBE3A deletions, and point mutations. We found a novel splice-site mutation of the UBE3A gene in a child with clinical and EEG features of Angelman syndrome. This case further points out the fact that individuals with Angelman syndrome and mutations of the UBE3A gene have a phenotype that tends to be rather mild, however, undistinguishable, both from the clinical and the electrophysiological points of view, from the Angelman syndrome phenotype due to other known molecular mechanisms.

  17. The NF1 gene in tumor syndromes and melanoma.

    Science.gov (United States)

    Kiuru, Maija; Busam, Klaus J

    2017-02-01

    Activation of the RAS/MAPK pathway is critical in melanoma. Melanoma can be grouped into four molecular subtypes based on their main genetic driver: BRAF-mutant, NRAS-mutant, NF1-mutant, and triple wild-type tumors. The NF1 protein, neurofibromin 1, negatively regulates RAS proteins through GTPase activity. Germline mutations in NF1 cause neurofibromatosis type I, a common genetic tumor syndrome caused by dysregulation of the RAS/MAPK pathway, ie, RASopathy. Melanomas with NF1 mutations typically occur on chronically sun-exposed skin or in older individuals, show a high mutation burden, and are wild-type for BRAF and NRAS. Additionally, NF1 mutations characterize certain clinicopathologic melanoma subtypes, specifically desmoplastic melanoma. This review discusses the current knowledge of the NF1 gene and neurofibromin 1 in neurofibromatosis type I and in melanoma.

  18. Nucleolin inhibits G4 oligonucleotide unwinding by Werner helicase.

    Directory of Open Access Journals (Sweden)

    Fred E Indig

    Full Text Available BACKGROUND: The Werner protein (WRNp, a member of the RecQ helicase family, is strongly associated with the nucleolus, as is nucleolin (NCL, an important nucleolar constituent protein. Both WRNp and NCL respond to the effects of DNA damaging agents. Therefore, we have investigated if these nuclear proteins interact and if this interaction has a possible functional significance in DNA damage repair. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that WRNp interacts with the RNA-binding protein, NCL, based on immunoprecipitation, immunofluorescent co-localization in live and fixed cells, and direct binding of purified WRNp to nucleolin. We also map the binding region to the C-terminal domains of both proteins. Furthermore, treatment of U2OS cells with 15 µM of the Topoisomerase I inhibitor, camptothecin, causes the dissociation of the nucleolin-Werner complex in the nucleolus, followed by partial re-association in the nucleoplasm. Other DNA damaging agents, such as hydroxyurea, Mitomycin C, and aphidicolin do not have these effects. Nucleolin or its C-terminal fragment affected the helicase, but not the exonuclease activity of WRNp, by inhibiting WRN unwinding of G4 tetraplex DNA structures, as seen in activity assays and electrophoretic mobility shift assays (EMSA. CONCLUSIONS/SIGNIFICANCE: These data suggest that nucleolin may regulate G4 DNA unwinding by WRNp, possibly in response to certain DNA damaging agents. We postulate that the NCL-WRNp complex may contain an inactive form of WRNp, which is released from the nucleolus upon DNA damage. Then, when required, WRNp is released from inhibition and can participate in the DNA repair processes.

  19. Genetic analysis of the CHD7 gene in Korean patients with CHARGE syndrome.

    Science.gov (United States)

    Cho, Hyun-Ju; Song, Mee Hyun; Choi, Soo-Young; Kim, Jeongho; Lee, Jinwook; Kim, Un-Kyung; Bok, Jinwoong; Choi, Jae Young

    2013-04-01

    CHARGE syndrome is an autosomal dominant congenital disorder known to be caused by the haploinsufficiency of the CHD7 gene. Heterozygous mutations in the CHD7 gene have been identified in approximately 60-70% of patients clinically diagnosed with CHARGE syndrome. Although there have been many reports on the mutational spectrum of the CHD7 gene in patients with CHARGE syndrome worldwide, little is known about this syndrome in the Korean population. In this study, three Korean patients with CHARGE syndrome including one patient with Patau syndrome were evaluated for genetic analysis of the CHD7 gene using direct sequencing of all 38 exons and the flanking intronic regions. One nonsense and two novel missense mutations were identified in the CHD7 gene. Clinical symptoms caused by the missense mutations were much milder compared to the nonsense mutation, confirming the previously determined genotype-phenotype correlation in CHARGE syndrome. Our study demonstrates the importance of mutational screening of CHD7 in patients who have been diagnosed with other syndromes but display clinical features of CHARGE syndrome. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Syndromes and disorders associated with omphalocele (III): single gene disorders, neural tube defects, diaphragmatic defects and others.

    Science.gov (United States)

    Chen, Chih-Ping

    2007-06-01

    Omphalocele can be associated with single gene disorders, neural tube defects, diaphragmatic defects, fetal valproate syndrome, and syndromes of unknown etiology. This article provides a comprehensive review of omphalocele-related disorders: otopalatodigital syndrome type II; Melnick-Needles syndrome; Rieger syndrome; neural tube defects; Meckel syndrome; Shprintzen-Goldberg omphalocele syndrome; lethal omphalocele-cleft palate syndrome; cerebro-costo-mandibular syndrome; fetal valproate syndrome; Marshall-Smith syndrome; fibrochondrogenesis; hydrolethalus syndrome; Fryns syndrome; omphalocele, diaphragmatic defects, radial anomalies and various internal malformations; diaphragmatic defects, limb deficiencies and ossification defects of skull; Donnai-Barrow syndrome; CHARGE syndrome; Goltz syndrome; Carpenter syndrome; Toriello-Carey syndrome; familial omphalocele; Cornelia de Lange syndrome; C syndrome; Elejalde syndrome; Malpuech syndrome; cervical ribs, Sprengel anomaly, anal atresia and urethral obstruction; hydrocephalus with associated malformations; Kennerknecht syndrome; lymphedema, atrial septal defect and facial changes; and craniosynostosismental retardation syndrome of Lin and Gettig. Perinatal identification of omphalocele should alert one to the possibility of omphalocele-related disorders and familial inheritance and prompt a thorough genetic counseling for these disorders.

  1. Syndromes and Disorders Associated with Omphalocele (III: Single Gene Disorders, Neural Tube Defects, Diaphragmatic Defects and Others

    Directory of Open Access Journals (Sweden)

    Chih-Ping Chen

    2007-06-01

    Full Text Available Omphalocele can be associated with single gene disorders, neural tube defects, diaphragmatic defects, fetal valproate syndrome, and syndromes of unknown etiology. This article provides a comprehensive review of omphalocele-related disorders: otopalatodigital syndrome type II; Melnick–Needles syndrome; Rieger syndrome; neural tube defects; Meckel syndrome; Shprintzen–Goldberg omphalocele syndrome; lethal omphalocele-cleft palate syndrome; cerebro-costo-mandibular syndrome; fetal valproate syndrome; Marshall–Smith syndrome; fibrochondrogenesis; hydrolethalus syndrome; Fryns syndrome; omphalocele, diaphragmatic defects, radial anomalies and various internal malformations; diaphragmatic defects, limb deficiencies and ossification defects of skull; Donnai–Barrow syndrome; CHARGE syndrome; Goltz syndrome; Carpenter syndrome; Toriello–Carey syndrome; familial omphalocele; Cornelia de Lange syndrome; C syndrome; Elejalde syndrome; Malpuech syndrome; cervical ribs, Sprengel anomaly, anal atresia and urethral obstruction; hydrocephalus with associated malformations; Kennerknecht syndrome; lymphedema, atrial septal defect and facial changes; and craniosynostosis- mental retardation syndrome of Lin and Gettig. Perinatal identification of omphalocele should alert one to the possibility of omphalocele-related disorders and familial inheritance and prompt a thorough genetic counseling for these disorders.

  2. [From gene to disease; EVC, EVC2, and Ellis-van Creveld syndrome].

    Science.gov (United States)

    van Hagen, J M; Baart, J A; Gille, J J P

    2005-04-23

    Ellis-van Creveld syndrome is an autosomal recessive disorder characterised by short stature with short limbs, postaxial polydactyly and congenital cardiac defects. The syndrome can be caused by mutations in the EVC gene or the EVC2 gene. The genes are located close to each other in a head-to-head configuration on chromosome 4p16. Clinical diagnosis can be confirmed by DNA analysis, which is currently offered by two laboratories in Italy.

  3. LMNA mutations in progeroid syndromes.

    Science.gov (United States)

    Huang, Shurong; Kennedy, Brian K; Oshima, Junko

    2005-01-01

    Segmental progeroid syndromes are disorders in which affected individuals. present various features that suggest accelerated ageing. The two best-known examples are Hutchinson-Gilford progeria syndrome (HGPS, 'Progeria of childhood') and Werner syndrome (WS, 'Progeria of the adult'). A novel, recurrent de novo mutation in the LMNA gene, responsible for the majority of HGPS cases, results in an in-frame deletion of 50 amino acids, including endoproteolytic sites required for processing of prelamin A to mature lamin A protein. Another mutation results in a 35 amino acid in-frame deletion with a milder HGPS phenotype. WRN, the gene responsible for the majority of WS cases, encodes a multifunctional nuclear protein with exonuclease and helicase activities and may participate in optimizing DNA repair/recombination. A subset of WS patients do not show mutations at the WRN locus (atypical WS), but show heterozygous amino acid substitutions in the heptad repeat region of lamin A. Structural analysis suggests that mutations in atypical WS may interfere with protein-protein interactions. When compared to WRN-mutant WS, LMNA-mutant atypical WS patients appear to show earlier onset and possibly more severe ageing-related symptoms.

  4. Quantum Discord and Entanglement of Quasi-Werner States Based on Bipartite Entangled Coherent States

    Science.gov (United States)

    Mishra, Manoj K.; Maurya, Ajay K.; Prakash, Hari

    2016-06-01

    Present work is an attempt to compare quantum discord and quantum entanglement of quasi-Werner states formed with the four bipartite entangled coherent states (ECS) used recently for quantum teleportation of a qubit encoded in superposed coherent state. Out of these, the quasi-Werner states based on maximally ECS due to its invariant nature under local operation is independent of measurement basis and mean photon numbers, while for quasi-Werner states based on non-maximally ECS, it depends upon measurement basis as well as on mean photon number. However, for large mean photon numbers since non-maximally ECS becomes almost maximally entangled therefore dependence of quantum discord for non-maximally ECS based quasi-Werner states on the measurement basis disappears.

  5. ON THE CONVERGENCE OF KING-WERNER ITERATIONMETHOD IN BANACH SPACE

    Institute of Scientific and Technical Information of China (English)

    Zheng-da Huang

    2000-01-01

    In this paper , a Kantorovitch-Ostrowskitype convergence theorem and an error estimate ofusing the information of higher derivativesat the center between initial points for King-Werner iteration method in Banachspace are established.

  6. Entanglement of Formation for Werner States and Isotropic States via Logical Gates

    Science.gov (United States)

    Bertini, Cesarino; Chiara, Maria Luisa Dalla; Leporini, Roberto

    To what extent is a logical characterization of entanglement possible? We investigate some correlations that hold between the concept of entanglement of formation for Werner states and for isotropic states and the probabilistic behavior of some quantum logical gates.

  7. Severe neonatal Marfan syndrome resulting from a de novo 3-bp insertion into the fibrillin gene on chromosome 15.

    OpenAIRE

    Milewicz, D M; Duvic, M

    1994-01-01

    Severe neonatal Marfan syndrome has features of the Marfan syndrome and congenital contractural arachnodactyly present at birth, along with unique features such as loose, redundant skin and pulmonary emphysema. Since the Marfan syndrome and congenital contractural arachnodactyly are due to mutations in different genes, it has been uncertain whether neonatal Marfan syndrome is due to mutations in the fibrillin gene on chromosome 15 or in another gene. We studied an infant with severe neonatal ...

  8. Investigation of Monnose-Binding Lectin gene Polymorphism in Patients with Erythema Multiforme, Stevens-Johnson Syndrome and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Overlap Syndrome

    Directory of Open Access Journals (Sweden)

    Sevil Toka

    2012-09-01

    Full Text Available Objective: Monnose-Binding lectin (MBL appears to play an important role in the immune system. The genetic polymorphisms in the MBL2 gene can result in a reduction of serum levels, leading to a predisposition to recurrent infection. The aim of this study is to investigate the influence of a polymorphism in codon 54 of the MBL2 gene on the susceptibility to Erythema Multiforme, Stevens-Johnson Syndrome and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Overlap Syndrome (EM, SJS and SJS/TEN overlap syndrome. Material and Methods: Our study included 64 patients who were clinically and/or histopathologically diagnosed with EM, SJS, and SJS/TEN overlap syndrome and 66 healthy control subjects who were genotyped for the MBL2 gene codon 54 polymorphism using the PCR-RFLP method. For all statistical analyses, the level of significance was set at p<0.05. Results: The prevalence of the B allele was 18% in the EM, SJS and SJS/TEN patient groups and 13% in the control group. No significant differences in allele frequencies of any polymorphism were observed between the patient and control groups, although the B allele was more frequent in the patient groups (p=0.328.Conclusion: Our results provide no evidence of a relationship between MBL2 gene codon 54 polymorphism and the susceptibility to EM, SJS and SJS/TEN overlap syndrome. However, these findings should be confirmed in studies with a larger sample size.

  9. [From gene to disease; craniosynostosis syndromes due to FGFR2-mutation

    NARCIS (Netherlands)

    Ravenswaaij-Arts, C.M.A. van; Ouweland, A.M.W. van den; Hoogeboom, A.J.M.; Herbergs, J.; Pals, G.

    2002-01-01

    One of the genes involved in craniosynostosis syndromes is the fibroblast growth factor receptor 2 (FGFR2) gene, a tyrosine kinase receptor gene. Upon ligand binding the FGFR2 receptors dimerise, and this is followed by activation of the intracellular tyrosine kinase domains. This initiates a cascad

  10. Lemierre's syndrome with double heterozygote status in the methylenetetrahydrofolate reductase gene

    Institute of Scientific and Technical Information of China (English)

    Mostafa Behpour-Oskooee; Abdollah Karimi; Shirin Sayyahfar

    2014-01-01

    Background: There are some risk factors being more vulnerable to Lemierre's syndrome such as a hypercoagulable state. Methods: We report a rare case of Lemierre's syndrome with ethmoid and maxillary sinusitis, bilateral mastoiditis, and sigmoid sinus thrombosis. Results: Genetic study revealed a double heterozygote status in the methylenetetrahydrofolate reductase gene including C677T and A1298C. Conclusion: It is suggested to screen patients with Lemierre's syndrome for a hypercoagulable state to consider anticoagulant therapy.

  11. Brief Report: Aggression and Stereotypic Behavior in Males with Fragile X Syndrome-- Moderating Secondary Genes in a "Single Gene" Disorder

    Science.gov (United States)

    Hessl, David; Tassone, Flora; Cordeiro, Lisa; Koldewyn, Kami; McCormick, Carolyn; Green, Cherie; Wegelin, Jacob; Yuhas, Jennifer; Hagerman, Randi J.

    2008-01-01

    Although fragile X syndrome (FXS) is a single gene disorder with a well-described phenotype, it is not known why some individuals develop more significant maladaptive behaviors such as aggression or autistic symptoms. Here, we studied two candidate genes known to affect mood and aggression, the serotonin transporter (5-HTTLPR) and monoamine…

  12. Brief Report: Aggression and Stereotypic Behavior in Males with Fragile X Syndrome-- Moderating Secondary Genes in a "Single Gene" Disorder

    Science.gov (United States)

    Hessl, David; Tassone, Flora; Cordeiro, Lisa; Koldewyn, Kami; McCormick, Carolyn; Green, Cherie; Wegelin, Jacob; Yuhas, Jennifer; Hagerman, Randi J.

    2008-01-01

    Although fragile X syndrome (FXS) is a single gene disorder with a well-described phenotype, it is not known why some individuals develop more significant maladaptive behaviors such as aggression or autistic symptoms. Here, we studied two candidate genes known to affect mood and aggression, the serotonin transporter (5-HTTLPR) and monoamine…

  13. Genes, Brain Development and Psychiatric Phenotypes in Velo-Cardio-Facial Syndrome

    Science.gov (United States)

    Gothelf, Doron; Schaer, Marie; Eliez, Stephan

    2008-01-01

    Velo-cardio-facial syndrome (VCFS) has been in the focus of intensive research over the last 15 years. The syndrome represents a homogeneous model for studying the effect of a decreased dosage of genes on the development of brain structure and function and, consequently, on the emergence of schizophrenia-like psychotic disorder. In this review, we…

  14. Differential Impact of the "FMR1" Gene on Visual Processing in Fragile X Syndrome

    Science.gov (United States)

    Kogan, Cary S.; Boutet, Isabelle; Cornish, Kim; Zangenehpour, Shahin; Mullen, Kathy T.; Holden, Jeanette J. A.; Kaloustian, Vazken M. Der; Andermann, Eva; Chaudhuri, Avi

    2004-01-01

    Fragile X syndrome (FXS) is the most common form of heritable mental retardation, affecting (~ around) 1 in 4000 males. The syndrome arises from expansion of a trinucleotide repeat in the 5'-untranslated region of the fragile X mental retardation 1 ("FMR1") gene, leading to methylation of the promoter sequence and lack of the fragile X mental…

  15. Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies.

    Science.gov (United States)

    Guerrini, Renzo; Parrini, Elena

    2012-12-01

    Rett syndrome is an X-linked neurodevelopmental disorder that manifests in early childhood with developmental stagnation, and loss of spoken language and hand use, with the development of distinctive hand stereotypies, severe cognitive impairment, and autistic features. About 60% of patients have epilepsy. Seizure onset before the age of 3 years is unlikely, and onset after age 20 is rare. Diagnosis of Rett syndrome is based on key clinical elements that identify "typical" Rett syndrome but also "variant" or "atypical" forms. Diagnostic criteria have been modified only slightly over time, even after discovering that MECP2 gene alterations are present in >90% of patients with typical Rett syndrome but only in 50-70% of atypical cases. Over the last several years, intragenic or genomic alterations of the CDKL5 and FOXG1 genes have been associated with severe cognitive impairment, early onset epilepsy and, often, dyskinetic movement disorders, which have variably been defined as Rett variants. It is now clearly emerging that epilepsy has distinctive characteristics in typical Rett syndrome and in the different syndromes caused by CDKL5 and FOXG1 gene alterations. The progressive parting of CDKL5- and FOXG1-gene-related encephalopathies from the core Rett syndrome is reflected by the effort to produce clearer diagnostic criteria for typical and atypical Rett syndrome. Efforts to characterize the molecular pathology underlying these developmental encephalopathies are pointing to abnormalities of telencephalic development, neuronal morphogenesis, maturation and maintenance, and dendritic arborization.

  16. [Mutational analysis of the MECP2 gene by direct sequencing in Hungarian patients with Rett syndrome

    NARCIS (Netherlands)

    Karteszi, J.; Hollody, K.; Bene, J.; Morava, E.; Hadzsiev, K.; Czako, M.; Melegh, B.; Kosztolanyi, G.Y.

    2004-01-01

    INTRODUCTION: Rett syndrome is an X-linked neurodevelopmental disorder characterized by loss of acquired skills and stereotypical hand movements. Mutations in the gene encoding methyl-CpG-binding protein 2 have been identified as cause of Rett syndrome in 1999. AIM: The authors initialized mutation

  17. Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome.

    Science.gov (United States)

    Olson, Heather E; Tambunan, Dimira; LaCoursiere, Christopher; Goldenberg, Marti; Pinsky, Rebecca; Martin, Emilie; Ho, Eugenia; Khwaja, Omar; Kaufmann, Walter E; Poduri, Annapurna

    2015-09-01

    Rett syndrome and neurodevelopmental disorders with features overlapping this syndrome frequently remain unexplained in patients without clinically identified MECP2 mutations. We recruited a cohort of 11 patients with features of Rett syndrome and negative initial clinical testing for mutations in MECP2. We analyzed their phenotypes to determine whether patients met formal criteria for Rett syndrome, reviewed repeat clinical genetic testing, and performed exome sequencing of the probands. Using 2010 diagnostic criteria, three patients had classical Rett syndrome, including two for whom repeat MECP2 gene testing had identified mutations. In a patient with neonatal onset epilepsy with atypical Rett syndrome, we identified a frameshift deletion in STXBP1. Among seven patients with features of Rett syndrome not fulfilling formal diagnostic criteria, four had suspected pathogenic mutations, one each in MECP2, FOXG1, SCN8A, and IQSEC2. MECP2 mutations are highly correlated with classical Rett syndrome. Genes associated with atypical Rett syndrome, epilepsy, or intellectual disability should be considered in patients with features overlapping with Rett syndrome and negative MECP2 testing. While most of the identified mutations were apparently de novo, the SCN8A variant was inherited from an unaffected parent mosaic for the mutation, which is important to note for counseling regarding recurrence risks.

  18. Obesity and the metabolic syndrome: Impact of gene-diet interaction ...

    African Journals Online (AJOL)

    Obesity and the metabolic syndrome: Impact of gene-diet interaction. ... Individuals exposed to the same environmental risk factors or treatment strategies ... It is therefore important to know how certain genomic and lifestyle factors combine in ...

  19. Bardet-Biedl syndrome in Denmark-report of 13 novel sequence variations in six genes

    DEFF Research Database (Denmark)

    Hjortshøj, Tina Duelund; Grønskov, Karen; Philp, Alisdair R

    2010-01-01

    Bardet-Biedl syndrome (BBS) is an autosomal recessive disease characterized by retinal dystrophy, polydactyly, obesity, learning disabilities, renal involvement, and male hypogenitalism. BBS is genetically heterogeneous with mutations of 14 genes, accounting for approximately 70% of cases. Triall...

  20. A case study: neuroleptic malignant syndrome with risperidone and CYP2D6 gene variation.

    Science.gov (United States)

    Ochi, Shinichiro; Kawasoe, Koichiro; Abe, Masao; Fukuhara, Ryuji; Sonobe, Kantaro; Kawabe, Kentaro; Ueno, Shu-ichi

    2011-01-01

    We present a schizophrenic patient who experienced neuroleptic malignant syndrome with risperidone treatment due to variants of the CYP2D6 gene with reduced function. Clinicians need to be aware of this potential complication.

  1. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome.

    NARCIS (Netherlands)

    Frank, V.; Hollander, A.I. den; Bruchle, N.O.; Zonneveld, M.N.; Nurnberg, G.; Becker, C.; Bois, G. Du; Kendziorra, H.; Roosing, S.; Senderek, J.; Nurnberg, P.; Cremers, F.P.M.; Zerres, K.; Bergmann, C.

    2008-01-01

    Meckel-Gruber syndrome (MKS) is an autosomal recessive, lethal multisystemic disorder characterized by meningooccipital encephalocele, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Recently, genes for MKS1 and MKS3 were identified, putting MKS on the

  2. Distinct Gene Expression Signatures in Lynch Syndrome and Familial Colorectal Cancer Type X

    DEFF Research Database (Denmark)

    Valentin, Mev; Therkildsen, Christina; Veerla, Srinivas;

    2013-01-01

    Heredity is estimated to cause at least 20% of colorectal cancer. The hereditary nonpolyposis colorectal cancer subset is divided into Lynch syndrome and familial colorectal cancer type X (FCCTX) based on presence of mismatch repair (MMR) gene defects.......Heredity is estimated to cause at least 20% of colorectal cancer. The hereditary nonpolyposis colorectal cancer subset is divided into Lynch syndrome and familial colorectal cancer type X (FCCTX) based on presence of mismatch repair (MMR) gene defects....

  3. CAGE-defined promoter regions of the genes implicated in Rett Syndrome

    DEFF Research Database (Denmark)

    Vitezic, Morana; Bertin, Nicolas; Andersson, Robin;

    2014-01-01

    BACKGROUND: Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other...... for each gene and the common transcription factors likely to regulate the three genes. Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum CONCLUSIONS: Our analyses provide a comprehensive picture of the regulatory regions of the three genes involved in Rett...... Syndrome....

  4. [The birth of acknowledgement: Michel Foucault and Werner Leibbrand].

    Science.gov (United States)

    Mildenberger, Florian

    2006-01-01

    In 1964, Werner Leibbrand (1896-1974) was the first German medical historian to present, in Sudhoffs Archiv, a review of the work of Michel Foucault (1926-1984). This paper examines some of the reasons leading to the fact that Leibbrand's own generation refused to acknowledge the importance of Foucault's ideas, while, later on, younger German medical historians, although impressed with Foucault's writings, failed to acknowledge, first, the close relationship between Leibbrand's and Foucault's world views, and, second, Leibbrand's attempts at introducing Foucault to German medical historians. Leibbrand with his Jewish wife had survived the Nazi period partly in hiding. His attempts at clearing post-war German psychiatry and medical historiography of NS-sympathizers isolated him among his colleagues, many of whom had begun their career during the Third Reich. Leibbrand enjoyed the support by the Swiss medical historian and avowed Communist Erwin Ackerknecht (1906-1988), but later turned against him, possibly because Acknerknecht had called Leibbrand's writings "unscientific". Leibbrand was unable to overcome his antagonisms with his contemporaries. At the same time, opposition to Ackerknecht made him appear a respresentative of the past in the eyes of the younger generation. Thus, when Foucault was accepted by the latter, they were not prepared to examine the work of Leibbrand and realize how close some of the ideas developed by Leibbrand and Foucault had been.

  5. Werner Hacke:卒中治疗的先驱

    Institute of Scientific and Technical Information of China (English)

    Geoff Watts; 李兆伟(译)

    2009-01-01

    作为其所在学科的权威,Werner Hacke早年的经历可谓一波三折。尽管他后来成为了德国海德堡大学神经病学系的主任,但通往这一职位的道路并非一帆风顺,一开始就困难重重。作为一名学习不太刻苦的高中生,Hacke曾决定学习医科,希望在将来能够将行医与他唯一擅长的学科——运动——结合起来。但他的成绩不够上医学院校,因此眼完兵役后,他开始主修心理学学位。他非常喜欢这门学科,

  6. Lyman-Werner UV escape fractions from primordial haloes

    Science.gov (United States)

    Schauer, Anna T. P.; Whalen, Daniel J.; Glover, Simon C. O.; Klessen, Ralf S.

    2015-12-01

    Population III (Pop III) stars can regulate star formation in the primordial Universe in several ways. They can ionize nearby haloes, and even if their ionizing photons are trapped by their own haloes, their Lyman-Werner (LW) photons can still escape and destroy H2 in other haloes, preventing them from cooling and forming stars. LW escape fractions are thus a key parameter in cosmological simulations of early reionization and star formation but have not yet been parametrized for realistic haloes by halo or stellar mass. To do so, we perform radiation hydrodynamical simulations of LW UV escape from 9-120 M⊙ Pop III stars in 105-107 M⊙ haloes with ZEUS-MP. We find that photons in the LW lines (i.e. those responsible for destroying H2 in nearby systems) have escape fractions ranging from 0 to 85 per cent. No LW photons escape the most massive halo in our sample, even from the most massive star. Escape fractions for photons elsewhere in the 11.18-13.6 eV energy range, which can be redshifted into the LW lines at cosmological distances, are generally much higher, being above 60 per cent for all but the least massive stars in the most massive haloes. We find that shielding of H2 by neutral hydrogen, which has been neglected in most studies to date, produces escape fractions that are up to a factor of 3 smaller than those predicted by H2 self-shielding alone.

  7. Lyman-Werner UV Escape Fractions from Primordial Halos

    CERN Document Server

    Schauer, Anna T P; Glover, Simon C O; Klessen, Ralf S

    2015-01-01

    Population III stars can regulate star formation in the primordial Universe in several ways. They can ionize nearby halos, and even if their ionizing photons are trapped by their own halos, their Lyman-Werner (LW) photons can still escape and destroy H$_2$ in other halos, preventing them from cooling and forming stars. LW escape fractions are thus a key parameter in cosmological simulations of early reionization and star formation but have not yet been parametrized for realistic halos by halo or stellar mass. To do so, we perform radiation hydrodynamical simulations of LW UV escape from 9--120 M$_{\\odot}$ Pop III stars in $10^5$ to $10^7$ M$_{\\odot}$ halos with ZEUS-MP. We find that photons in the LW lines (i.e. those responsible for destroying H$_{2}$ in nearby systems) have escape fractions ranging from 0% to 85%. No LW photons escape the most massive halo in our sample, even from the most massive star. Escape fractions for photons elsewhere in the 11.18--13.6~eV energy range, which can be redshifted into t...

  8. Prenatal exclusion of von Hippel-Lindau syndrome in a Mexican family carrying a novel VHL gene mutation

    National Research Council Canada - National Science Library

    Chacón-Camacho, Oscar Francisco; Benitez-Granados, Jesús; Zenteno, Juan Carlos

    2013-01-01

    Von Hippel-Lindau syndrome is an autosomal dominant and familial multisystemic syndrome that is caused by the inactivation of the VHL gene and it is characterized by diverse types of high vasculated...

  9. Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome

    Energy Technology Data Exchange (ETDEWEB)

    Ballabio, A.; Andria, G. (Univ. of Reggio Calabria, Catanzaro (Italy)); Bardoni, B.; Fraccaro, M.; Maraschio, P.; Zuffardi, O.; Guioli, S.; Camerino, G. (Univ. of Pavia (Italy)); Carrozzo, R. (Univ. of Naples (Italy)); Bick, D.; Campbell, L. (Univ. of Texas, San Antonio (USA)); Hamel, B. (Univ. of Nijmegen (Netherlands)); Ferguson-Smith, M.A. (Univ. of Cambridge (England)); Gimelli, G. (G. Gaslini Institute, Genoa (Italy))

    1989-12-01

    Mendelian inherited disorders to deletions of adjacent genes on a chromosome have been described as contiguous gene syndromes. Short stature, chondrodysplasia punctata, mental retardation, steroid sulfatase deficiency, and Kallmann syndrome have been found as isolated entities or associated in various combination in 27 patients with interstitial and terminal deletions involving the distal short are of the X chromosome. The use of cDNA and genomic probes from the Xp22-pter region allowed us to identify 12 different deletion intervals and to confirm, and further refine, the chromosomal assignment of X-linked recessive chondrodysplasia punctata and Kallmann syndrome genes. A putative pseudoautosomal gene affecting height and an X-linked nonspecific mental retardation gene have been tentatively assigned to specific intervals. The deletion panel described is a useful tool for mapping new sequences and orienting chromosome walks in the region.

  10. Síndrome de Diógenes Diogenes syndrome

    Directory of Open Access Journals (Sweden)

    Bárbara Perdigão Stumpf

    2010-01-01

    Full Text Available A síndrome de Diógenes (SD caracteriza-se por descuido extremo com a higiene pessoal, negligência com o asseio da própria moradia, isolamento social, suspeição e comportamento paranoico, sendo frequente a ocorrência de colecionismo. A incidência anual é de 5/10.000 entre aqueles acima de 60 anos, e pelo menos a metade é portadora de demência ou algum outro transtorno psiquiátrico. As principais hipóteses etiológicas são: (1 a condição representaria o "estágio final" de um transtorno de personalidade; (2 a síndrome seria uma manifestação de demência do lobo frontal; (3 a SD seria o estágio final do subtipo hoarding do TOC; (4 a SD seria uma via final comum a diferentes transtornos psiquiátricos, especialmente aqueles associados ao colecionismo; (5 a síndrome seria precipitada por estressores biológicos, psicológicos e sociais, associados com a idade, em indivíduos com traços de personalidade predisponentes. É conhecido que existem apenas relatos de casos envolvendo tratamentos específicos para a SD, particularmente a risperidona. Por se tratar de condição grave, com elevada mortalidade por problemas clínicos, estudos se fazem necessários para determinar as melhores estratégias de abordagem desses pacientes. Os autores descrevem o caso de uma paciente com SD e fazem uma breve revisão da literatura.Diogenes syndrome (DSis characterized by extreme self-neglect, domestic squalor, social withdrawal, suspiciousness and paranoid behaviour and is often accompanied by excessive hoarding. The annual incidence is five per ten thousand of the population aged over 60, at least half of whom will have dementia or some other form of mental illness. The main etiological hypotheses are: (1 the condition represents the "end-stage" of a personality disorder; (2 the syndrome is a manifestation of a frontal-lobe dementia; (3 DS may be an end stage of the hoarding subtype of OCD; (4 DS may be a final common pathway of different

  11. Missense mutations of the fibrillin-1 gene in two Chinese patients with severe Marfan syndrome

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective To describe two Chinese patients with severe forms of Marfan syndrome and to report findings of mutational analysis of the fibrillin-1 (FBN1) gene.Methods Two Chinese patients were studied, one suffering from Marfan syndrome of infantile onset and the other of neonatal onset. Their clinical features were described. Mutational analysis of the FBN1 gene was performed using polymerase chain reaction (PCR) technique and direct sequencing of exons 23 - 32,where the mutational hotspots for severe forms of Marfan syndrome are located.Results Two missense mutations were successfully identified, a G3037A transition and an A3083T transversion, the latter being an unreported mutation.Conclusion Taking advantage of the clustering phenomenon of mutations in severe forms of Marfan syndrome, one can identify FBN1 mutations in these patients by first screening the mutational hotspots,thus reducing the effort that would otherwise be much greater because of the size of the gene.

  12. Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome.

    Science.gov (United States)

    Kress, Wolfram; Schropp, Christian; Lieb, Gabriele; Petersen, Birgit; Büsse-Ratzka, Maria; Kunz, Jürgen; Reinhart, Edeltraut; Schäfer, Wolf-Dieter; Sold, Johanna; Hoppe, Florian; Pahnke, Jan; Trusen, Andreas; Sörensen, Niels; Krauss, Jürgen; Collmann, Hartmut

    2006-01-01

    The Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with uni- or bilateral coronal synostosis and mild limb deformities. It is caused by loss-of-function mutations of the TWIST 1 gene. In an attempt to delineate functional features separating SCS from Muenke's syndrome, we screened patients presenting with coronal suture synostosis for mutations in the TWIST 1 gene, and for the Pro250Arg mutation in FGFR3. Within a total of 124 independent pedigrees, 39 (71 patients) were identified to carry 25 different mutations of TWIST 1 including 14 novel mutations, to which six whole gene deletions were added. The 71 patients were compared with 42 subjects from 24 pedigrees carrying the Pro250Arg mutation in FGFR3 and 65 subjects from 61 pedigrees without a detectable mutation. Classical SCS associated with a TWIST 1 mutation could be separated phenotypically from the Muenke phenotype on the basis of the following features: low-set frontal hairline, gross ptosis of eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and hallux valgus or broad great toe with bifid distal phalanx. Functional differences were even more important: intracranial hypertension as a consequence of early progressive multisutural fusion was a significant problem in SCS only, while mental delay and sensorineural hearing loss were associated with the Muenke's syndrome. Contrary to previous reports, SCS patients with complete loss of one TWIST allele showed normal mental development.

  13. Study of nucleophosmin (NPM) gene mutation in patients with acute myeloid leukemia and myelodysplastic syndromes

    Institute of Scientific and Technical Information of China (English)

    张悦

    2006-01-01

    Objective To investigate nucleophosmin (NPM) gene mutations in patients with de novo acute myeloid leukemia (AML) with normal cytogenetics and primary myelodysplastic syndromes (MDS). Methods Genomic DNA corresponding to exon 12 of NPM gene was amplified by polymerase chain reaction (PCR) in 40 AML patients (28 case untreated and 12 in first remission) and

  14. Mutation Analysis in WRN Gene in a Patient with Werner Syndrome accompanied by Nerve Deafness%1例伴神经性耳聋的Werner综合征患者WRN基因突变研究

    Institute of Scientific and Technical Information of China (English)

    任军; 刘晓坤; 李新生; 王晓慧; 王官清; 陈婷婷; 曾抗

    2012-01-01

    目的:检测1例伴神经性耳聋Werner综合征患者的WRN基因突变情况.方法:收集1例伴神经性耳聋Werner综合征患者及其亲属的外周血标本,提取其外周血总RNA进行RT-PCR,将cDNA产物测序;提取患者外周血基因组DNA进行PCR,将DNA产物测序验证突变,以同样方法检测其1例亲属及30例健康对照.结果:患者WRN基因发现4处碱基改变:内含子2967+237 A>G和3309+26 C>T、同义突变c.2361 G>T和c.3237 G>A.结论:该例伴神经性耳聋Werner综合征患者存在WRN基因2个内含子SNP和2个已报道cSNPs.

  15. LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation.

    Science.gov (United States)

    Blakely, Emma L; de Silva, Rajith; King, Andrew; Schwarzer, Verena; Harrower, Tim; Dawidek, Gervase; Turnbull, Douglass M; Taylor, Robert W

    2005-05-01

    Pathogenic point mutations in the mitochondrial MTND1 gene have previously been described in association with two distinct clinical phenotypes -- Leber hereditary optic neuropathy (LHON) and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Here we report the first heteroplasmic mitochondrial DNA (mtDNA) point mutation (3376G>A) in the MTND1 gene associated with an overlap syndrome comprising the clinical features of both LHON and MELAS. Muscle histochemistry revealed subtle mitochondrial abnormalities, while biochemical analysis showed an isolated complex I deficiency. Our findings serve to highlight the growing importance of mutations in mitochondrial complex I structural genes in MELAS and its associated overlap syndromes.

  16. A new gene, EVC2, is mutated in Ellis-van Creveld syndrome.

    Science.gov (United States)

    Galdzicka, M; Patnala, S; Hirshman, M G; Cai, J-F; Nitowsky, H; Egeland, J A; Ginns, E I

    2002-12-01

    Ellis-van Creveld syndrome (EvC; MIM 225500) is an autosomal recessive chondrodysplastic dwarfism. Thus far, the identified mutations in the EVC gene located on chromosome 4p16 have only accounted for illness in a small proportion of affected individuals. In this report we describe a novel gene, EVC2, that is mutated in an Ashkenazi individual with EvC syndrome. Our findings demonstrate for the first time that the heterogeneity observed in this disorder is not solely the result of mutations in a single gene.

  17. Long QT interval in Turner syndrome--a high prevalence of LQTS gene mutations.

    Directory of Open Access Journals (Sweden)

    Christian Trolle

    Full Text Available OBJECTIVES: QT-interval prolongation of unknown aetiology is common in Turner syndrome. This study set out to explore the presence of known long QT mutations in Turner syndrome and to examine the corrected QT-interval (QTc over time and relate the findings to the Turner syndrome phenotype. METHODS: Adult women with Turner syndrome (n = 88 were examined thrice and 68 age-matched healthy controls were examined once. QTc was measured by one blinded reader (intra-reader variability: 0.7%, and adjusted for influence of heart rate by Bazett's (bQTc and Hodges's formula (hQTc. The prevalence of mutations in genes related to Long QT syndrome was determined in women with Turner syndrome and a QTc >432.0 milliseconds (ms. Echocardiographic assessment of aortic valve morphology, 24-hour blood pressures and blood samples were done. RESULTS: The mean hQTc in women with Turner syndrome (414.0 ± 25.5 ms compared to controls (390.4 ± 17.8 ms was prolonged (p432 ms, 7 had mutations in major Long QT syndrome genes (SCN5A and KCNH2 and one in a minor Long QT syndrome gene (KCNE2. CONCLUSION: There is a high prevalence of mutations in the major LQTS genes in women with TS and prolonged QTc. It remains to be settled, whether these findings are related to the unexplained excess mortality in Turner women. CLINICAL TRIAL REGISTRATION: NCT00624949. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol/sid/S0001FLI/selectaction/View/ts/3/uid/U000099E.

  18. Tuberous sclerosis complex and polycystic kidney disease contiguous gene syndrome with Moyamoya disease.

    Science.gov (United States)

    Lai, Jonathan; Modi, Lopa; Ramai, Daryl; Tortora, Matthew

    2017-04-01

    Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are two diseases sharing close genetic loci on chromosome 16. Due to contiguous gene syndrome, also known as contiguous gene deletion syndrome, the proximity of TSC2 and PKD1 genes increases the risk of co-deletion resulting in a shared clinical presentation. Furthermore, Moyamoya disease (MMD) is a rare vaso-occlusive disease in the circle of Willis. We present the first case of TSC2/PKD1 contiguous gene syndrome in a patient with MMD along with detailed histopathologic, radiologic, and cytogenetic analyses. We also highlight the clinical presentation and surgical complications in this case. Copyright © 2017 Elsevier GmbH. All rights reserved.

  19. Excitation of the Werner bands of H2 by electron impact.

    Science.gov (United States)

    Stone, E. J.; Zipf, E. C.

    1972-01-01

    Absolute cross sections for the excitation of the Werner band system of molecular hydrogen have been measured from energy threshold to 300 eV for electron impact on molecular hydrogen. The bands were observed in emission in the wavelength region of 1100 to 1250 A. From a comparison of the measured cross sections with previously calculated transition probabilities, it is concluded that the Werner bands are suitable as the basis for relative spectral response calibration only when the bands are observed under sufficiently high resolution. The effect of the perturbation interaction between the B and C states of the hydrogen molecule was observed in the rotational intensity distribution of the Werner (3,7) and (3,6) bands.

  20. Marfan syndrome with a complex chromosomal rearrangement including deletion of the FBN1 gene

    Directory of Open Access Journals (Sweden)

    Colovati Mileny ES

    2012-01-01

    Full Text Available Abstract Background The majority of Marfan syndrome (MFS cases is caused by mutations in the fibrillin-1 gene (FBN1, mapped to chromosome 15q21.1. Only few reports on deletions including the whole FBN1 gene, detected by molecular cytogenetic techniques, were found in literature. Results We report here on a female patient with clinical symptoms of the MFS spectrum plus craniostenosis, hypothyroidism and intellectual deficiency who presents a 1.9 Mb deletion, including the FBN1 gene and a complex rearrangement with eight breakpoints involving chromosomes 6, 12 and 15. Discussion This is the first report of MFS with a complex chromosome rearrangement involving a deletion of FBN1 and contiguous genes. In addition to the typical clinical findings of the Marfan syndrome due to FBN1 gene haploinsufficiency, the patient presents features which may be due to the other gene deletions and possibly to the complex chromosome rearrangement.

  1. IMPACT OF ANGIOTENSIN-CONVERTING ENZYME GENE POLYMORPHISM ON THE DEVELOPMENT OF INSULIN RESISTANCE SYNDROME

    Directory of Open Access Journals (Sweden)

    G. E. Roitberg

    2014-07-01

    Full Text Available Objective: to analyze the distribution of components of insulin resistance (IR syndrome and to study the frequency of their combinations in relation to the genotypes and allelic variants of the angiotensin-converting enzyme (ACE gene.Subjects and methods. A group of clinically healthy patients (50 women and 42 men with different genotypes of the ACE gene was examined.The distribution of IR syndrome components and the frequency of their combinations were analyzed in relation to the genotypes and allelicvariants of the ACE gene.Results. A group of D allele carriers compared to A allele ones showed a pronounced tendency for the frequency of IR to reduce due to thehigher proportion of patients with complete IR syndrome. This observation becomes statistically significant in the assessment of homozygous variants of the ACE gene. At the same time dyslipidemia and hypertension in the presence of IR significantly more frequently occurred in patients with the DD genotype than in those with genotype II.Conclusion. There was a marked predominance of the manifestations of IR syndrome with a complete set of components in the DD genotypicgroup, which confirms the significant strong association between ACE gene polymorphism and IR syndrome.

  2. IMPACT OF ANGIOTENSIN-CONVERTING ENZYME GENE POLYMORPHISM ON THE DEVELOPMENT OF INSULIN RESISTANCE SYNDROME

    Directory of Open Access Journals (Sweden)

    G. E. Roitberg

    2013-01-01

    Full Text Available Objective: to analyze the distribution of components of insulin resistance (IR syndrome and to study the frequency of their combinations in relation to the genotypes and allelic variants of the angiotensin-converting enzyme (ACE gene.Subjects and methods. A group of clinically healthy patients (50 women and 42 men with different genotypes of the ACE gene was examined.The distribution of IR syndrome components and the frequency of their combinations were analyzed in relation to the genotypes and allelicvariants of the ACE gene.Results. A group of D allele carriers compared to A allele ones showed a pronounced tendency for the frequency of IR to reduce due to thehigher proportion of patients with complete IR syndrome. This observation becomes statistically significant in the assessment of homozygous variants of the ACE gene. At the same time dyslipidemia and hypertension in the presence of IR significantly more frequently occurred in patients with the DD genotype than in those with genotype II.Conclusion. There was a marked predominance of the manifestations of IR syndrome with a complete set of components in the DD genotypicgroup, which confirms the significant strong association between ACE gene polymorphism and IR syndrome.

  3. Alfred Werner's role in the mid-20th century flourishing of American inorganic chemistry.

    Science.gov (United States)

    Labinger, Jay A

    2014-01-01

    The development of organic and physical chemistry as specialist fields, during the middle and end of the 19th century respectively, left inorganic behind as a decidedly less highly regarded subfield of chemistry. Despite Alfred Werner's groundbreaking studies of coordination chemistry in the early 20th century, that inferior status remained in place - particularly in the US - until the 1950s, when the beginnings of a resurgence that eventually restored its parity with the other subfields can be clearly observed. This paper explores the extent to which Werner's heritage - both direct, in the form of academic descendants, and indirect - contributed to those advances.

  4. Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome

    DEFF Research Database (Denmark)

    Jönsson, Jenny-Maria; Bartuma, Katarina; Dominguez-Valentin, Mev

    2014-01-01

    Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer...... ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified...... for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic...

  5. Mutations of the AAAS gene in an Indian family with Allgrove's syndrome

    Institute of Scientific and Technical Information of China (English)

    Ashis Mukhopadhya; Sumita Danda; Angela Huebner; Ashok Chacko

    2006-01-01

    The triple A or Allgrove's syndrome is an autosomal recessive disorder characterized by the triad of achalasia cardia, alacrima and ACTH resistant adrenocortical insufficiency. Mutations of the Achalasia-Addisonianism-Alacrima-Syndrome (AAAS) gene on chromosome 12q13 are associated with this syndrome. We report an Indian family where two siblings were homozygous for a known mutation of the AAAS gene and presented with the classical triad of symptoms. The mother and the brother were heterozygous and asymptomatic. The affected siblings had iron deficiency anemia and the younger sister had pes cavus and palmoplantar keratosis.Neurological symptoms were absent in both affected children. Recognition of this syndrome can lead to early treatment of adrenal insufficency and genetic counselling.

  6. Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts.

    NARCIS (Netherlands)

    Barrow, L.L.; Bokhoven, J.H.L.M. van; Daack-Hirsch, S.; Andersen, T.; Beersum, S.E.C. van; Gorlin, R.; Murray, J.C.

    2002-01-01

    EEC syndrome is an autosomal dominant disorder with the cardinal signs of ectrodactyly, ectodermal dysplasia, and orofacial clefts. EEC syndrome has been linked to chromosome 3q27 and heterozygous p63 mutations were detected in unrelated EEC families. In addition, homozygous p63 null mice exhibit cr

  7. Gene expression signature of cerebellar hypoplasia in a mouse model of Down syndrome during postnatal development

    Directory of Open Access Journals (Sweden)

    Vitalis Tania

    2009-03-01

    Full Text Available Abstract Background Down syndrome is a chromosomal disorder caused by the presence of three copies of chromosome 21. The mechanisms by which this aneuploidy produces the complex and variable phenotype observed in people with Down syndrome are still under discussion. Recent studies have demonstrated an increased transcript level of the three-copy genes with some dosage compensation or amplification for a subset of them. The impact of this gene dosage effect on the whole transcriptome is still debated and longitudinal studies assessing the variability among samples, tissues and developmental stages are needed. Results We thus designed a large scale gene expression study in mice (the Ts1Cje Down syndrome mouse model in which we could measure the effects of trisomy 21 on a large number of samples (74 in total in a tissue that is affected in Down syndrome (the cerebellum and where we could quantify the defect during postnatal development in order to correlate gene expression changes to the phenotype observed. Statistical analysis of microarray data revealed a major gene dosage effect: for the three-copy genes as well as for a 2 Mb segment from mouse chromosome 12 that we show for the first time as being deleted in the Ts1Cje mice. This gene dosage effect impacts moderately on the expression of euploid genes (2.4 to 7.5% differentially expressed. Only 13 genes were significantly dysregulated in Ts1Cje mice at all four postnatal development stages studied from birth to 10 days after birth, and among them are 6 three-copy genes. The decrease in granule cell proliferation demonstrated in newborn Ts1Cje cerebellum was correlated with a major gene dosage effect on the transcriptome in dissected cerebellar external granule cell layer. Conclusion High throughput gene expression analysis in the cerebellum of a large number of samples of Ts1Cje and euploid mice has revealed a prevailing gene dosage effect on triplicated genes. Moreover using an enriched cell

  8. Could familial Mediterranean fever gene mutations be related to PFAPA syndrome?

    Science.gov (United States)

    Celiksoy, Mehmet H; Ogur, Gonul; Yaman, Elif; Abur, Ummet; Fazla, Semanur; Sancak, Recep; Yildiran, Alisan

    2016-02-01

    The cause and pathophysiology of PFAPA syndrome is unknown. The aim of this study was to determine all MEFV gene variants relevant to familial Mediterranean fever in children with PFAPA syndrome. All MEFV gene variants were analyzed in patients with PFAPA syndrome. All patients were evaluated using the Gaslini scoring system. Serum immunoglobulin levels were also determined upon admission. We evaluated 64 patients with PFAPA syndrome. The median age at diagnosis was 37.5 (min-max: 6-96) months, and the percentage of male patients was 55.0%. The Gaslini diagnostic score for periodic fever was high in 81.0% of the patients. An MEFV gene mutation was found in 42 (66.0%) children. Mostly, heterozygous or compound heterozygous variants of the MEFV gene were found. Two patients were homozygous for R202Q. MEFV gene mutations were not detected in 22 (34.0%) patients. No significant differences in clinical or laboratory findings were observed between the two groups (p > 0.05), and there were no significant differences in period and duration of the fever episodes (p > 0.05). The fever of all 47 patients (100.0%) who received prednisolone during the episodes decreased within hours and did not recur. Eighteen of the patients using prednisolone underwent prophylaxis with colchicine, and the fever episodes of 9/18 (50.0%) patients using colchicine decreased within months. Most patients presenting with PFAPA syndrome have heterozygous MEFV gene mutations. Whether carrying a heterozygous MEFV gene is the primary cause of this syndrome requires further investigation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. [MVK gene abnormality and new approach to treatment of hyper IgD syndrome and periodic fever syndrome].

    Science.gov (United States)

    Naruto, Takuya

    2007-04-01

    Hyper IgD and periodic fever syndrome (HIDS; OMIM 260920) is one of the hereditary autoinflammatory syndromes characterized by recurrent episodes of fever and inflammation.. HIDS is an autosomal recessive disorder characterized by recurrent fever attacks in early childhood. HIDS caused by mevalonate kinase (MK) mutations, also that is the gene of mevalonic aciduria (OMIM 251170). During febrile episodes, urinary mevalonate concentrations were found to be significantly elevated in patients. Diagnosis of HIDS was retrieving gene or measurement of the enzyme activity in peripheral blood lymphocyte in general. This of HIDS is an activity decline of MK, and a complete deficiency of MK becomes a mevalonic aciduria with a nervous symptom. The relation between the fever and inflammation of mevalonate or isoprenoid products are uncertain. The therapy attempt with statins, which is inhibited the next enzyme after HMG-CoA reductase, or inhibit the proinflammatory cytokines.

  10. Novel Mutation in the α-Myosin Heavy Chain Gene Is Associated With Sick Sinus Syndrome

    OpenAIRE

    Ishikawa, Taisuke; Jou, Chuanchau J.; Nogami, Akihiko; Kowase, Shinya; Arrington, Cammon B.; Barnett, Spencer M.; Harrell, Daniel T.; Arimura, Takuro; Tsuji, Yukiomi; Kimura, Akinori; Makita, Naomasa

    2015-01-01

    Recent genome-wide association studies have demonstrated an association between MYH6, the gene encoding α-myosin heavy chain (α-MHC), and sinus node function in the general population. Moreover, a rare MYH6 variant, R721W, predisposing susceptibility to sick sinus syndrome has been identified. However, the existence of disease-causing MYH6 mutations for familial sick sinus syndrome and their underlying mechanisms remain unknown. Methods and Results-We screened 9 genotype-negative probands wit...

  11. Mitchell-Riley Syndrome: A Novel Mutation in RFX6 Gene

    Directory of Open Access Journals (Sweden)

    Marta Zegre Amorim

    2015-01-01

    Full Text Available A novel RFX6 homozygous missense mutation was identified in an infant with Mitchell-Riley syndrome. The most common features of Mitchell-Riley syndrome were present, including severe neonatal diabetes associated with annular pancreas, intestinal malrotation, gallbladder agenesis, cholestatic disease, chronic diarrhea, and severe intrauterine growth restriction. Perijejunal tissue similar to pancreatic tissue was found in the submucosa, a finding that has not been previously reported in this syndrome. This case associating RFX6 mutation with structural and functional pancreatic abnormalities reinforces the RFX6 gene role in pancreas development and β-cell function, adding information to the existent mutation databases.

  12. Polymorphisms in genes RFC-1/CBS as maternal risk factors for Down syndrome in China.

    Science.gov (United States)

    Wang, Shao-shuai; Wang, Chao; Qiao, Fu-yuan; Lv, Juan-juan; Feng, Ling

    2013-08-01

    To explore the relationship between genetic polymorphisms in reduced folate carrier 1 (RFC-1), cystathionine b-synthase (CBS), two key genes in folate metabolism, and the risk of Down syndrome in China. Genomic DNA was isolated from the peripheral lymphocytes of 104 mothers born children with Down syndrome and 184 age-matched control mothers. Polymerase chain reaction and restriction-fragment length polymorphism were used to examine the polymorphisms of RFC-1 A80G, CBS T833C and the relationship between these genotypes and the risk of Down syndrome was analyzed. We found that there were significant differences between RFC-1 G80G, CBS C833C polymorphisms among mothers of children with Down syndrome than among control mothers, with odds ratio of 1.51 (95 % CI 1.05-2.18), 1.53 (95 % CI 1.07-2.18) respectively. The combined presence of RFC1 mutant alleles and the CBS homozygous mutant allele (15/104) was associated with a 4.81-fold increased risk of having a child with Down syndrome (95 % CI 1.82-12.68, P = 0.0007). We concluded that RFC-1 and CBS gene mutation alleles are related to Down syndrome, and women with mutation RFC-1 G80G, CBS C833C OR combined with RFC-1 A80G and CBS 833TT genotype increase the risk of Down syndrome in China.

  13. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome in China

    Institute of Scientific and Technical Information of China (English)

    Shao-shuai WANG; Fu-yuan QIAO; Ling FENG; Juan-juan LV

    2008-01-01

    Objective: To explore the relationship between genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), the central enzymes in folate metabolism that affects DNA methylation and synthesis, and the risk of Down syndrome in China. Methods: Genomic DNA was isolated from the peripheral lymphocytes of 64 mothers of children with Down syndrome and 70 age matched control subjects. Polymerase chain reaction and restriction fragment length polymorphism were used to examine the polymorphisms of MTHFR 677C→T, MTRR 66A→G and the relationship between these genotypes and the risk of Down syndrome was analyzed. Results: The results show that the MTHFR 677C→T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio of 3.78 (95% confidence interval (CI), 1.78~8.47). In addition, the homozygous MTRR 66A→G polymorphism was independently associated with a 5.2-fold increase in estimated risk (95% CI, 1.90~14.22). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than the presence of either alone, with an odds ratio of 6.0 (95% CI, 2.058~17.496).The two polymorphisms appear to act without a multiplicative interaction. Conclusion: MTHFR and MTRR gene mutation alleles are related to Down syndrome, and CT, TT and GG gene mutation types increase the risk of Down syndrome.

  14. Fine genetic mapping of the gene for nevoid basal cell carcinoma syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Wicking, C.; Berkman, J.; Wainwright, B. [Univ. of Queensland, Brisbane (Australia)] [and others

    1994-08-01

    Nevoid basal cell carcinoma syndrome (NBCCS, or Gorlin syndrome) is a cancer predisposition syndrome characterized by multiple basal cell carcinomas and diverse developmental defects. The gene responsible for NBCCS, which is most likely to be a tumor suppressor gene, has previously been mapped to 9q22.3-q31 in a 12-cM interval between the microsatellite marker loci D9S12.1 and D9S109. Combined multipoint and haplotype analyses of additional polymorphisms in this region in our collection of Australasian pedigrees have further refined the localization of the gene to between the markers D9S196 and D9S180, an interval reported to be approximately 2 cM. 27 refs., 4 figs., 1 tab.

  15. 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.

  16. Treating TRAPS Syndrome with a Previously Undescribed TNF α Gene Receptor Mutation Successfully with Canakinumab

    Directory of Open Access Journals (Sweden)

    T. V. Sleptsova

    2016-01-01

    Full Text Available The article presents an observation of one of the most common autoinflammatory syndromes — TRAPS (periodic syndrome associated with a mutation in the TNF α receptor gene. During a molecular-genetic examination of a 9-year-old child, a c.337_339del deletion in the heterozygous state of the TNFRSF1A gene exon 04, leading to a p.Glu113del amino acid deletion, was found. This mutation has not been described previously in TRAPS patients, and according to computer analysis (Alamut Visual the issue is pathogenic. This observation indicates the presence of families with TRAPS in the Russian population, who can have «atypical» TNFRSF1A gene mutations. A successful use of monoclonal antibodies to interleukin 1 — canakinumab — in the patient is described. As a result, fever and abdominal syndromes have completely stopped, while knee joints pain decreased a day later. After a week of treatment, the child’s disease activity laboratory indices returned to normal (ESR, C-reactive protein. No exacerbations were fixed over the next 32 weeks. No adverse effects were registered during canakinumab therapy. Thus, canakinumab has demonstrated a high level of effectiveness and safety for the patient suffering from a periodic syndrome associated with a mutation in the TNF α  gene receptor. This indicates therapeutic use prospects for the interleukin 1 β blocker in TRAPS syndrome patients.

  17. Non-syndromic retinal ciliopathies: translating gene discovery into therapy

    NARCIS (Netherlands)

    Estrada-Cuzcano, A.; Roepman, R.; Cremers, F.P.; Hollander, A.I. den; Mans, D.A.

    2012-01-01

    Homozygosity mapping and exome sequencing have accelerated the discovery of gene mutations and modifier alleles implicated in inherited retinal degeneration in humans. To date, 158 genes have been found to be mutated in individuals with retinal dystrophies. Approximately one-third of the gene defect

  18. On the Work of the German-American Artist Werner Klotz

    DEFF Research Database (Denmark)

    Kacunko, Slavko

    2010-01-01

    A closer look is a must if we want to begin to appreciate the reflecting material and reflexive effect of German-American artist Werner Klotz’s array of Wahrnehmungsinstrumenten – his Instruments of Perception from today’s standpoint, better still one taken a step aside from the exploding Art...

  19. Werner Koch Maschinenfabrik:先进的模块化辅助加工技术

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Werner Koch Maschinenfabrik拥有33年的历史,是全球知名的专业化混料、定量给料、输送、干燥系统供应商,其产品以创新、高精确度、灵活和低成本而著称。

  20. Computer Series, 85. Werner and Jorgensen: Presenting History with a Computer.

    Science.gov (United States)

    Whisnant, David M.

    1987-01-01

    Describes a computer simulation which deals with the Werner-Jorgensen controversy from the standpoint of Kuhn's description of scientific change. Encourages the use of such instructional approaches to introduce general chemistry students to the process of science, including how (1) theories develop, (2) change occurs, and (3) scientists behave.…

  1. Werner-Type Matrix Valued Rational Interpolation and Its Recurrence Algorithms

    Institute of Scientific and Technical Information of China (English)

    顾传青; 王金波

    2004-01-01

    In this paper, a practical Werner-type continued fraction method for solving matrix valued rational interpolation problem isprovided by using a generalized inverse of matrices. In order to reduce the continued fraction form to rational function form of the in-terpolants, an efficient forward recurrence algorithm is obtained.

  2. Generation of Werner-like stationary states of two qubits in a thermal reservoir

    CERN Document Server

    Jakobczyk, Lech

    2009-01-01

    The dynamics of entanglement between two-level atoms immersed in a common photon reservoir at finite temperature is investigated. It is shown that in the regime of strong correlations there are nontrivial asymptotic states which can be interpreted in terms of thermal generalization of Werner states.

  3. Gene expression analysis of induced pluripotent stem cells from aneuploid chromosomal syndromes

    Science.gov (United States)

    2013-01-01

    Background Human aneuploidy is the leading cause of early pregnancy loss, mental retardation, and multiple congenital anomalies. Due to the high mortality associated with aneuploidy, the pathophysiological mechanisms of aneuploidy syndrome remain largely unknown. Previous studies focused mostly on whether dosage compensation occurs, and the next generation transcriptomics sequencing technology RNA-seq is expected to eventually uncover the mechanisms of gene expression regulation and the related pathological phenotypes in human aneuploidy. Results Using next generation transcriptomics sequencing technology RNA-seq, we profiled the transcriptomes of four human aneuploid induced pluripotent stem cell (iPSC) lines generated from monosomy × (Turner syndrome), trisomy 8 (Warkany syndrome 2), trisomy 13 (Patau syndrome), and partial trisomy 11:22 (Emanuel syndrome) as well as two umbilical cord matrix iPSC lines as euploid controls to examine how phenotypic abnormalities develop with aberrant karyotype. A total of 466 M (50-bp) reads were obtained from the six iPSC lines, and over 13,000 mRNAs were identified by gene annotation. Global analysis of gene expression profiles and functional analysis of differentially expressed (DE) genes were implemented. Over 5000 DE genes are determined between aneuploidy and euploid iPSCs respectively while 9 KEGG pathways are overlapped enriched in four aneuploidy samples. Conclusions Our results demonstrate that the extra or missing chromosome has extensive effects on the whole transcriptome. Functional analysis of differentially expressed genes reveals that the genes most affected in aneuploid individuals are related to central nervous system development and tumorigenesis. PMID:24564826

  4. Animal models for human contiguous gene syndromes and other genomic disorders

    Directory of Open Access Journals (Sweden)

    Katherina Walz

    2004-01-01

    Full Text Available Genomic disorders refer to a group of syndromes caused by DNA rearrangements, such as deletions and duplications, which result in an alteration of normal gene dosage. The chromosomal rearrangements are usually relatively small and often difficult to detect cytogenetically. In a subset of such conditions the rearrangements comprise multiple unrelated contiguous genes that are physically linked and thus have been referred to as contiguous gene syndromes (CGS. In general, each syndrome presents a complex clinical phenotype that has been attributed generally to dosage sensitive gene(s present in the responsible chromosomal interval. A common mechanism for CGS resulting from interstitial deletion/duplication has recently been elucidated. The DNA rearrangements result from nonallelic homologous recombination (NAHR utilizing flanking low-copy repeats (LCRs as recombination substrates. The resulting rearrangements often involve the same genomic region, a common deletion or duplication, making it difficult to assign a specific phenotype or endophenotype to a single responsible gene. The human and mouse genome sequencing projects, in conjunction with the ability to engineer mouse chromosome rearrangements, have enabled the production of mouse models for CGS and genomic disorders. In this review we present an overview of different techniques utilized to generate mouse models for selected genomic disorders. These models foment novel insights into the specific genes that convey the phenotype by dosage and/or position effects and provide opportunities to explore therapeutic options.

  5. Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome.

    Science.gov (United States)

    Dong, Chen; Zhou, Hui; Shen, Chong; Yu, Lu-Gang; Ding, Yi; Zhang, Yong-Hong; Guo, Zhi-Rong

    2015-05-15

    Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are the serious public health problems worldwide. Moreover, it is estimated that MetS patients have about five-fold greater risk of the T2DM development compared with people without the syndrome. Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2DM. All three members of the peroxisome proliferator-activated receptor (PPAR) nuclear receptor subfamily, PPARα, PPARβ/δ and PPARγ are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, and blood pressure. Recently, more and more studies indicated that the gene polymorphism of PPARs, such as Leu(162)Val and Val(227)Ala of PPARα, +294T > C of PPARβ/δ, Pro(12)Ala and C1431T of PPARγ, are significantly associated with the onset and progressing of MetS and T2DM in different population worldwide. Furthermore, a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes. However, given the complexity pathogenesis of metabolic disease, it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes. Thus, gene-gene interactions and gene-environment interactions associated with T2DM and MetS need future comprehensive studies.

  6. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.

    Science.gov (United States)

    Tassabehji, M; Newton, V E; Read, A P

    1994-11-01

    Waardenburg syndrome type 2 (WS2) is a dominantly inherited syndrome of hearing loss and pigmentary disturbances. We recently mapped a WS2 gene to chromosome 3p12.3-p14.1 and proposed as a candidate gene MITF, the human homologue of the mouse microphthalmia (mi) gene. This encodes a putative basic-helix-loop-helix-leucine zipper transcription factor expressed in adult skin and in embryonic retina, otic vesicle and hair follicles. Mice carrying mi mutations show reduced pigmentation of the eyes and coat, and with some alleles, microphthalmia, hearing loss, osteopetrosis and mast cell defects. Here we show that affected individuals in two WS2 families have mutations affecting splice sites in the MITF gene.

  7. Histone Modifications Depict an Aberrantly Heterochromatinized FMR1 Gene in Fragile X Syndrome

    OpenAIRE

    Coffee, Bradford; Zhang, Fuping; Ceman, Stephanie; Warren, Stephen T.; Reines, Daniel

    2002-01-01

    Fragile X syndrome is caused by an expansion of a polymorphic CGG triplet repeat that results in silencing of FMR1 expression. This expansion triggers methylation of FMR1's CpG island, hypoacetylation of associated histones, and chromatin condensation, all characteristics of a transcriptionally inactive gene. Here, we show that there is a graded spectrum of histone H4 acetylation that is proportional to CGG repeat length and that correlates with responsiveness of the gene to DNA demethylation...

  8. Clinical features of Bloom syndrome and function of the causative gene, BLM helicase.

    Science.gov (United States)

    Kaneko, Hideo; Kondo, Naomi

    2004-05-01

    Bloom syndrome is a rare autosomal recessive genetic disorder characterized by growth deficiency, unusual facies, sun-sensitive telangiectatic erythema, immunodeficiency and predisposition to cancer. The causative gene for Bloom syndrome is BLM, which encodes the BLM RecQ helicase homolog protein. The first part of this review describes a long-term follow-up study of two Bloom syndrome siblings. Subsequently, the focus is placed on the functional domains of BLM. Laboratory diagnosis of Bloom syndrome by detecting mutations in BLM is laborious and impractical, unless there are common mutations in a population. Immunoblot and immunohistochemical analyses for the detection of the BLM protein using a polyclonal BLM antibody, which are useful approaches for clinical diagnosis of Bloom syndrome, are also described. In addition, a useful adjunct for the diagnosis of Bloom syndrome in terms of the BLM function is investigated, since disease cells must have the defective BLM helicase function. This review also discusses the nuclear localization signal of BLM, the proteins that interact with BLM and tumors originating from Bloom syndrome.

  9. Prospects for Gene Therapy in the Fragile X Syndrome

    Science.gov (United States)

    Rattazzi, Mario C.; LaFauci, Giuseppe; Brown, W. Ted

    2004-01-01

    Gene therapy is unarguably the definitive way to treat, and possibly cure, genetic diseases. A straightforward concept in theory, in practice it has proven difficult to realize, even when directed to easily accessed somatic cell systems. Gene therapy for diseases in which the central nervous system (CNS) is the target organ presents even greater…

  10. Prospects for Gene Therapy in the Fragile X Syndrome

    Science.gov (United States)

    Rattazzi, Mario C.; LaFauci, Giuseppe; Brown, W. Ted

    2004-01-01

    Gene therapy is unarguably the definitive way to treat, and possibly cure, genetic diseases. A straightforward concept in theory, in practice it has proven difficult to realize, even when directed to easily accessed somatic cell systems. Gene therapy for diseases in which the central nervous system (CNS) is the target organ presents even greater…

  11. Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome

    DEFF Research Database (Denmark)

    Drost, Mark; Lützen, Anne; van Hees, Sandrine

    2013-01-01

    In many individuals suspected of the common cancer predisposition Lynch syndrome, variants of unclear significance (VUS), rather than an obviously pathogenic mutations, are identified in one of the DNA mismatch repair (MMR) genes. The uncertainty of whether such VUS inactivate MMR, and therefore...... for the translation of personalized genomics into targeted healthcare....

  12. CAGE-defined promoter regions of the genes implicated in Rett Syndrome

    DEFF Research Database (Denmark)

    Vitezic, Morana; Bertin, Nicolas; Andersson, Robin;

    2014-01-01

    BACKGROUND: Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other...

  13. The Morquio A syndrome (mucopolysaccharidosis IVA) gene maps to 16q24. 3

    Energy Technology Data Exchange (ETDEWEB)

    Baker, E.; Xiaohui Guo; Orsborn, A.M.; Sutherland, G.R.; Callen, D.F.; Hopwood, J.J.; Morris, C.P. (Adelaide Children' s Hospital, North Adelaide (Australia))

    1993-01-01

    The gene for N-acetylgalactosamine-6-sulfatase, the deficiency of which results in Morquio A syndrome (mucopolysaccharidosis type IVA), was assigned to chromosome 16 at band q24.3 by fluorescence in situ hybridization. Localization to this band was confirmed by PCR analysis of a somatic cell hybrid panel used for fine mapping of chromosome 16. 12 refs., 1 fig., 1 tab.

  14. Gene variants of unknown clinical significance in Lynch syndrome. An introduction for clinicians

    NARCIS (Netherlands)

    Sijmons, Rolf H.; Greenblatt, Marc S.; Genuardi, Maurizio

    2013-01-01

    Clinicians referring patients for genetic testing for Lynch syndrome will sooner or later receive results for DNA Mismatch Repair (MMR) genes reporting DNA changes that are unclear from a clinical point of view. These changes are referred to as variants of unknown, or unclear, clinical significance

  15. Maternal Environment Interacts with Modifier Genes to Influence Progression of Nephrotic Syndrome

    Science.gov (United States)

    Ratelade, Julien; Lavin, Tiphaine Aguirre; Muda, Andrea Onetti; Morisset, Ludivine; Mollet, Géraldine; Boyer, Olivia; Chen, Deborah S.; Henger, Anna; Kretzler, Matthias; Hubner, Norbert; Théry, Clotilde; Gubler, Marie-Claire; Montagutelli, Xavier; Antignac, Corinne; Esquivel, Ernie L.

    2008-01-01

    Mutations in the NPHS2 gene, which encodes podocin, are responsible for some cases of sporadic and familial autosomal recessive steroid-resistant nephrotic syndrome. Inter- and intrafamilial variability in the progression of renal disease among patients bearing NPHS2 mutations suggests a potential role for modifier genes. Using a mouse model in which the podocin gene is constitutively inactivated, we sought to identify genetic determinants of the development and progression of renal disease as a result of the nephrotic syndrome. We report that the evolution of renal disease as a result of nephrotic syndrome in Nphs2-null mice depends on genetic background. Furthermore, the maternal environment significantly interacts with genetic determinants to modify survival and progression of renal disease. Quantitative trait locus mapping suggested that these genetic determinants may be encoded for by genes on the distal end of chromosome 3, which are linked to proteinuria, and on the distal end of chromosome 7, which are linked to a composite trait of urea, creatinine, and potassium. These loci demonstrate epistatic interactions with other chromosomal regions, highlighting the complex genetics of renal disease progression. In summary, constitutive inactivation of podocin models the complex interactions between maternal and genetically determined factors on the progression of renal disease as a result of nephrotic syndrome in mice. PMID:18385421

  16. Catecholamine-related gene expression in blood correlates with tic severity in tourette syndrome

    NARCIS (Netherlands)

    Gunther, Joan; Tian, Yingfang; Stamova, Boryana; Lit, Lisa; Corbett, Blythe; Ander, Brad; Zhan, Xinhua; Jickling, Glen; Bos-Veneman, Netty; Liu, Da; Hoekstra, Pieter; Sharp, Frank

    2012-01-01

    Tourette syndrome (TS) is a heritable disorder characterized by tics that are decreased in some patients by treatment with alpha adrenergic agonists and dopamine receptor blockers. Thus, this study examines the relationship between catecholamine gene expression in blood and tic severity. TS diagnosi

  17. Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome.

    NARCIS (Netherlands)

    Dauwerse, J.G.; Dixon, J.; Seland, S.; Ruivenkamp, C.A.; Haeringen, A. van; Hoefsloot, L.H.; Peters, D.J.; Boers, A.C.; Daumer-Haas, C.; Maiwald, R.; Zweier, C.; Kerr, B.; Cobo, A.M.; Toral, J.F.; Hoogeboom, A.J.M.; Lohmann, D.R.; Hehr, U.; Dixon, M.J.; Breuning, M.H.; Wieczorek, D.

    2011-01-01

    We identified a deletion of a gene encoding a subunit of RNA polymerases I and III, POLR1D, in an individual with Treacher Collins syndrome (TCS). Subsequently, we detected 20 additional heterozygous mutations of POLR1D in 252 individuals with TCS. Furthermore, we discovered mutations in both allele

  18. Gene, Brain, and Behavior Relationships in Fragile X Syndrome: Evidence from Neuroimaging Studies

    Science.gov (United States)

    Lightbody, Amy A.; Reiss, Allan L.

    2009-01-01

    Fragile X syndrome (FraX) remains the most common inherited cause of intellectual disability and provides a valuable model for studying gene-brain-behavior relationships. Over the past 15 years, structural and functional magnetic resonance imaging studies have emerged with the goal of better understanding the neural pathways contributing to the…

  19. Serotonin transporter gene polymorphisms in irritable bowel syndrome and their impact on tegaserod treatment

    Institute of Scientific and Technical Information of China (English)

    李瑜元

    2006-01-01

    Objective To investigate the serotonin reuptake transporter (SERT) genetic polymorphisms in the 5 -hydroxytryptamine (5-HT) transporter gene-linked polymorphic region (5-HTTLPR) and the variable number tandem repeats (VNTRs) in intron 2 among Chinese people, and their relationship to the pathogenesis of irritable bowel syndrome (IBS);and to investigate the im-

  20. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome.

    NARCIS (Netherlands)

    Frank, V.; Hollander, A.I. den; Bruchle, N.O.; Zonneveld, M.N.; Nurnberg, G.; Becker, C.; Bois, G. Du; Kendziorra, H.; Roosing, S.; Senderek, J.; Nurnberg, P.; Cremers, F.P.M.; Zerres, K.; Bergmann, C.

    2008-01-01

    Meckel-Gruber syndrome (MKS) is an autosomal recessive, lethal multisystemic disorder characterized by meningooccipital encephalocele, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Recently, genes for MKS1 and MKS3 were identified, putting MKS on the li

  1. Clopidogrel metabolism related gene polymorphisms in Chinese patients with acute coronary syndrome

    Institute of Scientific and Technical Information of China (English)

    冯广迅

    2013-01-01

    Objective To detect the single nucleotide polymorphisms of clopidogrel metabolism related genes(CYP2C19,ABCB1 and PON1) in Chinese patients with acute coronary syndrome(ACS) by genotype analysis. Methods Genetic analysis was performed in patients admitted to

  2. Gene, Brain, and Behavior Relationships in Fragile X Syndrome: Evidence from Neuroimaging Studies

    Science.gov (United States)

    Lightbody, Amy A.; Reiss, Allan L.

    2009-01-01

    Fragile X syndrome (FraX) remains the most common inherited cause of intellectual disability and provides a valuable model for studying gene-brain-behavior relationships. Over the past 15 years, structural and functional magnetic resonance imaging studies have emerged with the goal of better understanding the neural pathways contributing to the…

  3. Combined folate gene MTHFD and TC polymorphisms as maternal risk factors for Down syndrome in China.

    Science.gov (United States)

    Liao, Y P; Zhang, D; Zhou, W; Meng, F M; Bao, M S; Xiang, P; Liu, C Q

    2014-03-17

    We examined whether polymorphisms in the methylenetetrahydrofolate dehydrogenase (MTHFD) and transcobalamin (TC) genes, which are involved in folate metabolism, affect maternal risk for Down syndrome. We investigated 76 Down syndrome mothers and 115 control mothers from Bengbu, China. Genomic DNA was isolated from the peripheral lymphocytes. Polymerase chain reaction and restriction fragment length polymorphism were used to examine the polymorphisms of MTHFD G1958A and TC C776G. The frequencies of the polymorphic alleles were 24.3 and 19.1% for MTHFD 1958A, 53.9 and 54.2% for TC 776G, in the case and control groups, respectively. No significant differences were found between two groups in relation to either the allele or the genotype frequency for both polymorphisms. However, when gene-gene interactions between these two polymorphisms together with previous studied C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene were analyzed, the combined MTHFR 677CT/TT and MTHFD 1958AA/GA genotype was found to be significantly associated with the risk of having a Down syndrome child [odds ratio (OR) = 3.11; 95% confidence interval (95%CI) = 1.07-9.02]. In addition, the combined TC 776CG and MTHFR 677TT genotype increased the risk of having a child with Down syndrome 3.64-fold (OR = 3.64; 95%CI = 1.28-10.31). In conclusion, neither MTHFD G1958A nor TC C776G polymorphisms are an independent risk factor for Down syndrome. However, the combined MTHFD/MTHFR, TC/MTHFR genotypes play a role in the risk of bearing a Down syndrome child in the Chinese population.

  4. An atypical case of fragile X syndrome caused by a deletion that includes FMRI gene

    Energy Technology Data Exchange (ETDEWEB)

    Quan, F.; Zonana, J.; Gunter, K.; Peterson, K.L.; Magenis, R.E., Popovich, B.W. [Shriners Hospital for Crippled Children, Portland, OR (United States)

    1995-05-01

    Fragile X syndrome is the most common form of inherited mental retardation and results from the transcriptional inactivation of the FMR1 gene. In the vast majority of cases, this is caused by the expansion of an unstable CGG repeat in the first exon of the FMR1 gene. We describe here a phenotypically atypical case of fragile X syndrome, caused by a deletion that includes the entire FMR1 gene and {ge}9.0 Mb of flanking DNA. The proband, RK, was a 6-year-old mentally retarded male with obesity and anal atresia. A diagnosis of fragile X syndrome was established by the failure of RK`s DNA to hybridize to a 558-bp PstI-XhoI fragment (pfxa3) specific for the 5{prime}-end of the FMR1 gene. The analysis of flanking markers in the interval from Xq26.3-q28 indicated a deletion extending from between 160-500 kb distal and 9.0 Mb proximal to the FMR1 gene. High-resolution chromosome banding confirmed a deletion with breakpoints in Xq26.3 and Xq27.3. This deletion was maternally transmitted and arose as a new mutation on the grandpaternal X chromosome. The maternal transmission of the deletion was confirmed by FISH using a 34-kb cosmid (c31.4) containing most of the FMR1 gene. These results indicated that RK carried a deletion of the FMR1 region with the most proximal breakpoint described to date. This patient`s unusual clinical presentation may indicate the presence of genes located in the deleted interval proximal to the FMR1 locus that are able to modify the fragile X syndrome phenotype. 36 refs., 7 figs.

  5. Premature aging syndrome.

    Science.gov (United States)

    Coppedè, Fabio

    2012-01-01

    Hutchinson-Gilford progeria syndrome and Werner syndrome are two of the best characterized human progeroid diseases with clinical features mimicking physiological aging at an early age. Both disorders have been the focus of intense research in recent years since they might provide insights into the pathology of normal human aging. The chapter contains a detailed description of the clinical features of both disorders and then it focuses on the genetics, the resulting biochemical alterations at the protein level and the most recent findings and hypotheses concerning the molecular basis of the premature aging phenotypes. A description of available diagnostic and therapeutic approaches is included.

  6. GDNF Gene Is Associated With Tourette Syndrome in a Family Study

    Science.gov (United States)

    Huertas-Fernández, Ismael; Gómez-Garre, Pilar; Madruga-Garrido, Marcos; Bernal-Bernal, Inmaculada; Bonilla-Toribio, Marta; Martín-Rodríguez, Juan Francisco; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Carrillo, Fátima; Pascual, Alberto; Tischfield, Jay A.; King, Robert A.; Heiman, Gary A.; Mir, Pablo

    2016-01-01

    Background Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. Methods We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). Results The polymorphism rs3096140 in glial cell line–derived neurotrophic factor gene (GDNF) was significant in the discovery cohort after correction (P = 1.5 × 10−4). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort (P = 0.01). No association with any comorbidity was found. Conclusions As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary. PMID:26096985

  7. Identification of defects in the fibrillin gene and protein in individuals with the Marfan syndrome and related disorders.

    OpenAIRE

    Milewicz, D M

    1994-01-01

    The Marfan syndrome is an autosomal dominant disorder with pleiotropic manifestations that involve the cardiovascular, ocular, and skeletal systems. Through a number of investigational approaches, the gene encoding for fibrillin, the FBN1 gene on chromosome 15, has been identified as the defective gene causing the Marfan syndrome. Fibrillin is the large glycoprotein with a repetitive domain structure and is a major protein component of microfibrils, a fibrillar system closely associated with ...

  8. Glucagon receptor gene mutations with hyperglucagonemiabut without the glucagonoma syndrome

    Institute of Scientific and Technical Information of China (English)

    Helen C Miller; Mark Kidd; Irvin M Modlin; Patrizia Cohen; Roberto Dina; Panagiotis Drymousis; Panagiotis Vlavianos; Günter Kl?ppel; Andrea Frilling

    2015-01-01

    Pancreatic neoplasms producing exclusively glucagonassociated with glucagon cell hyperplasia of the isletsand not related to hereditary endocrine syndromes havebeen recently described. They represent a novel entitywithin the panel of non-syndromic disorders associatedwith hyperglucagonemia. This case report describesa 36-year-old female with a 10 years history of nonspecificabdominal pain. No underlying cause was evidentdespite extensive diagnostic work-up. More recentlyshe was diagnosed with gall bladder stones. Abdominalultrasound, computerised tomography and magneticresonance imaging revealed no pathologic findings apartfrom cholelithiasis. Endoscopic ultrasound revealed a 5.5mm pancreatic lesion. Fine needle aspiration showedcells focally expressing chromogranin, suggestive butnot diagnostic of a low grade neuroendocrine tumor.OctreoScan? was negative. Serum glucagon was elevatedto 66 pmol/L (normal: 0-50 pmol/L). Other gut hormones,chromogranin A and chromogranin B were normal.Cholecystectomy and enucleation of the pancreatic lesionwere undertaken. Postoperatively, abdominal symptomsresolved and serum glucagon dropped to 7 pmol/L.Although H and E staining confirmed normal pancreatictissue, immunohistochemistry was initially thought to besuggestive of alpha cell hyperplasia. A count of glucagonpositive cells from 5 islets, compared to 5 islets from 5normal pancreata indicated that islet size and glucagoncell ratios were increased, however still within the widerange of normal physiological findings. Glucagon receptorgene (GCGR) sequencing revealed a heterozygous deletion,K349_G359del and 4 missense mutations. This case may potentially represent a progenitor stage of glucagon cell adenomatosis with hyperglucagonemia in the absence of glucagonoma syndrome. The identification of novel GCGR mutations suggests that these may represent the underlying cause of this condition.

  9. [Recent advances of studies on abnormal HOX gene in myelodysplastic syndromes and its molecular mechanisms].

    Science.gov (United States)

    Xie, Xin-Yan; Shao, Zong-Hong

    2015-02-01

    HOX gene encodes a group of homeodomain transcription factors which are highly conserved. The caudal-type homeobox (CDX) , ten-eleven translocation (TET) genes and polycomb group (PcG) , trithorax group (TrxG) proteins act as upstream regulators of HOX genes that manipulate the targeted gene expression through genetic and epigenetic mechanisms. The abnormal expression of HOX genes and their fusions contribute to myelodysplastic syndromes (MDS) pathogenesis. Aberrant DNA methylation and NUP98-HOX translocation serve as molecular mediators of dysfunction in MDS which can be used for the evaluation of biology and therapy. This article provides an overview of recent advances of studies on HOX gene and its abnormal molecular mechanisms, as well as potential correlation with MDS.

  10. A PAIDERASTIA SOB O HISTORICISMO DE WERNER JAEGER. (Dossiê: O Mundo Antigo: Literatura e Historiografia

    Directory of Open Access Journals (Sweden)

    Daniel Barbo

    2015-09-01

    Full Text Available Resumo: Este texto faz uma análise do modo historicista com que o historiador alemão Werner Jaeger, nas décadas de 1930 e 1940, aborda o homoerotismo grego (paiderastia e sua relação com a pedagogia em sua obra Paidéia, a formação do homem grego. Palavras-Chave: Homoerotismo Grego, Historicismo, Werner Jaeger Abstract: This text analyzes the historicist manner with which the German historian Werner Jaeger, in the 1930s and 1940s, addresses the Greek homoeroticism (paiderastia and its relation to pedagogy in his work Paideia, the ideals of the Greek culture. Keywords: Greek Homoerotiscism, Historicism, Werner Jaeger Recebido em: 069/08/2015  – Aceito em 10/09/2015

  11. Ghrelin receptor gene polymorphisms are associated with female metabolic syndrome in Chinese population

    Institute of Scientific and Technical Information of China (English)

    LI Wei-ju; ZHEN Yi-song; SUN Kai; XUE Hao; SONG Xiao-dong; WANG Yi-bo; FAN Xiao-han; HAN Yun-feng; HUI Ru-tai

    2008-01-01

    Background The ghrelin plays an important role in the regulation of food intake and energy homeostasis.Therefore,the ghrelin receptor gene (GHSR) is an excellent candidate for studying metabolic syndrome.This study aimed to investigate whether polymorphisms in ghrelin receptor gene are associated with metabolic syndrome in Chinese population.Methods Subjects consisted of 698 patients aged 41 to 80 years,diagnosed as metabolic syndrome by International Diabetes Federation (IDF) 2005 criteria,and 762 age-and gender-matched controls.Three variants within the GHSR were selected and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP).Odds ratios were estimated using a case-control study design by controlling confounding factors.Results The NA genotype (rs2922126) in the promoter was associated with metabolic syndrome (OR 1.41,95%CI 1.03-1.94),increased waist circumference (OR 1.75,95%CI 1.26-2.42),and increased fast blood glucose (OR 1.49,95%CI 1.07-2.06) in women.The A/A genotype (rs509030) in the intron was associated with lower plasma high density lipoprotein in women (OR 1.37,95%CI 1.02-1.84).Conclusion The polymorphisms within GHSR might be a genetic risk factor for metabolic syndrome in women.

  12. Three cases with L1 syndrome and two novel mutations in the L1CAM gene.

    Science.gov (United States)

    Marín, Rosario; Ley-Martos, Miriam; Gutiérrez, Gema; Rodríguez-Sánchez, Felicidad; Arroyo, Diego; Mora-López, Francisco

    2015-11-01

    Mutations in the L1CAM gene have been identified in the following various X-linked neurological disorders: congenital hydrocephalus; mental retardation, aphasia, shuffling gait, and adducted thumbs (MASA) syndrome; spastic paraplegia; and agenesis of the corpus callosum. These conditions are currently considered different phenotypes of a single entity known as L1 syndrome. We present three families with L1 syndrome. Sequencing of the L1CAM gene allowed the identification of the following mutations involved: a known splicing mutation (c.3531-12G>A) and two novel ones: a missense mutation (c.1754A>C; p.Asp585Ala) and a nonsense mutation (c.3478C>T; p.Gln1160Stop). The number of affected males and carrier females identified in a relatively small population suggests that L1 syndrome may be under-diagnosed. L1 syndrome should be considered in the differential diagnosis of intellectual disability or mental retardation in children, especially when other signs such as hydrocephalus or adducted thumbs are present.

  13. The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16

    Energy Technology Data Exchange (ETDEWEB)

    Polymeropoulos, M.H.; Ide, S.E. [National Institute of Health, Bethesda, MD (United States); Wright, M. [Univ. of Newcastle Upon Tyne (United Kingdom)] [and others

    1996-07-01

    Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by disproportionate dwarfism, polydactyly, and congenital heart disease. This rare disorder is found with increased frequency among the Old Order Amish community in Lancaster County, Pennsylvania. We have used linkage analysis to localize the gene responsible for the EVC phenotype in nine interrelated Amish pedigrees and three unrelated families from Mexico, Ecuador, and Brazil. We now report the linkage for the Ellisvan Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Z{sub max} = 6.91 at {theta} = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype. 17 refs., 2 figs., 1 tab.

  14. The pink gene encodes the Drosophila orthologue of the human Hermansky-Pudlak syndrome 5 (HPS5) gene.

    Science.gov (United States)

    Syrzycka, Monika; McEachern, Lori A; Kinneard, Jennifer; Prabhu, Kristel; Fitzpatrick, Kathleen; Schulze, Sandra; Rawls, John M; Lloyd, Vett K; Sinclair, Donald A R; Honda, Barry M

    2007-06-01

    Hermansky-Pudlak syndrome (HPS) consists of a set of human autosomal recessive disorders, with symptoms resulting from defects in genes required for protein trafficking in lysosome-related organelles such as melanosomes and platelet dense granules. A number of human HPS genes and rodent orthologues have been identified whose protein products are key components of 1 of 4 different protein complexes (AP-3 or BLOC-1, -2, and -3) that are key participants in the process. Drosophila melanogaster has been a key model organism in demonstrating the in vivo significance of many genes involved in protein trafficking pathways; for example, mutations in the "granule group" genes lead to changes in eye colour arising from improper protein trafficking to pigment granules in the developing eye. An examination of the chromosomal positioning of Drosophila HPS gene orthologues suggested that CG9770, the Drosophila HPS5 orthologue, might correspond to the pink locus. Here we confirm this gene assignment, making pink the first eye colour gene in flies to be identified as a BLOC complex gene.

  15. Heterochromatic Genes Undergo Epigenetic Changes and Escape Silencing in Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) Syndrome

    Science.gov (United States)

    Brun, Marie-Elisabeth; Lana, Erica; Rivals, Isabelle; Lefranc, Gérard; Sarda, Pierre; Claustres, Mireille; Mégarbané, André; De Sario, Albertina

    2011-01-01

    Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) syndrome is a rare autosomal recessive disorder that is characterized by a marked immunodeficiency, severe hypomethylation of the classical satellites 2 and 3 associated with disruption of constitutive heterochromatin, and facial anomalies. Sixty percent of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In the present study, we have shown that, in ICF lymphoblasts and peripheral blood, juxtacentromeric heterochromatic genes undergo dramatic changes in DNA methylation, indicating that they are bona fide targets of the DNMT3B protein. DNA methylation in heterochromatic genes dropped from about 80% in normal cells to approximately 30% in ICF cells. Hypomethylation was observed in five ICF patients and was associated with activation of these silent genes. Although DNA hypomethylation occurred in all the analyzed heterochromatic genes and in all the ICF patients, gene expression was restricted to some genes, every patient having his own group of activated genes. Histone modifications were preserved in ICF patients. Heterochromatic genes were associated with histone modifications that are typical of inactive chromatin: they had low acetylation on H3 and H4 histones and were slightly enriched in H3K9Me3, both in ICF and controls. This was also the case for those heterochromatic genes that escaped silencing. This finding suggests that gene activation was not generalized to all the cells, but rather was restricted to a clonal cell population that may contribute to the phenotypic variability observed in ICF syndrome. A slight increase in H3K27 monomethylation was observed both in heterochromatin and active euchromatin in ICF patients; however, no correlation between this modification and activation of heterochromatic genes was found. PMID:21559330

  16. Heterochromatic genes undergo epigenetic changes and escape silencing in immunodeficiency, centromeric instability, facial anomalies (ICF syndrome.

    Directory of Open Access Journals (Sweden)

    Marie-Elisabeth Brun

    Full Text Available Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF syndrome is a rare autosomal recessive disorder that is characterized by a marked immunodeficiency, severe hypomethylation of the classical satellites 2 and 3 associated with disruption of constitutive heterochromatin, and facial anomalies. Sixty percent of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B gene, encoding a de novo DNA methyltransferase. In the present study, we have shown that, in ICF lymphoblasts and peripheral blood, juxtacentromeric heterochromatic genes undergo dramatic changes in DNA methylation, indicating that they are bona fide targets of the DNMT3B protein. DNA methylation in heterochromatic genes dropped from about 80% in normal cells to approximately 30% in ICF cells. Hypomethylation was observed in five ICF patients and was associated with activation of these silent genes. Although DNA hypomethylation occurred in all the analyzed heterochromatic genes and in all the ICF patients, gene expression was restricted to some genes, every patient having his own group of activated genes. Histone modifications were preserved in ICF patients. Heterochromatic genes were associated with histone modifications that are typical of inactive chromatin: they had low acetylation on H3 and H4 histones and were slightly enriched in H3K9Me(3, both in ICF and controls. This was also the case for those heterochromatic genes that escaped silencing. This finding suggests that gene activation was not generalized to all the cells, but rather was restricted to a clonal cell population that may contribute to the phenotypic variability observed in ICF syndrome. A slight increase in H3K27 monomethylation was observed both in heterochromatin and active euchromatin in ICF patients; however, no correlation between this modification and activation of heterochromatic genes was found.

  17. Treacher Collins syndrome with a de Novo 5-bp deletion in the TCOF1 gene.

    Science.gov (United States)

    Su, Pen-Hua; Chen, Jia-Yu; Chen, Suh-Jen; Yu, Ju-Shan

    2006-06-01

    Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development with features including malar hypoplasia, micrognathia, microtia, downward slanting palpebral fissures, lower eyelid coloboma, conductive hearing loss, and cleft palate. TCS is caused by mutations in the TCOF1 gene, which encodes the nuclear phosphoprotein treacle. Here, we describe a 1-day-old male infant with classical TCS presentation. A 5-bp deletion in exon 22 of the TCOF1 gene (3469del ACTCT) was found to cause a premature stop codon. This is the first report of TCOF1 gene mutation in the Taiwanese population.

  18. Hirschsprung disease in an infant with a contiguous gene syndrome of chromosome 13.

    Science.gov (United States)

    Shanske, A; Ferreira, J C; Leonard, J C; Fuller, P; Marion, R W

    2001-08-15

    Hirschsprung disease is a developmental disorder resulting from the arrest of the craniocaudal migration of enteric neurons from the neural crest along gastrointestinal segments of variable length; see Behrman [Nelson textbook of pediatrics, 1992:954-956]. It is a heterogeneous disorder in which familial cases map to at least three loci whose function is necessary for normal neural crest-derived cell development. Homozygous mutations in the endothelin-B receptor gene (EDNRB) on 13q22 have been identified in humans and mice with Hirschsprung disease type 2 (HSCR2). The auditory pigmentary disorder, Waardenburg-Shah syndrome, comprises Waardenburg syndrome and Hirschsprung disease and has also been mapped to the EDNRB locus. Hirschsprung disease, malrotation, isochromia, a profound sensorineural hearing loss, and several other anomalies were found in an infant with an interstitial deletion of 13q, suggesting the existence of a contiguous gene syndrome involving developmental genes necessary for the normal growth of the neural crest derivatives of the eye, inner ear, and colon. We report on an additional patient with a deletion in 13q and Hirschsprung disease. Congenital anomalies associated with deletions of the distal long arm of chromosome 13 are sufficiently consistent to suggest a clinical syndrome.

  19. Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly

    DEFF Research Database (Denmark)

    Møller, Rikke S; Kübart, Sabine; Hoeltzenbein, Maria;

    2008-01-01

    .2. DYRK1A belongs to the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family, which is highly conserved throughout evolution. Given its localization in both the Down syndrome critical region and in the minimal region for partial monosomy 21, the gene has been studied intensively...... in animals and in humans, and DYRK1A has been proposed to be involved in the neurodevelopmental alterations associated with these syndromes. In the present study, we show that truncating mutations of DYRK1A result in a clinical phenotype including microcephaly....

  20. Large deletions encompassing the TCOF1 and CAMK2A genes are responsible for Treacher Collins syndrome with intellectual disability.

    Science.gov (United States)

    Vincent, Marie; Collet, Corinne; Verloes, Alain; Lambert, Laetitia; Herlin, Christian; Blanchet, Catherine; Sanchez, Elodie; Drunat, Séverine; Vigneron, Jacqueline; Laplanche, Jean-Louis; Puechberty, Jacques; Sarda, Pierre; Geneviève, David

    2014-01-01

    Mandibulofacial dysostosis is part of a clinically and genetically heterogeneous group of disorders of craniofacial development, which lead to malar and mandibular hypoplasia. Treacher Collins syndrome is the major cause of mandibulofacial dysostosis and is due to mutations in the TCOF1 gene. Usually patients with Treacher Collins syndrome do not present with intellectual disability. Recently, the EFTUD2 gene was identified in patients with mandibulofacial dysostosis associated with microcephaly, intellectual disability and esophageal atresia. We report on two patients presenting with mandibulofacial dysostosis characteristic of Treacher Collins syndrome, but associated with unexpected intellectual disability, due to a large deletion encompassing several genes including the TCOF1 gene. We discuss the involvement of the other deleted genes such as CAMK2A or SLC6A7 in the cognitive development delay of the patients reported, and we propose the systematic investigation for 5q32 deletion when intellectual disability is associated with Treacher Collins syndrome.

  1. Heinz Werner: His Life, Ideas, and Contributions to Developmental Psychology in the First Half of the 20th Century.

    Science.gov (United States)

    Ostler, Teresa

    2016-01-01

    The author provides an overview of Heinz Werner's life and contributions to the field of developmental psychology during the first half of the 20th century. She focuses on his early work in Vienna and Munich as well as his tenure at the Psychological Institute in Hamburg, up through the time when he became a named Professor in Psychology at Clark University. Recognized as one of the founders of developmental psychology, Heinz Werner worked in the areas of perceptual development, comparative psychology, and symbol formation. Versatile in rigorous experimental methodologies, and in observational and phenomenological methodologies, Werner's approach to development stood in contrast to other approaches of development, both past and current. For Werner, development was a heuristic, a way of looking at processes in a variety of domains, including ontogeny, phylogeny, microgenesis, biology, developmental psychopathology, neuropsychology, and comparative psychology. Werner viewed development as proceeding from a state of relative globality and lack of differentiation to a state of increasing differentiation, articulation, and hierarchical integration, but he also stressed that individuals can function at different developmental levels under different times and conditions. Werner's holistic, organismic, comparative, and contextual approach to development transcended interdisciplinary boundaries, allowing him to study the interrelatedness between thought, language, feeling, perception, and culture.

  2. Severe neonatal Marfan syndrome resulting from a de novo 3-bp insertion into the fibrillin gene on chromosome 15.

    Science.gov (United States)

    Milewicz, D. M.; Duvic, M.

    1994-01-01

    Severe neonatal Marfan syndrome has features of the Marfan syndrome and congenital contractural arachnodactyly present at birth, along with unique features such as loose, redundant skin and pulmonary emphysema. Since the Marfan syndrome and congenital contractural arachnodactyly are due to mutations in different genes, it has been uncertain whether neonatal Marfan syndrome is due to mutations in the fibrillin gene on chromosome 15 or in another gene. We studied an infant with severe neonatal Marfan syndrome. Dermal fibroblasts were metabolically labeled and found to secret fibrillin inefficiently when compared with control cells. Reverse transcription and amplification of the proband's fibroblast RNA was used to identify a 3-bp insertion between nucleotides 480-481 or 481-482 of the fibrillin cDNA. The insertion maintains the reading frame of the protein and inserts a cysteine between amino acids 160 and 161 in an epidermal growth-factor-like motif of fibrillin. This 3-bp insertion was not found in the fibrillin gene in 70 unrelated, unaffected individuals and 11 unrelated individuals with the Marfan syndrome. We conclude that neonatal Marfan syndrome is the result of mutations in the fibrillin gene on chromosome 15 and is part of the Marfan syndrome spectrum. Images Figure 1 Figure 2 Figure 3 PMID:8116614

  3. Severe neonatal marfan syndrome resulting from a De Novo 3-bp insertion into the fibrillin gene on chromosome 15

    Energy Technology Data Exchange (ETDEWEB)

    Milewicz, D.M.; Duvic, M. (Univ. of Texas Medical School, Houston, TX (United States))

    1994-03-01

    Severe neonatal Marfan syndrome has features of the Marfan syndrome and congenital contractural arachnodactyly present at birth, along with unique features such as loose, redundant skin and pulmonary emphysema. Since the Marfan syndrome and congenital contractural arachnodactyly are due to mutations in different genes, it has been uncertain whether neonatal Marfan syndrome is due to mutations in the fibrillin gene on chromosome 15 or in another gene. The authors studied an infant with severe neonatal Marfan syndrome. Dermal fibroblasts were metabolically labeled and found to secrete fibrillin inefficiently when compared with control cells. Reverse transcription and amplification of the proband's fibroblast RNA was used to identify a 3-bp insertion between nucleotides 480-481 or 481-482 of the fibrillin cDNA. The insertion maintains the reading frame of the protein and inserts a cysteine between amino acids 160 and 161 in an epidermal growth-factor-like motif of fibrillin. This 3-bp insertion was not found in the fibrillin gene in 70 unrelated, unaffected individuals and 11 unrelated individuals with the Maran syndrome. The authors conclude that neonatal Marfan syndrome is the result of mutations in the fibrillin gene on chromosome 15 and is part of the Marfan syndrome spectrum. 32 refs., 3 figs.

  4. Analysis of Polymorphism of Angiotensin System Genes (ACE, AGTR1, and AGT) and Gene ITGB3 in Patients with Arterial Hypertension in Combination with Metabolic Syndrome.

    Science.gov (United States)

    Zotova, T Yu; Kubanova, A P; Azova, M M; Aissa, A Ait; Gigani, O O; Frolov, V A

    2016-07-01

    Changes in the frequencies of genotypes and mutant alleles of ACE, AGTR1, AGT, and ITGB3 genes were analyzed in patients with arterial hypertension coupled with metabolic syndrome (N=15) and compared with population data and corresponding parameters in patients with isolated hypertension (N=15). Increased frequency of genotype ID of ACE gene (hypertension predictor) was confirmed for both groups. In case of isolated hypertension, M235M genotype (gene AGT) was more frequent, in case of hypertension combined with metabolic syndrome, the frequency of genotypes A1166C and C1166C of the gene AGTR1 was higher in comparison with population data. Comparison of mutant allele frequencies in the two groups showed that at the 90% significance level allele T of the AGT gene was more frequent in hypertension coupled with metabolic syndrome (OR=1.26) and genotype A1166A of the AGTR1 gene was more frequent in the group with isolated hypertension.

  5. STUDIES ON PATHOGENESIS OF WAARDENBURG SYNDROME TYPE ⅡAND TIETZ SYNDROME RESULTING FROM MITF GENE MUTATIONS

    Institute of Scientific and Technical Information of China (English)

    ZHANG Hua; LI Jiada; LUO Hunjin; CHEN Hongsheng; MEI Lingyun; HE Chufeng; JIANG Lu; FENG Yong

    2013-01-01

    Microphthalmia-associated transcription factor (MITF) controls melanocyte survival and differentiation through directly regulating the expression of the tyrosinase (TYR) and tyrosinase-related proteins 1 and 2 (TYRP1 and TYRP2) genes. MITF mutations have been reported to result in an abnormal melanocyte devel-opment and lead to Waardenburg syndrome type 2 (WS2), characterized by variable degrees of sensorineu-ral hearing loss and patchy regional distribution of hypopigmentation. Recently, MITF was also indicated as a causative gene for a more severe syndrome, the Tietz Syndrome (TS), characterized by generalized hy-popigmentation and complete hearing loss. However, few functional studies have been performed to com-pare the diseases-causing mutations. Here, we analyzed the in vitro activity of two recent identified WS2-as-sociated mutation (p.R217I and p.T192fsX18) and one TS-associated mutation p.N210K. The R217I MITF retained partial activity, normal DNA-binding ability and nuclear distribution, whereas the T192fsX18 MITF failed to activate TYR promoter due to loss of DNA-binding activity, and aberrant subcellular localization. The aberrant subcellular localization of T192fsX18 MITF may be caused by deletion of a putative nuclear localization signal (NLS) at aa 213-218 (ERRRRF). Indeed, MITF with deletion of the NLS fragment failed to translocate into the nucleus and activated the TYR promoter. Tagging this NLS to GFP promoted the green fluorescence protein (GFP) translocated into the nucleus. The surprising finding of our study is that a TS-as-sociated MITF mutation, N210K, showed comparable in vitro activity as WT. Thus, the possible involve-ment of MITF in TS and its underlying mechanisms still need further investigation.

  6. Quantum information transmission in the quantum wireless multihop network based on Werner state

    Science.gov (United States)

    Shi, Li-Hui; Yu, Xu-Tao; Cai, Xiao-Fei; Gong, Yan-Xiao; Zhang, Zai-Chen

    2015-05-01

    Many previous studies about teleportation are based on pure state. Study of quantum channel as mixed state is more realistic but complicated as pure states degenerate into mixed states by interaction with environment, and the Werner state plays an important role in the study of the mixed state. In this paper, the quantum wireless multihop network is proposed and the information is transmitted hop by hop through teleportation. We deduce a specific expression of the recovered state not only after one-hop teleportation but also across multiple intermediate nodes based on Werner state in a quantum wireless multihop network. We also obtain the fidelity of multihop teleportation. Project supported by the Prospective Future Network Project of Jiangsu Province, China (Grant No. BY2013095-1-18) and the Independent Project of State Key Laboratory of Millimeter Waves (Grant No. Z201504).

  7. Identification of defects in the fibrillin gene and protein in individuals with the Marfan syndrome and related disorders.

    Science.gov (United States)

    Milewicz, D M

    1994-01-01

    The Marfan syndrome is an autosomal dominant disorder with pleiotropic manifestations that involve the cardiovascular, ocular, and skeletal systems. Through a number of investigational approaches, the gene encoding for fibrillin, the FBN1 gene on chromosome 15, has been identified as the defective gene causing the Marfan syndrome. Fibrillin is the large glycoprotein with a repetitive domain structure and is a major protein component of microfibrils, a fibrillar system closely associated with elastin in connective tissue. Mutational analysis of defects in the FBN1 gene in patients with the Marfan syndrome has revealed that most mutations are private or unique in an affected individual or family. Analysis of fibrillin protein or gene defects in individuals with related phenotypes has revealed that a perinatal lethal syndrome, termed neonatal Marfan syndrome, is due to FBN1 gene mutations. In addition, fibroblast cell strains from a subset of patients with idiopathic scoliosis have fibrillin protein defects. Last, fibroblasts from calves affected with bovine Marfan syndrome display defects in the fibrillin protein. These studies have wide-ranging implications in the diagnosis, treatment, and prevention of Marfan syndrome and related disorders. Images PMID:8180508

  8. Identification of the immediate-early genes of white spot syndrome virus.

    Science.gov (United States)

    Li, Fang; Li, Mingyuan; Ke, Wei; Ji, Yongchang; Bian, Xiaofang; Yan, Xiumin

    2009-03-01

    During viral infection, viral immediate-early (IE) genes encode regulatory proteins critical for the viral life cycle. Here we screened white spot syndrome virus (WSSV) IE genes with cycloheximide (CHX)-treated primary culture of crayfish hemocyte and a WSSV genome tiling microarray. Sixteen ORFs, including a known WSSV IE gene (ie1/wsv069), were identified and confirmed by RT-PCR and time course studies. The 16 identified IE proteins contain four proteins (wsv051, wsv069, wsv100, wsv079) with transcription activity, one (wsv083) with Ser/Thr kinase domain and one (wsv249) previously described to function as an ubiquitin E3 ligase. Furthermore, most of the identified WSSV IE genes cluster in a 14 kb genomic region (WSSV China isolate: 36,052 to 50,300 bp). This type of arrangement may facilitate the coordinate control and rapid expression of IE genes.

  9. Molecular analysis of genes on Xp controlling Turner syndrome and premature ovarian failure (POF).

    Science.gov (United States)

    Zinn, A R; Ross, J L

    2001-06-01

    Monosomy X has been known to be the chromosomal basis of Turner syndrome (TS) for more than four decades. A large body of cytogenetic data indicates that most TS features are due to reduced dosage of genes on the short arm of the X chromosome (Xp). Phenotype mapping studies using molecular cytogenetic and genetic techniques are beginning to localize the Xp genes that are important for various TS features, and a comprehensive catalog of candidate genes is becoming available through the Human Genome Project and related research. It is now possible to assess the contributions of individual genes to the TS phenotype by mutational analysis of karyotypically normal persons with specific TS features. This strategy has succeeded in identifying a gene involved in short stature and is being applied to premature ovarian failure and other TS phenotypes.

  10. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome.

    Science.gov (United States)

    Aiuti, Alessandro; Biasco, Luca; Scaramuzza, Samantha; Ferrua, Francesca; Cicalese, Maria Pia; Baricordi, Cristina; Dionisio, Francesca; Calabria, Andrea; Giannelli, Stefania; Castiello, Maria Carmina; Bosticardo, Marita; Evangelio, Costanza; Assanelli, Andrea; Casiraghi, Miriam; Di Nunzio, Sara; Callegaro, Luciano; Benati, Claudia; Rizzardi, Paolo; Pellin, Danilo; Di Serio, Clelia; Schmidt, Manfred; Von Kalle, Christof; Gardner, Jason; Mehta, Nalini; Neduva, Victor; Dow, David J; Galy, Anne; Miniero, Roberto; Finocchi, Andrea; Metin, Ayse; Banerjee, Pinaki P; Orange, Jordan S; Galimberti, Stefania; Valsecchi, Maria Grazia; Biffi, Alessandra; Montini, Eugenio; Villa, Anna; Ciceri, Fabio; Roncarolo, Maria Grazia; Naldini, Luigi

    2013-08-23

    Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.

  11. Neurodevelopmental Disorders Associated with Abnormal Gene Dosage: Smith-Magenis and Potocki-Lupski Syndromes.

    Science.gov (United States)

    Neira-Fresneda, Juanita; Potocki, Lorraine

    2015-09-01

    Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal contiguous gene syndromes within the well-characterized 17p11.2 region. Approximately 3.6 Mb microduplication of 17p11.2, known as PTLS, represents the mechanistically predicted homologous recombination reciprocal of the SMS microdeletion, both resulting in multiple congenital anomalies. Mouse model studies have revealed that the retinoic acid-inducible 1 gene (RAI1) within the SMS and PTLS critical genomic interval is the dosage-sensitive gene responsible for the major phenotypic features in these disorders. Even though PTLS and SMS share the same genomic region, clinical manifestations and behavioral issues are distinct and in fact some mirror traits may be on opposite ends of a given phenotypic spectrum. We describe the neurobehavioral phenotypes of SMS and PTLS patients during different life phases as well as clinical guidelines for diagnosis and a multidisciplinary approach once diagnosis is confirmed by array comparative genomic hybridization or RAI1 gene sequencing. The main goal is to increase awareness of these rare disorders because an earlier diagnosis will lead to more timely developmental intervention and medical management which will improve clinical outcome.

  12. Neurodevelopmental Disorders Associated with Abnormal Gene Dosage: Smith–Magenis and Potocki–Lupski Syndromes

    Science.gov (United States)

    Neira-Fresneda, Juanita; Potocki, Lorraine

    2015-01-01

    Smith–Magenis syndrome (SMS) and Potocki–Lupski syndrome (PTLS) are reciprocal contiguous gene syndromes within the well-characterized 17p11.2 region. Approximately 3.6 Mb microduplication of 17p11.2, known as PTLS, represents the mechanistically predicted homologous recombination reciprocal of the SMS microdeletion, both resulting in multiple congenital anomalies. Mouse model studies have revealed that the retinoic acid–inducible 1 gene (RAI1) within the SMS and PTLS critical genomic interval is the dosage-sensitive gene responsible for the major phenotypic features in these disorders. Even though PTLS and SMS share the same genomic region, clinical manifestations and behavioral issues are distinct and in fact some mirror traits may be on opposite ends of a given phenotypic spectrum. We describe the neurobehavioral phenotypes of SMS and PTLS patients during different life phases as well as clinical guidelines for diagnosis and a multidisciplinary approach once diagnosis is confirmed by array comparative genomic hybridization or RAI1 gene sequencing. The main goal is to increase awareness of these rare disorders because an earlier diagnosis will lead to more timely developmental intervention and medical management which will improve clinical outcome. PMID:27617127

  13. Oculo-facio-cardio-dental (OFCD) syndrome: the first Italian case of BCOR and co-occurring OTC gene deletion.

    Science.gov (United States)

    Di Stefano, C; Lombardo, B; Fabbricatore, C; Munno, C; Caliendo, I; Gallo, F; Pastore, L

    2015-04-01

    Oculo-facio-cardio-dental (OFCD) syndrome is a rare genetic disorder affecting ocular, facial, dental and cardiac systems. The syndrome is an X-linked dominant trait and it might be lethal in males. This syndrome is usually caused by mutations in the BCL6 interacting co-repressor gene (BCOR). We described a female child with mild phenotype of oculo-facio-cardio-dental syndrome. Array-comparative genomic hybridization (a-CGH) analysis revealed a de novo heterozygous deletion in the Xp11.4 region of approximately 2.3 Mb, involving BCOR and ornithine carbamoyl-transferase (OTC) genes. The deletion observed was subsequently confirmed by real time PCR. In this study we report a first case with co-occurrence of BCOR and OTC genes completely deleted in OFCD syndrome.

  14. Role of UGT1A1 gene polymorphism in the pathogenesis of Gilbert syndrome

    Directory of Open Access Journals (Sweden)

    SONG Jinyun

    2016-03-01

    Full Text Available As a bilirubin metabolic disorder, Gilbert syndrome belongs to the category of congenital non-hemolytic jaundice. Deficiency or decrease in the activity of bilirubin-uridine diphosphate glucuronyltransferase (UGT is an important reason for the pathogenesis of Gilbert syndrome. UGT1A1, an isoenzyme of UGT, is a key enzyme to direct bilirubin in the liver. Mutations in UGT1A1 gene lead to the structural abnormality of UGT, and thus result in the decrease or loss of the ability of UGT to bind bilirubin. This article summarizes the research advances in the role of UGTA1 and its polymorphism in the pathogenesis and diagnosis of Gilbert syndrome.

  15. Schrödinger cat and Werner state disentanglement simulated by trapped ion systems

    Science.gov (United States)

    Bittencourt, Victor A. S. V.; Bernardini, Alex E.

    2017-04-01

    Disentanglement and loss of quantum correlations due to one global collective noise effect are described for two-qubit Schrödinger cat and Werner states of a four level trapped ion quantum system. Once the Jaynes–Cummings ionic interactions are mapped onto a Dirac spinor structure, the elementary tools for computing quantum correlations of two-qubit ionic states are provided. With two-qubit quantum numbers related to the total angular momentum and to its projection onto the direction of an external magnetic field (which lifts the degeneracy of the ion’s internal levels), a complete analytical profile of entanglement for the Schrödinger cat and Werner states is obtained. Under vacuum noise (during spontaneous emission), the two-qubit entanglement in the Schrödinger cat states is shown to vanish asymptotically. Otherwise, the robustness of Werner states is concomitantly identified, with the entanglement content recovered by their noiseless-like evolution. Most importantly, our results point to a firstly reported sudden transition between classical and quantum decay regimes driven by a classical collective noise on the Schrödinger cat states, which has been quantified by the geometric discord.

  16. Stereochemistry of coordination compounds. From alfred werner to the 21st century.

    Science.gov (United States)

    von Zelewsky, Alex

    2014-01-01

    As a contribution to the scientific symposium, November 22nd, 2013, commemorating the Nobel Prize awarded to Alfred Werner in 1913, a presentation of the development of stereochemistry of coordination compounds during the past 120 years was given. Stereochemistry was fundamental to Werner's theory of coordination compounds. After Werner's death in 1919, stereochemistry in this field did not progress much further for almost 20 years, but then developed continuously. It was realized that stereochemical features of elements showing coordination numbers larger than four are responsible for an almost unlimited number of stereochemical possibilities, thus opening a molecular world of new structures. In the beginning of the 21st century, interest in the field rose again considerably, mainly due to the potential of stereoselective catalysis, and the self-assembly of supramolecular structures. An end of these developments is not in sight. Here an abbreviated version of the lecture is given. A PowerPoint(®) file, or a video of the presentation, can be downloaded.

  17. [RIT1: a novel gene associated with Noonan syndrome].

    Science.gov (United States)

    Arroyo-Carrera, I; Solo de Zaldivar-Tristancho, M; Martin-Fernandez, R; Vera-Torres, M; Gonzalez de Buitrago-Amigo, J F; Botet-Rodriguez, J

    2016-10-16

    Introduccion. El sindrome de Noonan es el mas frecuente del grupo de los sindromes malformativos congenitos originados por mutaciones germinales en genes de la via RAS/MAPK, denominados genericamente RAS-opatias, uno de los grupos mas comunes de alteraciones geneticas congenitas en la practica clinica. Recientemente se han descrito mutaciones en el gen RIT1 en pacientes con sindrome de Noonan. Caso clinico. Nina de 7 anos con diagnostico clinico de sindrome de Noonan, que entre sus manifestaciones clinicas incluye miocardiopatia hipertrofica, en la que se ha identificado una mutacion de novo en heterocigosis, en RIT1, c.295T>C (p.Phe99Leu), no descrita previamente, probablemente causal. Conclusiones. RIT1 comparte homologia con otras proteinas RAS y la expresion de alelos mutantes origina un efecto de ganancia de funcion que apoya su papel causal en el sindrome de Noonan. Podemos estimar actualmente que es responsable de un 3-5% de los casos del sindrome. Estos casos con sindrome de Noonan, respecto a los que presentan mutaciones en otros genes, se caracterizan por una mayor frecuencia de alteraciones prenatales, alta frecuencia de miocardiopatia hipertrofica y menor frecuencia de talla baja y deformidad toracica. Destaca la importancia de incorporar los nuevos genes identificados en los paneles diagnosticos.

  18. Marfan Syndrome

    Science.gov (United States)

    Marfan syndrome is a disorder that affects connective tissue. Connective tissues are proteins that support skin, bones, ... fibrillin. A problem with the fibrillin gene causes Marfan syndrome. Marfan syndrome can be mild to severe, ...

  19. Williams syndrome

    Science.gov (United States)

    Williams-Beuren syndrome ... Williams syndrome is caused by not having a copy of several genes. Parents may not have any family history of the condition. However, people with Williams syndrome have a 50% chance of passing the ...

  20. Identification of gene networks and pathways associated with Guillain-Barre syndrome.

    Directory of Open Access Journals (Sweden)

    Kuo-Hsuan Chang

    Full Text Available BACKGROUND: The underlying change of gene network expression of Guillain-Barré syndrome (GBS remains elusive. We sought to identify GBS-associated gene networks and signaling pathways by analyzing the transcriptional profile of leukocytes in the patients with GBS. METHODS AND FINDINGS: Quantitative global gene expression microarray analysis of peripheral blood leukocytes was performed on 7 patients with GBS and 7 healthy controls. Gene expression profiles were compared between patients and controls after standardization. The set of genes that significantly correlated with GBS was further analyzed by Ingenuity Pathways Analyses. 256 genes and 18 gene networks were significantly associated with GBS (fold change ≥2, P<0.05. FOS, PTGS2, HMGB2 and MMP9 are the top four of 246 significantly up-regulated genes. The most significant disease and altered biological function genes associated with GBS were those involved in inflammatory response, infectious disease, and respiratory disease. Cell death, cellular development and cellular movement were the top significant molecular and cellular functions involved in GBS. Hematological system development and function, immune cell trafficking and organismal survival were the most significant GBS-associated function in physiological development and system category. Several hub genes, such as MMP9, PTGS2 and CREB1 were identified in the associated gene networks. Canonical pathway analysis showed that GnRH, corticotrophin-releasing hormone and ERK/MAPK signaling were the most significant pathways in the up-regulated gene set in GBS. CONCLUSIONS: This study reveals the gene networks and canonical pathways associated with GBS. These data provide not only networks between the genes for understanding the pathogenic properties of GBS but also map significant pathways for the future development of novel therapeutic strategies.

  1. Lenz-Majewski syndrome: Report of a case with novel mutation in PTDSS1 gene.

    Science.gov (United States)

    Tamhankar, Parag M; Vasudevan, Lakshmi; Bansal, Vandana; Menon, Shyla R; Gawde, Harshavardhan M; D'Souza, Aruna; Babu, Shiny; Kondurkar, Shweta; Adhia, Rashmi; Das, Dhanjit Kumar

    2015-08-01

    Lenz-Majewski syndrome (LMS) is an extremely rare syndrome characterized by osteosclerosis, intellectual disability, characteristic facies and distinct craniofacial, dental, cutaneous and distal - limb anomalies. Recently, mutations in PTDSS1 gene have been identified as causative in six unrelated individuals. We report the seventh mutation proven case of LMS and provide a concise review of all known patients till date.

  2. Clinical Variability in a Family with an Ectodermal Dysplasia Syndrome and a Nonsense Mutation in the TP63 Gene

    NARCIS (Netherlands)

    Eisenkraft, A.; Pode-Shakked, B.; Goldstein, N.; Shpirer, Z.; Bokhoven, H. van; Anikster, Y.

    2015-01-01

    Mutations in the TP63 gene have been associated with a variety of ectodermal dysplasia syndromes, among which the clinically overlapping Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) and the Rapp-Hodgkin syndromes. We report a multiplex nonconsanguineous family of Ashkenazi-Jewish

  3. Identification of the causative gene for Simmental arachnomelia syndrome using a network-based disease gene prioritization approach.

    Directory of Open Access Journals (Sweden)

    Shihui Jiao

    Full Text Available Arachnomelia syndrome (AS, mainly found in Brown Swiss and Simmental cattle, is a congenital lethal genetic malformation of the skeletal system. In this study, a network-based disease gene prioritization approach was implemented to rank genes in the previously reported ∼7 Mb region on chromosome 23 associated with AS in Simmental cattle. The top 6 ranked candidate genes were sequenced in four German Simmental bulls, one known AS-carrier ROMEL and a pooled sample of three known non-carriers (BOSSAG, RIFURT and HIRMER. Two suspicious mutations located in coding regions, a mis-sense mutation c.1303G>A in the bystin-like (BYSL gene and a 2-bp deletion mutation c.1224_1225delCA in the molybdenum cofactor synthesis step 1 (MOCS1 gene were detected. Bioinformatic analysis revealed that the mutation in MOCS1 was more likely to be the causative mutation. Screening the c.1224_1225delCA site in 383 individuals from 12 cattle breeds/lines, we found that only the bull ROMEL and his 12 confirmed progeny carried the mutation. Thus, our results confirm the conclusion of Buitkamp et al. that the 2-bp deletion mutation c.1224_1225delCA in exon 11 of the MOCS1 gene is causative for AS in Simmental cattle. Furthermore, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP was developed to detect the causative mutation.

  4. Genetic Syndromes and Genes Involved in the Development of the Female Reproductive Tract: A Possible Role for Gene Therapy.

    Science.gov (United States)

    Connell, Mt; Owen, Cm; Segars, Jh

    2013-01-01

    Müllerian and vaginal anomalies are congenital malformations of the female reproductive tract resulting from alterations in the normal developmental pathway of the uterus, cervix, fallopian tubes, and vagina. The most common of the Müllerian anomalies affect the uterus and may adversely impact reproductive outcomes highlighting the importance of gaining understanding of the genetic mechanisms that govern normal and abnormal development of the female reproductive tract. Modern molecular genetics with study of knock out animal models as well as several genetic syndromes featuring abnormalities of the female reproductive tract have identified candidate genes significant to this developmental pathway. Further emphasizing the importance of understanding female reproductive tract development, recent evidence has demonstrated expression of embryologically significant genes in the endometrium of adult mice and humans. This recent work suggests that these genes not only play a role in the proper structural development of the female reproductive tract but also may persist in adults to regulate proper function of the endometrium of the uterus. As endometrial function is critical for successful implantation and pregnancy maintenance, these recent data suggest a target for gene therapy. Future research will be needed to determine if gene therapy may improve reproductive outcomes for patients with demonstrated deficient endometrial expression related to abnormal gene expression.

  5. Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC)*

    OpenAIRE

    Srivastava, Jyoti; Robertson, Chadia L.; Gredler, Rachel; Siddiq, Ayesha; Rajasekaran, Devaraja; Akiel, Maaged A; Emdad, Luni; Mas, Valeria; Mukhopadhyay, Nitai D.; FISHER, PAUL B.; Sarkar, Devanand

    2015-01-01

    Background: Astrocyte elevated gene-1 (AEG-1) inhibits retinoid X receptor (RXR) function and is overexpressed in human hepatocellular carcinoma (HCC), which is associated with non-thyroidal illness syndrome (NTIS).

  6. Prenatal exclusion of von Hippel-Lindau syndrome in a Mexican family carrying a novel VHL gene mutation

    National Research Council Canada - National Science Library

    Chacón-Camacho, Oscar Francisco; Benitez-Granados, Jesús; Zenteno, Juan Carlos

    2014-01-01

    von Hippel-Lindau (VHL) disease is an autosomal dominant and familial multisystemic syndrome that is caused by the inactivation of the VHL gene and it is characterized by diverse types of high vasculated tumours of benign and malign nature...

  7. Haploinsufficiency of RPS14 in 5q− syndrome is associated with deregulation of ribosomal- and translation-related genes

    Science.gov (United States)

    Pellagatti, Andrea; Hellström-Lindberg, Eva; Giagounidis, Aristoteles; Perry, Janet; Malcovati, Luca; Della Porta, Matteo G; Jädersten, Martin; Killick, Sally; Fidler, Carrie; Cazzola, Mario; Wainscoat, James S; Boultwood, Jacqueline

    2008-01-01

    We have previously demonstrated haploinsufficiency of the ribosomal gene RPS14, which is required for the maturation of 40S ribosomal subunits and maps to the commonly deleted region, in the 5q− syndrome. Patients with Diamond-Blackfan anaemia (DBA) show haploinsufficiency of the closely related ribosomal protein RPS19, and show a consequent downregulation of multiple ribosomal- and translation-related genes. By analogy with DBA, we have investigated the expression profiles of a large group of ribosomal- and translation-related genes in the CD34+ cells of 15 myelodysplastic syndrome (MDS) patients with 5q− syndrome, 18 MDS patients with refractory anaemia (RA) and a normal karyotype, and 17 healthy controls. In this three-way comparison, 55 of 579 ribosomal- and translation-related probe sets were found to be significantly differentially expressed, with approximately 90% of these showing lower expression levels in the 5q− syndrome patient group. Using hierarchical clustering, patients with the 5q− syndrome could be separated both from other patients with RA and healthy controls solely on the basis of the deregulated expression of ribosomal- and translation-related genes. Patients with the 5q− syndrome have a defect in the expression of genes involved in ribosome biogenesis and in the control of translation, suggesting that the 5q− syndrome represents a disorder of aberrant ribosome biogenesis. PMID:18477045

  8. The M235T polymorphism of the angiotensinogen gene in women with polycystic ovary syndrome.

    Science.gov (United States)

    Zulian, Elisa; Sartorato, Paola; Schiavi, Francesca; Moghetti, Paolo; Castello, Roberto; Mantero, Franco; Opocher, Giuseppe; Scaroni, Carla

    2005-11-01

    To explore the relationship between variation in AGT M235T gene and the development of the polycystic ovary syndrome (PCOS) and its sequelae, in the present study we evaluated AGT polymorphism M235T in women with PCOS and in a control group. Moreover, to detect any relationship between AGT M235T variation and intermediate and quantitative traits relevant to the pathogenesis of cardiovascular disease and PCOS, we looked for genotype-dependent differences within the subjects with PCOS.

  9. Lesch-Nyhan syndrome in an Indian family with novel mutation in the HPRT1 gene.

    Science.gov (United States)

    Sharma, Suvasini; Jiménez, Rosa Torres; Aneja, Satinder; Garcia, Marta G; Sethi, Gulshan R

    2012-11-01

    The authors report two brothers who presented with motor delay and stiffness. The elder boy had auto-mutilation of lips and fingers. Serum uric acid was elevated in both the children. Both the boys had undetectable hypoxanthine-guanine phosphoribosyl transferase activity in hemolysate, confirming the diagnosis of Lesch-Nyhan syndrome. Molecular genetic testing revealed a new mutation in the HPRT1 gene.

  10. Gene expression profiling provides insights into pathways of oxaliplatin-related sinusoidal obstruction syndrome in humans

    OpenAIRE

    Rubbia-Brandt, Laura; Tauzin, Sébastien; Brezault, Catherine; Delucinge-Vivier, Céline; Descombes, Patrick; Dousset, Bertand; Majno, Pietro; Mentha, Gilles; Terris, Benoit

    2011-01-01

    Sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) is a well-established complication of hematopoietic stem cell transplantation, pyrrolizidine alkaloid intoxication, and widely used chemotherapeutic agents such as oxaliplatin. It is associated with substantial morbidity and mortality. Pathogenesis of SOS in humans is poorly understood. To explore its molecular mechanisms, we used Affymetrix U133 Plus 2.0 microarrays to investigate the gene expression profile of 11 human l...

  11. Mutation in the Human HPRT1 Gene and the Lesch-Nyhan Syndrome.

    Science.gov (United States)

    Nguyen, Khue Vu; Nyhan, William L

    2016-08-02

    Lesch-Nyhan syndrome (LNS) is a rare X-linked inherited neurogenetic disorder of purine metabolism in which the enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt) is defective. The authors report a novel mutation which led to HGprt-related neurological dysfunction (HND) in two brothers from the same family with a missense mutation in exon 6 of the coding region of the HPRT1 gene: c.437T>C, p.L146S. Molecular diagnosis discloses the genetic heterogeneity of the HPRT1 gene responsible for HGprt deficiency. It allows fast, accurate carrier detection and genetic counseling.

  12. A unique mosaic Turner syndrome patient with androgen receptor gene derived marker chromosome.

    Science.gov (United States)

    Kalkan, Rasime; Özdağ, Nermin; Bundak, Rüveyde; Çirakoğlu, Ayşe; Serakinci, Nedime

    2016-01-01

    Patients with Turner syndrome are generally characterized by having short stature with no secondary sexual characteristics. Some abnormalities, such as webbed neck, renal malformations (>50%) and cardiac defects (10%) are less common. The intelligence of these patients is considered normal. Non-mosaic monosomy X is observed in approximately 45% of postnatal patients with Turner syndrome and the rest of the patients have structural abnormalities or mosaicism involving 46,X,i(Xq), 45,X/46,XX, 45,X and other variants. The phenotype of 45,X/46,X,+mar individuals varies by the genetic continent and degree of the mosaicism. The gene content of the marker chromosome is the most important when correlating the phenotype with the genotype. Here we present an 11-year-old female who was referred for evaluation of her short stature and learning disabilities. Conventional cytogenetic investigation showed a mosaic 45,X/46,X,+mar karyotype. Fluorescence in situ hybridization showed that the marker chromosome originated from the X chromosome within the androgen receptor (AR) and X-inactive specific transcript (XIST) genes. Therefore, it is possible that aberrant activation of the marker chromosome, compromising the AR and XIST genes, may modify the Turner syndrome phenotype.

  13. TMEM231 Gene Conversion Associated with Joubert and Meckel-Gruber Syndromes in the Same Family.

    Science.gov (United States)

    Maglic, Dino; Stephen, Joshi; Malicdan, May Christine V; Guo, Jennifer; Fischer, Roxanne; Konzman, Daniel; Mullikin, James C; Gahl, William A; Vilboux, Thierry; Gunay-Aygun, Meral

    2016-11-01

    Joubert and Meckel-Gruber syndromes (JS and MGS) are ciliopathies with overlapping features. JS patients manifest the "molar tooth sign" on brain imaging and variable eye, kidney, and liver disease. MGS presents with polycystic kidneys, occipital encephalocele, and polydactyly; it is typically perinatally fatal. Both syndromes are genetically heterogeneous; some genes cause either syndrome. Here, we report two brothers married to unrelated women. The first brother had three daughters with JS and a son with polycystic kidneys who died at birth. The second brother's wife had a fetal demise due to MGS. Whole exome sequencing identified TMEM231 NM_001077416.2: c.784G>A; p.(Asp262Asn) in all children and the wife of the first brother; the second brother's wife had a c.406T>G;p.(Trp136Gly) change. In-depth analysis uncovered a rare gene conversion event in TMEM231, leading to loss of exon 4, in all the affected children of first brother. We believe that the combination of this gene conversion with different missense mutations led to a spectrum of phenotypes that span JS and MGS. © 2016 WILEY PERIODICALS, INC.

  14. Non-viral transfer approaches for the gene therapy of mucopolysaccharidosis type II (Hunter syndrome).

    Science.gov (United States)

    Tomanin, R; Friso, A; Alba, S; Piller Puicher, E; Mennuni, C; La Monica, N; Hortelano, G; Zacchello, F; Scarpa, M

    2002-01-01

    Hunter syndrome is a rare X-linked lysosomal storage disorder caused by the deficiency of the housekeeping enzyme iduronate-2-sulphatase (IDS). Deficiency of IDS causes accumulation of undegraded dermatan and heparan-sulphate in various tissues and organs. Approaches have been proposed for the symptomatic therapy of the disease, including bone marrow transplantation and, very recently, enzyme replacement. To date, gene therapy strategies have considered mainly retroviral and adenoviral transduction of the correct cDNA. In this paper, two non-viral somatic gene therapy approaches are proposed: encapsulated heterologous cells and muscle electro-gene transfer (EGT). Hunter primary fibroblasts were co-cultured with either cell clones over-expressing the lacking enzyme or with the same incorporated in alginate microcapsules. For EGT, plasmid vector was injected into mouse quadriceps muscle, which was then immediately electro-stimulated. Co-culturing Hunter primary fibroblasts with cells over-expressing IDS resulted in a three- to fourfold increase in fibroblast enzyme activity with respect to control cells. Fibroblast IDS activity was also increased after co-culture with encapsulated cells. EGT was able to transduce genes in mouse muscle, resulting in at least a tenfold increase in IDS activity 1-5 weeks after treatment. Although preliminary, results from encapsulated heterologous cell clones and muscle EGT encourage further evaluations for possible application to gene therapy for Hunter syndrome.

  15. Novel Mutations in MLH1 and MSH2 Genes in Mexican Patients with Lynch Syndrome

    Science.gov (United States)

    Moreno-Ortiz, Jose Miguel; Ayala-Madrigal, María de la Luz; Corona-Rivera, Jorge Román; Maciel-Gutiérrez, Víctor; Franco-Topete, Ramón Antonio; Armendáriz-Borunda, Juan; Pérez-Carbonell, Lucia; Rhees, Jennifer; Gutiérrez-Angulo, Melva

    2016-01-01

    Background. Lynch Syndrome (LS) is characterized by germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. This syndrome is inherited in an autosomal dominant pattern and is characterized by early onset colorectal cancer (CRC) and extracolonic tumors. The aim of this study was to identify mutations in MMR genes in three Mexican patients with LS. Methods. Immunohistochemical analysis was performed as a prescreening method to identify absent protein expression. PCR, Denaturing High Performance Liquid Chromatography (dHPLC), and Sanger sequencing complemented the analysis. Results. Two samples showed the absence of nuclear staining for MLH1 and one sample showed loss of nuclear staining for MSH2. The mutations found in MLH1 gene were c.2103+1G>C in intron 18 and compound heterozygous mutants c.1852_1854delAAG (p.K618del) and c.1852_1853delinsGC (p.K618A) in exon 16. In the MSH2 gene, we identified mutation c.638dupT (p.L213fs) in exon 3. Conclusions. This is the first report of mutations in MMR genes in Mexican patients with LS and these appear to be novel. PMID:27247567

  16. Novel Mutations in MLH1 and MSH2 Genes in Mexican Patients with Lynch Syndrome

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    Jose Miguel Moreno-Ortiz

    2016-01-01

    Full Text Available Background. Lynch Syndrome (LS is characterized by germline mutations in the DNA mismatch repair (MMR genes MLH1, MSH2, MSH6, and PMS2. This syndrome is inherited in an autosomal dominant pattern and is characterized by early onset colorectal cancer (CRC and extracolonic tumors. The aim of this study was to identify mutations in MMR genes in three Mexican patients with LS. Methods. Immunohistochemical analysis was performed as a prescreening method to identify absent protein expression. PCR, Denaturing High Performance Liquid Chromatography (dHPLC, and Sanger sequencing complemented the analysis. Results. Two samples showed the absence of nuclear staining for MLH1 and one sample showed loss of nuclear staining for MSH2. The mutations found in MLH1 gene were c.2103+1G>C in intron 18 and compound heterozygous mutants c.1852_1854delAAG (p.K618del and c.1852_1853delinsGC (p.K618A in exon 16. In the MSH2 gene, we identified mutation c.638dupT (p.L213fs in exon 3. Conclusions. This is the first report of mutations in MMR genes in Mexican patients with LS and these appear to be novel.

  17. No association between DLST gene and Alzheimer's disease or Wernicke-Korsakoff syndrome.

    Science.gov (United States)

    Matsushita, S; Arai, H; Yuzuriha, T; Kato, M; Matsui, T; Urakami, K; Higuchi, S

    2001-01-01

    Among many candidate genes for the genetically heterogeneous Alzheimer's disease (AD), only apolipoprotein E (ApoE) has been confirmed. Another candidate is the dihydrolipoyl succinyltransferase (DLST) gene, one of three components of thiamine-dependent mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC), because KGDHC activity is reported reduced in AD patients. Also characterized by reduced KGDHC activity is another neuropsychiatric disease, Wernicke-Korsakoff syndrome (WKS), which results from thiamine deficiency. Examination of specific DLST gene polymorphism in 247 Japanese AD patients, 53 alcoholic WKS patients, and 368 nondemented Japanese control subjects revealed no significant differences in DLST genotypes and failed to replicate the findings of earlier studies indicating an association between DLST gene polymorphism and AD.

  18. Mixed gonadal dysgenesis in 45,X Turner syndrome with SRY gene.

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    Jung, Jae Yeop; Yang, Sohyoung; Jeong, Eun-Hwan; Lee, Ho-Chang; Lee, Yong-Moon; Han, Heon-Seok; Yi, Kyung Hee

    2015-12-01

    Turner syndrome is the most common chromosomal disorder in girls. Various phenotypic features show depending upon karyotype from normal female through ambiguous genitalia to male. Usually, Turner girls containing 45,X/46,XY mosaicism, or sex-determining region Y (SRY) gene may have mixed gonadal dysgenesis with various external sexual differentiation. We experienced a short statured 45,X Turner girl with normal external genitalia. Because SRY gene was positive, laparoscopic gonadectomy was performed. The dysgenetic gonads revealed bilateral ovotesticular tissues. The authors report a mixed gonadal dysgenesis case found in clinical 45,X Turner patient with positive SRY gene. Screening for SRY gene should be done even the karyotype is 45,X monosomy and external genitalia is normal.

  19. 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.

  20. Localization of candidate regions for a novel gene for Kartagener syndrome.

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    Gutierrez-Roelens, Ilse; Sluysmans, Thierry; Jorissen, Mark; Amyere, Mustapha; Vikkula, Miikka

    2006-07-01

    Asymmetric positioning of internal organs is a characteristics of vertebrates. The normal left-right anatomic positioning, situs solitus, sometimes does not occur normaly, leading to laterality defects. Studies in animal models have shown that laterality decisions are mediated by a cascade of genes that lead to the asymmetric expression of Nodal, LEFTA, LEFTB and PITX2 in the lateral plate mesoderm. A search for mutations in genes implicated in left-right patterning in animal models allowed genes associated with heterotaxia defects in humans to be identified. However, these genes explain only a small percentage of human situs defects, suggesting that other genes must play a role. In this study, we report a consanguineous family of Turkish origin, composed of two unaffected parents and three children, two of whom presented Kartagener syndrome. On the basis of their family history, we hypothesize autosomal recessive mode of inheritance. A genotype analysis with polymorphic markers did not show linkage with any known genes or loci causing laterality disorders. Array CGH did not detect a duplication or microdeletion greater than 1 Mb as a possible cause. Genome wide screening using 10 K Affymetrix SNP chips was performed, allowing the identification of two regions of autozygosity, one in chromosome 1 and the other on chromosome 7. In the chromosome 1 locus, a strong candidate gene, encoding the kinesin-associated protein 3 (KIF3AP) was not mutated, based on SSCP/heteroduplex analysis and direct sequencing. These data provide a basis for the identification of a novel gene implicated in Kartagener syndrome.

  1. Comparative analysis of differentially expressed genes in normal and white spot syndrome virus infected Penaeus monodon

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    Juan Hsueh-Fen

    2007-05-01

    Full Text Available Abstract Background White spot syndrome (WSS is a viral disease that affects most of the commercially important shrimps and causes serious economic losses to the shrimp farming industry worldwide. However, little information is available in terms of the molecular mechanisms of the host-virus interaction. In this study, we used an expressed sequence tag (EST approach to observe global gene expression changes in white spot syndrome virus (WSSV-infected postlarvae of Penaeus monodon. Results Sequencing of the complementary DNA clones of two libraries constructed from normal and WSSV-infected postlarvae produced a total of 15,981 high-quality ESTs. Of these ESTs, 46% were successfully matched against annotated genes in National Center of Biotechnology Information (NCBI non-redundant (nr database and 44% were functionally classified using the Gene Ontology (GO scheme. Comparative EST analyses suggested that, in postlarval shrimp, WSSV infection strongly modulates the gene expression patterns in several organs or tissues, including the hepatopancreas, muscle, eyestalk and cuticle. Our data suggest that several basic cellular metabolic processes are likely to be affected, including oxidative phosphorylation, protein synthesis, the glycolytic pathway, and calcium ion balance. A group of immune-related chitin-binding protein genes is also likely to be strongly up regulated after WSSV infection. A database containing all the sequence data and analysis results is accessible at http://xbio.lifescience.ntu.edu.tw/pm/. Conclusion This study suggests that WSSV infection modulates expression of various kinds of genes. The predicted gene expression pattern changes not only reflect the possible responses of shrimp to the virus infection but also suggest how WSSV subverts cellular functions for virus multiplication. In addition, the ESTs reported in this study provide a rich source for identification of novel genes in shrimp.

  2. Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome

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    Tai Dessmon

    2005-01-01

    Full Text Available Abstract Background Severe acute respiratory syndrome (SARS emerged in later February 2003, as a new epidemic form of life-threatening infection caused by a novel coronavirus. However, the immune-pathogenesis of SARS is poorly understood. To understand the host response to this pathogen, we investigated the gene expression profiles of peripheral blood mononuclear cells (PBMCs derived from SARS patients, and compared with healthy controls. Results The number of differentially expressed genes was found to be 186 under stringent filtering criteria of microarray data analysis. Several genes were highly up-regulated in patients with SARS, such as, the genes coding for Lactoferrin, S100A9 and Lipocalin 2. The real-time PCR method verified the results of the gene array analysis and showed that those genes that were up-regulated as determined by microarray analysis were also found to be comparatively up-regulated by real-time PCR analysis. Conclusions This differential gene expression profiling of PBMCs from patients with SARS strongly suggests that the response of SARS affected patients seems to be mainly an innate inflammatory response, rather than a specific immune response against a viral infection, as we observed a complete lack of cytokine genes usually triggered during a viral infection. Our study shows for the first time how the immune system responds to the SARS infection, and opens new possibilities for designing new diagnostics and treatments for this new life-threatening disease.

  3. Disruption of DNA methylation-dependent long gene repression in Rett syndrome

    Science.gov (United States)

    Gabel, Harrison W.; Kinde, Benyam Z.; Stroud, Hume; Gilbert, Caitlin S.; Harmin, David A.; Kastan, Nathaniel R.; Hemberg, Martin; Ebert, Daniel H.; Greenberg, Michael E.

    2015-01-01

    Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism1. MECP2 encodes a methyl-DNA-binding protein2 that has been proposed to function as a transcriptional repressor, but despite numerous studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 regulates transcription3–9. Here we identify a genome-wide length-dependent increase in gene expression in MeCP2 mutant mouse models and human RTT brains. We present evidence that MeCP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MeCP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, we find that long genes as a population are enriched for neuronal functions and selectively expressed in the brain. These findings suggest that mutations in MeCP2 may cause neurological dysfunction by specifically disrupting long gene expression in the brain. PMID:25762136

  4. Association analysis between Tourette's syndrome and dopamine D1 receptor gene in Taiwanese children

    Institute of Scientific and Technical Information of China (English)

    ICTsai; CHLee; CCKuo; HTHsu; YALi; CITsai

    2005-01-01

    Objective Recent research suggests that Tourette's syndrome (TS) may result from a defect in the dopamine system. The dopamine 1 receptor (DRD 1) gene is a candidate gene in the study of the etiology of neuropsychiatric diseases that may involve dopaminergic abnormalities. We sought to test the hypothesis that the DRD 1 gene might play a role in TS.Methods By performing an association study, we collected an independent sample of patients from the midland region of Taiwan and investigated whether DRD 1 gene polymorphisms can be used as markers of susceptibility to TS. A total of 148 children with TS and 83 normal control subjects were included in the study. A polymerase chain reaction was used to identify the A/G polymorphism of the DRD 1 gene. Genotypes and allelic frequencies for the DRD 1 gene polymorphisms in both groups were compared.Results The results showed that genotypes and allelic frequencies for the DRD 1 gene polymorphisms in both groups were not significantly different.Conclusion These data suggest that DRD 1 gene may not be a useful marker for prediction of the susceptibility of TS.

  5. Down's syndrome-associated single minded gene as a novel tumor marker.

    Science.gov (United States)

    Deyoung, Maurice Phil; Scheurle, Daniela; Damania, Hema; Zylberberg, Claudia; Narayanan, Ramaswamy

    2002-01-01

    The Cancer Genome Anatomy Project (CGAP) database has thousands of Expressed Sequence Tags encompassing both known and novel genes. Bioinformatics of the CGAP database led to the prediction that Single Minded Gene (sim2) could be specific to colon tumors. The sim2 gene is located in a minimum region of the chromosome 21 often implicated in trisomia called Down's Syndrome Critical Region. To date, the sim proteins have not been shown to be involved in cancer. Intrigued by the possible association of a Down's syndrome-related gene to solid tumors, efforts were undertaken to validate the expression specificity. The sim2 isoform (sim2-short-form, sim2-s) expression was seen in carcinomas of colon, pancreas and prostate, but not in corresponding normal tissues. Stage-specific expression of the sim2-s protein was seen in normal matched paraffin sections of the colon tumors. In a matched set of tissues of Benign Prostatic Hyperplasia (BPH) and prostate carcinomas, sim2-s expression was detected in the BPH. The expression specificity of sim2-s in select solid tumors offers both diagnostic and therapeutic potential and warrants additional study.

  6. Polymorphisms in genes of respiratory control and sudden infant death syndrome.

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    Läer, Katharina; Dörk, Thilo; Vennemann, Marielle; Rothämel, Thomas; Klintschar, Michael

    2015-09-01

    Sudden infant death syndrome (SIDS) is a multifactorial syndrome and assumingly, among other mechanisms, a deficit in respiratory control leads to a failure of arousal and autoresuscitation when the child is challenged by a stressful homeostatic event, e.g., hypoxia. We hypothesize that genetic polymorphisms involved in respiratory control mediated in the medulla oblongata contribute to SIDS. Therefore, a total of 366 SIDS cases and 421 controls were genotyped for 48 SNPs in 41 candidate genes. Genotyping was performed using Fluidigm nanofluidic technology. Results were obtained for 356 SIDS and 406 controls and 38 SNPs. After correction for multiple testing, one SNP retained a nominally significant association with seasonal SIDS: rs1801030 in the phenol sulfotransferase 1A1 gene (subgroup: death occurring during summer). A borderline association could be also observed for rs563649 in the opioid receptor μ1 gene in a recessive model (subgroup: death occurring during autumn). As a conclusion, although these data suggest two SNPs to be associated with different subgroups of SIDS cases, none of them can fully explain the SIDS condition, consistent with its multifactorial etiology. Given the great complexity of respiratory control and our initial findings reported here, we believe it is worthwhile to further investigate genes involved in the respiratory system.

  7. The modifier effect of the BDNF gene in the phenotype of the WAGRO syndrome.

    Science.gov (United States)

    Rodríguez-López, Raquel; Pérez, José M Carbonell; Balsera, Aránzazu Margallo; Rodríguez, Guillermo Gervasini; Moreno, Trinidad Herrera; García de Cáceres, Mayte; Serrano, Marta González-Carpio; Freijo, Felipe Casanueva; Ruiz, Juan Ramón González; Angueira, Francisco Barros; Pérez, Pilar Méndez; Estévez, Manuela Núñez; Gómez, Enrique Galán

    2013-03-10

    Individuals who are carriers of deletions of various sizes that cause haploinsufficiency in the contiguous WT1 and PAX6 genes, located on chromosome 11p13 approximately 4 Mb centromeric to the BDNF gene, are susceptible to Wilms tumor, aniridia, mental retardation, genitourinary anomalies and obesity (WAGRO syndrome). The molecular characterization of the wide deletion 11p15.1p12 arr (18676926-36576388) x1 dn in a child with 3 years and 4 months of age only affected by aniridia, predicts not only other serious associated diseases, but also allows us to hypothesize a specific phenotype of mental impairment, conduct alterations and childhood obesity, possibly added to the onset of metabolic alterations. The variable appearance and/or description of haploinsufficiency for obesity susceptibility in the WAGR syndrome mainly depends on the critical region located within 80 kb of exon 1 of BDNF. The relationship between genetic variation based on the genotype combinations of the 4 gene SNPs tagging the BDNF gene and the body mass index (BMI) was studied. The polymorphic variability was similarly distributed in 218 children suffering a severe and non-syndromic obesity from families at high risk for obesity, as compared with 198 controls. The corroborated role of the BDNF gene as highly susceptible to severe syndromic obesity has not already been evidenced in the molecular basis of overweight attributed to the common polygenic principles. Its potential role as risk modifier variant to provoke more severe phenotype has not yet been demonstrated. Some genetic variants of brain-derived neurotrophic factor (BDNF) have resulted in important disorders of energy balance, but it is essential to know exactly their deleterious human capacity because they play a fundamental role in the development and plasticity of the central nervous system in regulating food intake. The existence of polymorphic amino acid changes of unknown functional significance in patients carrying the

  8. Connected Gene Communities Underlie Transcriptional Changes in Cornelia de Lange Syndrome.

    Science.gov (United States)

    Boudaoud, Imène; Fournier, Éric; Baguette, Audrey; Vallée, Maxime; Lamaze, Fabien C; Droit, Arnaud; Bilodeau, Steve

    2017-09-01

    Cornelia de Lange syndrome (CdLS) is a complex multisystem developmental disorder caused by mutations in cohesin subunits and regulators. While its precise molecular mechanisms are not well defined, they point toward a global deregulation of the transcriptional gene expression program. Cohesin is associated with the boundaries of chromosome domains and with enhancer and promoter regions connecting the three-dimensional genome organization with transcriptional regulation. Here, we show that connected gene communities, structures emerging from the interactions of noncoding regulatory elements and genes in the three-dimensional chromosomal space, provide a molecular explanation for the pathoetiology of CdLS associated with mutations in the cohesin-loading factor NIPBL and the cohesin subunit SMC1A NIPBL and cohesin are important constituents of connected gene communities that are centrally positioned at noncoding regulatory elements. Accordingly, genes deregulated in CdLS are positioned within reach of NIPBL- and cohesin-occupied regions through promoter-promoter interactions. Our findings suggest a dynamic model where NIPBL loads cohesin to connect genes in communities, offering an explanation for the gene expression deregulation in the CdLS. Copyright © 2017 by the Genetics Society of America.

  9. Gene, environment, and brain-gut interactions in irritable bowel syndrome.

    Science.gov (United States)

    Fukudo, Shin; Kanazawa, Motoyori

    2011-04-01

    The genetic predisposition and influence of environment may underlie in the pathogenesis and/or pathophysiology of irritable bowel syndrome (IBS). This phenomenon, gene x environment interaction together with brain-gut interactions is emerging area to be clarified in IBS research. Earlier studies focused on candidate genes of neurotransmitters, cytokines, and growth factors. Among them, some studies but not all studies revealed association between phenotypes of IBS and 5-hydroxytryptamine (5-HT)-related genes, noradrenaline-related genes, and cytokine genes. Recent prospective cohort study showed that genes encoding immune and adhesion molecules were associated with post-infectious etiology of IBS. Psychosocial stressors and intraluminal factors especially microbiota are keys to develop IBS. IBS patients may have abnormal gut microbiota as well as increased organic acids. IBS is disorder that relates to brain-gut interactions, emotional dysregulation, and illness behaviors. Brain imaging with or without combination of visceral stimulation enables us to depict the detailed information of brain-gut interactions. In IBS patients, thalamus, insula, anterior cingulate cortex, amygdala, and brainstem were more activated in response to visceral stimulation than controls. Corticotropin-releasing hormone and 5-HT are the candidate substances which regulate exaggerated brain-gut response. In conclusion, gene x environment interaction together with brain-gut interactions may play crucial roles in IBS development. Further fundamental research on this issue is warranted.

  10. Increased sleep spindle activity in patients with Costello syndrome (HRAS gene mutation).

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    Della Marca, Giacomo; Leoni, Chiara; Dittoni, Serena; Battaglia, Domenica; Losurdo, Anna; Testani, Elisa; Colicchio, Salvatore; Gnoni, Valentina; Gambardella, Maria L; Mariotti, Paolo; Alfieri, Paolo; Tartaglia, Marco; Zampino, Giuseppe

    2011-06-01

    Costello syndrome is a congenital disorder because of HRAS gene mutation, frequently associated with neurologic impairment and sleep disorders. The aims of the study were to evaluate the sleep EEG, and particularly the sleep spindles, in a population of patients with Costello syndrome and to compare them with those characterizing unaffected subjects. Eleven subjects (5 men and 6 women) with Costello syndrome were included in the study; age ranged between 18 months and 31 years (mean, 9.6 ± 9.4 years). The diagnosis was posed on the basis of established clinical criteria and confirmed molecularly. Sleep EEG was studied by means of full-night, laboratory-based video-polysomnography, performed overnight, during hospitalization. Sleep activity was quantified by means of power spectral analysis. Patients heterozygous for an HRAS mutation exhibited increased EEG power in 12- to 15-Hz activity band compared with age-matched control subjects. In conclusion, the authors observed a consistent increase in the amplitude of cortical sleep spindles in all our subjects with an HRAS mutation. These "giant" spindles were not associated with any evidence of structural damage of the cortex or the thalami and should be considered as phenotypic feature of sleep EEG activity in Costello syndrome because of HRAS mutation.

  11. Targeted re-sequencing analysis of 25 genes commonly mutated in myeloid disorders in del(5q) myelodysplastic syndromes

    Science.gov (United States)

    Fernandez-Mercado, Marta; Burns, Adam; Pellagatti, Andrea; Giagounidis, Aristoteles; Germing, Ulrich; Agirre, Xabier; Prosper, Felipe; Aul, Carlo; Killick, Sally; Wainscoat, James S.; Schuh, Anna; Boultwood, Jacqueline

    2013-01-01

    Interstitial deletion of chromosome 5q is the most common chromosomal abnormality in myelodysplastic syndromes. The catalogue of genes involved in the molecular pathogenesis of myelodysplastic syndromes is rapidly expanding and next-generation sequencing technology allows detection of these mutations at great depth. Here we describe the design, validation and application of a targeted next-generation sequencing approach to simultaneously screen 25 genes mutated in myeloid malignancies. We used this method alongside single nucleotide polymorphism-array technology to characterize the mutational and cytogenetic profile of 43 cases of early or advanced del(5q) myelodysplastic syndromes. A total of 29 mutations were detected in our cohort. Overall, 45% of early and 66.7% of advanced cases had at least one mutation. Genes with the highest mutation frequency among advanced cases were TP53 and ASXL1 (25% of patients each). These showed a lower mutation frequency in cases of 5q- syndrome (4.5% and 13.6%, respectively), suggesting a role in disease progression in del(5q) myelodysplastic syndromes. Fifty-two percent of mutations identified were in genes involved in epigenetic regulation (ASXL1, TET2, DNMT3A and JAK2). Six mutations had allele frequencies <20%, likely below the detection limit of traditional sequencing methods. Genomic array data showed that cases of advanced del(5q) myelodysplastic syndrome had a complex background of cytogenetic aberrations, often encompassing genes involved in myeloid disorders. Our study is the first to investigate the molecular pathogenesis of early and advanced del(5q) myelodysplastic syndromes using next-generation sequencing technology on a large panel of genes frequently mutated in myeloid malignancies, further illuminating the molecular landscape of del(5q) myelodysplastic syndromes. PMID:23831921

  12. "Computational Analysis of the Effect of fbn1 Gene Mutations in the Marfan Syndrome"

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    H Mohabatkar

    2004-07-01

    Full Text Available Fibrillin is a large glycoprotein synthesized in the tissues involved in Marfan syndrome, and known to be involved in tissue elasticity. The syndrome is corresponded to fbn1 gene and is characterized by cardiovascular, ocular, and skeletal abnormalities. N-terminus of fibrillin 1 binds to microfibril-associated glycoprotein 1 (MAGP-1 in a calcium-dependent manner. In this study, the amino acid sequence of fibrillin protein of a patient with Marfan syndrome (accession No. XM- 034890 has been compared to the amino acid sequence of normal fibrillin (accession No. P-35555. In this patient, mutations causing a Gly (267 to Thr and Tyr (532 to Cys amino acids changes have been occurred. Method of Garnier was used to predict the secondary structure of the proteins and probable N-glycosylation sites were searched. Results of these analyses show no significant structural difference between the mutant and normal fibrillin proteins. Although in some cases characterization of the binding requirements has shown that a folded, secondary structure of fibrillin was necessary for binding, our results are in agreement with those findings that at least in some cases, fibrillin gene defects are not sole determinants of Marfan phenotype.

  13. Genes, language, and the nature of scientific explanations: the case of Williams syndrome.

    Science.gov (United States)

    Musolino, Julien; Landau, Barbara

    2012-01-01

    In this article, we discuss two experiments of nature and their implications for the sciences of the mind. The first, Williams syndrome, bears on one of cognitive science's holy grails: the possibility of unravelling the causal chain between genes and cognition. We sketch the outline of a general framework to study the relationship between genes and cognition, focusing as our case study on the development of language in individuals with Williams syndrome. Our approach emphasizes the role of three key ingredients: the need to specify a clear level of analysis, the need to provide a theoretical account of the relevant cognitive structure at that level, and the importance of the (typical) developmental process itself. The promise offered by the case of Williams syndrome has also given rise to two strongly conflicting theoretical approaches-modularity and neuroconstructivism-themselves offshoots of a perennial debate between nativism and empiricism. We apply our framework to explore the tension created by these two conflicting perspectives. To this end, we discuss a second experiment of nature, which allows us to compare the two competing perspectives in what comes close to a controlled experimental setting. From this comparison, we conclude that the "meaningful debate assumption", a widespread assumption suggesting that neuroconstructivism and modularity address the same questions and represent genuine theoretical alternatives, rests on a fallacy.

  14. Altered Intra-Nuclear Organisation of Heterochromatin and Genes in ICF Syndrome

    Science.gov (United States)

    Jefferson, Andrew; Colella, Stefano; Moralli, Daniela; Wilson, Natalie; Yusuf, Mohammed; Gimelli, Giorgio; Ragoussis, Jiannis; Volpi, Emanuela V.

    2010-01-01

    The ICF syndrome is a rare autosomal recessive disorder, the most common symptoms of which are immunodeficiency, facial anomalies and cytogenetic defects involving decondensation and instability of chromosome 1, 9 and 16 centromeric regions. ICF is also characterised by significant hypomethylation of the classical satellite DNA, the major constituent of the juxtacentromeric heterochromatin. Here we report the first attempt at analysing some of the defining genetic and epigenetic changes of this syndrome from a nuclear architecture perspective. In particular, we have compared in ICF (Type 1 and Type 2) and controls the large-scale organisation of chromosome 1 and 16 juxtacentromeric heterochromatic regions, their intra-nuclear positioning, and co-localisation with five specific genes (BTG2, CNN3, ID3, RGS1, F13A1), on which we have concurrently conducted expression and methylation analysis. Our investigations, carried out by a combination of molecular and cytological techniques, demonstrate the existence of specific and quantifiable differences in the genomic and nuclear organisation of the juxtacentromeric heterochromatin in ICF. DNA hypomethylation, previously reported to correlate with the decondensation of centromeric regions in metaphase described in these patients, appears also to correlate with the heterochromatin spatial configuration in interphase. Finally, our findings on the relative positioning of hypomethylated satellite sequences and abnormally expressed genes suggest a connection between disruption of long-range gene-heterochromatin associations and some of the changes in gene expression in ICF. Beyond its relevance to the ICF syndrome, by addressing fundamental principles of chromosome functional organisation within the cell nucleus, this work aims to contribute to the current debate on the epigenetic impact of nuclear architecture in development and disease. PMID:20613881

  15. Integrated Weighted Gene Co-expression Network Analysis with an Application to Chronic Fatigue Syndrome

    Directory of Open Access Journals (Sweden)

    Rajeevan Mangalathu S

    2008-11-01

    Full Text Available Abstract Background Systems biologic approaches such as Weighted Gene Co-expression Network Analysis (WGCNA can effectively integrate gene expression and trait data to identify pathways and candidate biomarkers. Here we show that the additional inclusion of genetic marker data allows one to characterize network relationships as causal or reactive in a chronic fatigue syndrome (CFS data set. Results We combine WGCNA with genetic marker data to identify a disease-related pathway and its causal drivers, an analysis which we refer to as "Integrated WGCNA" or IWGCNA. Specifically, we present the following IWGCNA approach: 1 construct a co-expression network, 2 identify trait-related modules within the network, 3 use a trait-related genetic marker to prioritize genes within the module, 4 apply an integrated gene screening strategy to identify candidate genes and 5 carry out causality testing to verify and/or prioritize results. By applying this strategy to a CFS data set consisting of microarray, SNP and clinical trait data, we identify a module of 299 highly correlated genes that is associated with CFS severity. Our integrated gene screening strategy results in 20 candidate genes. We show that our approach yields biologically interesting genes that function in the same pathway and are causal drivers for their parent module. We use a separate data set to replicate findings and use Ingenuity Pathways Analysis software to functionally annotate the candidate gene pathways. Conclusion We show how WGCNA can be combined with genetic marker data to identify disease-related pathways and the causal drivers within them. The systems genetics approach described here can easily be used to generate testable genetic hypotheses in other complex disease studies.

  16. Altered expression of immune-related genes in children with Down syndrome.

    Directory of Open Access Journals (Sweden)

    Bruna Lancia Zampieri

    Full Text Available Individuals with Down syndrome (DS have a high incidence of immunological alterations with increased susceptibility to bacterial and viral infections and high frequency of different types of hematologic malignancies and autoimmune disorders. In the current study, we profiled the expression pattern of 92 immune-related genes in peripheral blood mononuclear cells (PBMCs of two different groups, children with DS and control children, to identify differentially expressed genes that might be of pathogenetic importance for the development and phenotype of the immunological alterations observed in individuals with DS. PBMCs samples were obtained from six DS individuals with karyotypically confirmed full trisomy 21 and six healthy control individuals (ages 2-6 years. Gene expression was profiled in duplicate according to the manufacturer's instructions provided by commercially available TaqMan Human Immune Array representing 92 immune function genes and four reference genes on a 96-plex gene card. A set of 17 differentially expressed genes, not located on chromosome 21 (HSA21, involved in immune and inflammatory pathways was identified including 13 genes (BCL2, CCL3, CCR7, CD19, CD28, CD40, CD40LG, CD80, EDN1, IKBKB, IL6, NOS2 and SKI significantly down-regulated and four genes (BCL2L1, CCR2, CCR5 and IL10 significantly up-regulated in children with DS. These findings highlight a list of candidate genes for further investigation into the molecular mechanism underlying DS pathology and reinforce the secondary effects of the presence of a third copy of HSA21.

  17. Association between Tourette Syndrome and the Dopamine D3 Receptor Gene Rs6280

    Institute of Scientific and Technical Information of China (English)

    Fan He; Yi Zheng; Huan-Huan Huang; Yu-Hang Cheng; Chuan-Yue Wang

    2015-01-01

    Background:Tourette syndrome (TS) is a complex,heterozygous genetic disorder.The number of molecular genetic studies have investigated several candidate genes,particularly those implicated in the dopamine system.The dopamine D3 receptor (DRD3) gene has been considered as a candidate gene in TS.There was not any report about the association study of TS and DRD3 gene in Han Chinese population.We combined a case-control genetic association analysis and nuclear pedigrees transmission disequilibrium test (TDT) analysis to investigate the association between DRD3 gene rs6280 single nucleotide polymorphisms (SNPs) and TS in a Han Chinese population.Methods:A total of 160 TS patients was diagnosed by the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition.The DRD3 gene rs6280 SNPs were genotyped by TaqMan SNP genotyping assay technique in all subjects.We used a case-control genetic association analysis to compare the difference in genotype and allele frequencies between 160 TS patients and 90 healthy controls.At the same time,we used TDT analysis to identify the DRD3 gene rs6280 transmission disequilibrium among 10l nuclear pedigrees.Results:The genotype and allele frequency of DRD3 gene rs6280 SNPs had no statistical difference between control group (90) and TS group (160) (x2 =3.647,P =0.161; x2 =0.643,P =0.423) using Chi-squared test.At the basis of the 101 nuclear pedigrees,TDT analysis showed no transmission disequilibrium ofDRD3 gene rs6280 SNPs (x2 =0; P =1).Conclusions:Our findings provide no evidence for an association between DRD3 gene rs6280 and TS in the Han Chinese population.

  18. Identification of rare variants of DSP gene in sudden unexplained nocturnal death syndrome in the southern Chinese Han population.

    Science.gov (United States)

    Zhao, Qianhao; Chen, Yili; Peng, Longlun; Gao, Rui; Liu, Nian; Jiang, Pingping; Liu, Chao; Tang, Shuangbo; Quan, Li; Makielski, Jonathan C; Cheng, Jianding

    2016-03-01

    Sudden unexplained nocturnal death syndrome (SUNDS) is a perplexing disorder to both forensic pathologists and clinic physicians. Desmoplakin (DSP) gene was the first desmosomal gene linked to arrhythmogenic right ventricular cardiomyopathy (ARVC) which was associated with sudden death. To identify the genetic variants of the DSP gene in SUNDS in the southern Chinese Han population, we genetically screened the DSP gene in 40 sporadic SUNDS victims, 16 Brugada syndrome (BrS) patients, and 2 early repolarization syndrome (ERS) patients using next generation sequencing (NSG) and direct Sanger sequencing. A total of 10 genetic variants of the DSP gene were detected in 11 cases, comprised of two novel missense mutations (p.I125F and p.D521A) and eight previously reported rare variants. Of eight reported variants, two were previously considered pathogenic (p.Q90R and p.R2639Q), three were predicted in silico to be pathogenic (p.R315C, p.E1357D and p.D2579H), and the rest three were predicted to be benign (p.N1234S, p.R1308Q, and p.T2267S). This is the first report of DSP genetic screening in Chinese SUNDS and Brugada syndrome. Our results imply that DSP mutations contribute to the genetic cause of some SUNDS victims and maybe a new susceptible gene for Brugada syndrome.

  19. A 380-kb Duplication in 7p22.3 Encompassing the LFNG Gene in a Boy with Asperger Syndrome

    NARCIS (Netherlands)

    Vulto-van Silfhout, A.T.; Brouwer, A.F. de; Leeuw, N. de; Obihara, C.C.; Brunner, H.G.; Vries, B.B. de

    2012-01-01

    De novo genomic aberrations are considered an important cause of autism spectrum disorders. We describe a de novo 380-kb gain in band p22.3 of chromosome 7 in a patient with Asperger syndrome. This duplicated region contains 9 genes including the LNFG gene that is an important regulator of NOTCH

  20. A 380-kb Duplication in 7p22.3 Encompassing the LFNG Gene in a Boy with Asperger Syndrome

    NARCIS (Netherlands)

    Vulto-van Silfhout, A.T.; Brouwer, A.F. de; Leeuw, N. de; Obihara, C.C.; Brunner, H.G.; Vries, B.B. de

    2012-01-01

    De novo genomic aberrations are considered an important cause of autism spectrum disorders. We describe a de novo 380-kb gain in band p22.3 of chromosome 7 in a patient with Asperger syndrome. This duplicated region contains 9 genes including the LNFG gene that is an important regulator of NOTCH sig

  1. A 380-kb Duplication in 7p22.3 Encompassing the LFNG Gene in a Boy with Asperger Syndrome

    NARCIS (Netherlands)

    Vulto-van Silfhout, A.T.; Brouwer, A.F. de; Leeuw, N. de; Obihara, C.C.; Brunner, H.G.; Vries, B.B. de

    2012-01-01

    De novo genomic aberrations are considered an important cause of autism spectrum disorders. We describe a de novo 380-kb gain in band p22.3 of chromosome 7 in a patient with Asperger syndrome. This duplicated region contains 9 genes including the LNFG gene that is an important regulator of NOTCH sig

  2. Symptoms of Attention-Deficit/Hyperactivity Disorder in Down Syndrome: Effects of the Dopamine Receptor D4 Gene

    Science.gov (United States)

    Mason, Gina Marie; Spanó, Goffredina; Edgin, Jamie

    2015-01-01

    This study examined individual differences in ADHD symptoms and executive function (EF) in children with Down syndrome (DS) in relation to the dopamine receptor D4 (DRD4) gene, a gene often linked to ADHD in people without DS. Participants included 68 individuals with DS (7-21 years), assessed through laboratory tasks, caregiver reports, and…

  3. Genetic testing of the FBN1 gene in Chinese patients with Marfan/Marfan-like syndrome.

    Science.gov (United States)

    Yang, Hang; Luo, Mingyao; Chen, Qianlong; Fu, Yuanyuan; Zhang, Jing; Qian, Xiangyang; Sun, Xiaogang; Fan, Yuxin; Zhou, Zhou; Chang, Qian

    2016-08-01

    Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder typically involving the ocular, skeletal and cardiovascular systems, and aortic aneurysms/dissection mainly contributes to its mortality. Here, we performed genetic testing of the FBN1 gene in 39 Chinese probands with Marfan/Marfan-like syndrome and their related family members by Sanger sequencing. In total, 29 pathogenic/likely pathogenic FBN1 mutations, including 17 novel ones, were identified. In addition, most MFS patients with aortic disease (62%) had a truncating or splicing mutation. These results expand the FBN1 mutation spectrum and enrich our knowledge of genotype-phenotype correlations. Genetic testing for MFS and its related aortic diseases is increasingly important for early intervention and treatment.

  4. [Clonality analysis and mutational status of IgVH gene in Hodgkin variant of Richter syndrome].

    Science.gov (United States)

    Mao, Zheng-rong; Rosenwald, Andreas; Zhang, Suo-jiang; Zhou, Ren; Mueller-Hermelink, Hans Konrad

    2008-08-01

    To detect the clonal relationship, the rearrangement, and the mutational status of IgVH gene; the influence of these molecular characteristics on the clinical outcome in Hodgkin variant of Richter syndrome; and the possible molecular pathogenesis in this transformation. The clonal rearrangements and mutational status of IgVH genes were analyzed in Hodgkin variant of Richter syndrome and B-CLL with Reed-Stemberg (R-S)-like cells by GeneScan analysis and sequencing. Semi-nest PCR based on laser capture microdissection was utilized to compare the clonal relationship between B-CLL and R-S/R-Slike cells. Immunohistochemical staining was used to detect the different expressions of ZAP70, p53, IRF-4 and LMP1 in the two components. (1) 5/6 B-CLL cases transformed to Hodgkin lymphoma (HL)/R-S-like cells carried the mutated IgVH genes; (2) 2 cases of R-S cells and 1 case of R-S-like cells were clonally distinct from B-CLL clone and express LMP1, whereas 1 case of R-S-like cells was relating to the surrounding B-CLL cells and did not express LMP1; (3) 2/6 B-CLL cases transformed to HL convey VH4-34 and VH3-48 respectively. (1) Richter transformation to HL/R-S-like cells evolves from the B-CLL which originates from the germinal center or post germinal center B cells, indicating that different lymphoma cells of different subtypes in Richter syndrome come from different B cell lineage and possibly involve a different pathogenesis and pathway; (2) HL and R-S-like cells evolve from either the B-CLL clone or may develop as a clonally unrelated lymphoma, the independent secondary malignancies are appear to be EBV-positive, possibly as a consequence of the underlying immunodeficiency; (3) The biased usage of IgVH genes suggested a role of antigens involved in the HL variant of Richter syndrome.

  5. Bilateral renal tumors in an adult man with Smith-Magenis syndrome: The role of the FLCN gene.

    Science.gov (United States)

    Dardour, Leila; Verleyen, Pieter; Lesage, Karl; Holvoet, Maureen; Devriendt, Koen

    2016-10-01

    Smith-Magenis syndrome (SMS) is a contiguous-gene disorder most commonly caused by a deletion of chromosome 17p11.2. We report a 57 year-old man with SMS who presents bilateral renal tumors. This is most likely related to haploinsufficiency of FLCN gene, located in the deleted region, and a known tumor suppressor gene. Haploinsufficiency of FLCN causes Birt-Hogg-Dubé syndrome (BHDS), characterized by pulmonary cysts, renal and skin tumors. The present observation suggests that the follow-up of patients with SMS should also focus on possible manifestations of BHDS.

  6. Saethre-Chotzen syndrome and hyper IgE syndrome in a patient with a novel 11 bp deletion of the TWIST gene.

    Science.gov (United States)

    Boeck, A; Kosan, C; Ciznar, P; Kunz, J

    2001-11-15

    Molecular genetic studies in a seven-year-old boy and his mother demonstrated a novel 11 bp deletion in the TWIST gene (127del11), causing Saethre-Chotzen syndrome. The mother had rather mild signs of the Saethre-Chotzen syndrome; however, her son presented with marked acrocephalosyndactyly type 3, leading to craniotomy at three years. He also had recurrent infections and laboratory findings comparable with the hyper IgE syndrome, a rare primary immunodeficiency disorder. It is likely that the 11bp deletion caused the Saethre-Chotzen syndrome in the patient and his mother, and another, not yet identified genetic defect, seen in the patient but not in the mother, is responsible for the hyper IgE phenotype. A combination of these two congenital conditions has not been described to date.

  7. A new tool for modeling dune field evolution based on an accessible, GUI version of the Werner dune model

    Science.gov (United States)

    Barchyn, Thomas E.; Hugenholtz, Chris H.

    2012-02-01

    Research into aeolian dune form and dynamics has benefited from simple and abstract cellular automata computer models. Many of these models are based upon a seminal framework proposed by Werner (1995). Unfortunately, most versions of this model are not publicly available or are not provided in a format that promotes widespread use. In our view, this hinders progress in linking model simulations to empirical data (and vice versa). To this end, we introduce an accessible, graphical user interface (GUI) version of the Werner model. The novelty of this contribution is that it provides a simple interface and detailed instructions that encourage widespread use and extension of the Werner dune model for research and training purposes. By lowering barriers for researchers to develop and test hypotheses about aeolian dune and dune field patterns, this release addresses recent calls to improve access to earth surface models.

  8. Novel mutation involving the translation initiation codon of the growth hormone receptor gene (GHR) in a patient with Laron syndrome.

    Science.gov (United States)

    Quinteiro, Celsa; Castro-Feijoo, Lidia; Loidi, Lourdes; Barreiro, Jesus; de la Fuente, Maria; Dominguez, Fernando; Pombo, Manuel

    2002-01-01

    Laron syndrome (LS) or growth hormone (GH) insensitivity syndrome (GHIS) is an autosomal recessive disease due to molecular defects in the GH receptor gene (GHR). Most of the identified mutations are located on the extracelular domain of the receptor. We studied the GHR gene in a patient with LS and found a homozygous missense mutation in exon 2. The novel mutation is an A-->T transversion (ATG -->TTG) that abolishes the translation initiation codon of the GHR gene. This mutation is expected to prevent the translation of the protein. We present clinical, biochemical and molecular evidence of Laron syndrome as the result of a mutation (ATG-->TTG) in the codon for the initial methionine of the GHR gene.

  9. Search of phenotype related candidate genes using gene ontology-based semantic similarity and protein interaction information: application to Brugada syndrome.

    Science.gov (United States)

    Massanet, Raimon; Gallardo-Chacon, Joan-Josep; Caminal, Pere; Perera, Alexandre

    2009-01-01

    This work presents a methodology for finding phenotype candidate genes starting from a set of known related genes. This is accomplished by automatically mining and organizing the available scientific literature using Gene Ontology-based semantic similarity. As a case study, Brugada syndrome related genes have been used as input in order to obtain a list of other possible candidate genes related with this disease. Brugada anomaly produces a typical alteration in the Electrocardiogram and carriers of the disease show an increased probability of sudden death. Results show a set of semantically coherent proteins that are shown to be related with synaptic transmission and muscle contraction physiological processes.

  10. Vom Hören der Sphärenharmonie in Werner Schulzes "Sokrates"

    OpenAIRE

    Molina Moreno, Francisco

    2003-01-01

    El compositor, pensador, investigador y profesor de la Universidad para la Música y las Artes Escénicas de Viena, Werner Schulze, es autor de un drama con música sobre la vida y personalidad de Sócrates. El soporte verbal del drama lo constituyen pasajes de Platón y Aristófanes, en su versión original en griego antiguo. La obra incluye una evocación musical del mito de Er, al final de la "República" de Platón, que constituye el primer testimonio griego de la música de las esferas. En este tra...

  11. Werner Aisslinger 环保可以如此前卫

    Institute of Scientific and Technical Information of China (English)

    岳彬

    2011-01-01

    当生态环保成为绝大多数设计师作秀的噱头时,Werner Aisslinger对其的设计理解已经超越了简单意义上的材质"绿色"。他以简洁和实用的设计理念,来确保环保设计的纯粹性,设计作品很多都充满了现代主义色彩。

  12. Suggestive evidence for association of two potassium channel genes with different idiopathic generalised epilepsy syndromes.

    Science.gov (United States)

    Chioza, B; Osei-Lah, A; Wilkie, H; Nashef, L; McCormick, D; Asherson, P; Makoff, A J

    2002-12-01

    Several potassium channel genes have been implicated in epilepsy. We have investigated three such genes, KCNJ3, KCNJ6 and KCNQ2, by association studies using a broad sample of idiopathic generalised epilepsy (IGE) unselected by syndrome. One of the two single nucleotide polymorphisms (SNPs) examined in one of the inward rectifying potassium channel genes, KCNJ3, was associated with IGE by genotype (P=0.0097), while its association by allele was of borderline significance (P=0.051). Analysis of the different clinical subgroups within the IGE sample showed more significant association with the presence of absence seizures (P=0.0041) and which is still significant after correction for multiple testing. Neither SNP in the other rectifying potassium channel gene, KCNJ6, was associated with IGE or any subgroup. None of the three SNPs in the voltage-gated potassium channel gene, KCNQ2, was associated with IGE. However, one SNP was associated with epilepsy with generalised tonic clonic seizures only (P=0.016), as was an SNP approximately 56 kb distant in the closely linked nicotinic acetylcholine gene CHRNA4 (P=0.014). These two SNPs were not in linkage disequilibrium with each other, suggesting that if they are not true associations they have independently occurred by chance. Neither association remains significant after correcting for multiple testing.

  13. Somatic hypermutation of immunoglobulin genes is independent of the Bloom's syndrome DNA helicase.

    Science.gov (United States)

    Sack, S Z; Liu, Y; German, J; Green, N S

    1998-05-01

    Immunoglobulin gene somatic mutation leads to antibody affinity maturation through the introduction of multiple point mutations in the antigen binding site. No genes have as yet been identified that participate in this process. Bloom's syndrome (BS) is a chromosomal breakage disorder with a mutator phenotype. Most affected individuals exhibit an immunodeficiency of undetermined aetiology. The gene for this disorder, BLM, has recently been identified as a DNA helicase. If this gene were to play a role in immunoglobulin mutation, then people with BS may lack normally mutated antibodies. Since germ-line, non-mutated immunoglobulin genes generally produce low affinity antibodies, impaired helicase activity might be manifested as the immunodeficiency found in BS. Therefore, we asked whether BLM is specifically involved in immunoglobulin hypermutation. Sequences of immunoglobulin variable (V) regions were analysed from small unsorted blood samples obtained from BS individuals and compared with germ-line sequences. BS V regions displayed the normal distribution of mutations, indicating that the defect in BS is not related to the mechanism of somatic mutation. These data strongly argue against BLM being involved in this process. The genetic approach to identifying the genes involved in immunoglobulin mutation will require further studies of DNA repair- and immunodeficient individuals.

  14. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis

    Directory of Open Access Journals (Sweden)

    Lacombe Didier

    2011-05-01

    Full Text Available Abstract Background Usher syndrome (USH combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3. Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool. Methods We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3. Results Biallelic mutations were detected in 39 patients (72% and monoallelic mutations in an additional 10 patients (18.5%. In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%, and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48% were novel. Conclusions Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.

  15. Evaluation of Lynch syndrome modifier genes in 748 MMR mutation carriers.

    Science.gov (United States)

    Houlle, Solene; Charbonnier, Françoise; Houivet, Estelle; Tinat, Julie; Buisine, Marie-Pierre; Caron, Olivier; Benichou, Jacques; Baert-Desurmont, Stéphanie; Frebourg, Thierry

    2011-08-01

    Several studies have reported that, in Lynch syndrome resulting from mutations of the mismatch repair (MMR) genes, a CA repeat ≤17 within the IGF1 promoter, SNPs within the xenobiotic metabolizing enzyme gene CYP1A1 and SNPs on 8q23.3 and 11q23.1 modify colorectal cancer (CRC) risk in MMR mutation carriers. We analysed the impact of these polymorphisms on CRC risk in 748 French MMR mutation carriers derived from 359 families. We also analysed the effect of the Novel 1 SNP (18q21), which has recently been shown to increase CRC risk in the general population. We observed a significant difference in the CRC-free survival time between males and females, between MSH2 and MSH6 mutation carriers and between MLH1 and MSH6, indicating that this series is representative of Lynch syndrome. In contrast, the univariate log-rank test, as well as multivariate Cox model analysis controlling for familial aggregation and mutated MMR gene, year of birth and gender showed that the polymorphic alleles tested were not associated with a significant CRC risk increase, neither on the entire sample nor among males and females. This discrepancy with previous reports might be explained both by the genetic heterogeneity between the different populations analysed and the allelic heterogeneity of the MMR mutations. We conclude that genotyping of these polymorphisms is not useful to evaluate CRC risk in MMR mutation carriers and to optimize their clinical follow-up.

  16. Influence of variants in the NPY gene on obesity and metabolic syndrome features in Spanish children.

    Science.gov (United States)

    Olza, Josune; Gil-Campos, Mercedes; Leis, Rosaura; Rupérez, Azahara I; Tojo, Rafael; Cañete, Ramón; Gil, Angel; Aguilera, Concepción M

    2013-07-01

    Variants in the neuropeptide Y (NPY) gene have been associated with obesity and its traits. The objective of the present study was to evaluate the association of single nucleotide polymorphisms (SNPs) in the NPY gene with obesity, metabolic syndrome features, and inflammatory and cardiovascular disease (CVD) risk biomarkers in Spanish children. We recruited 292 obese children and 242 normal-body mass index (BMI) children. Height, weight, BMI, waist circumference, clinical and metabolic markers, adipokines, and inflammatory (PCR, IL-6, IL-8 and TNF-α) and CVD risk biomarkers (MPO, MMP-9, sE-selectin, sVCAM, sICAM, and PAI-1) were analyzed. Seven SNPs in the NPY gene were genotyped. The results of our study indicate that anthropometric measurements, clinical and metabolic markers, adipokines (leptin and resistin), and inflammatory and CVD risk biomarkers were generally elevated in the obese group. The exceptions to this finding included cholesterol, HDL-c, and adiponectin, which were lower in the obese group, and glucose, LDL-c, and MMP-9, which did not differ between the groups. Both rs16147 and rs16131 were associated with the risk of obesity, and the latter was also associated with insulin resistance, triacylglycerols, leptin, and HDL-c. Thus, we confirm the association of rs16147 with obesity, and we demonstrate for the first time the association of rs16131 with obesity and its possible impact on the early onset of metabolic syndrome features, mainly triacylglycerols, in children.

  17. Bridging the Gene-Behavior Divide through Neuroimaging Deletion Syndromes: Velocardiofacial (22q11.2 Deletion) and Williams (7q11.23 Deletion) Syndromes

    Science.gov (United States)

    Eisenberg, Daniel Paul; Jabbi, Mbemba; Berman, Karen Faith

    2010-01-01

    Investigating the relationship between genes and the neural substrates of complex human behavior promises to provide essential insight into the pathophysiology of mental disorders. One approach to this inquiry is through neuroimaging of individuals with microdeletion syndromes that manifest in specific neuropsychiatric phenotypes. Both Velocardiofacial Syndrome (VCFS) and Williams Syndrome (WS) involve haploinsufficiency of a relatively small set of identified genes on the one hand and association with distinct, clinically-relevant behavioral and cognitive profiles on the other hand. In VCFS, there is a deletion in chromosomal region 22q11.2 and a resultant predilection toward psychosis, poor arithmetic proficiency, and low performance intelligence quotients. In WS, there is a deletion in chromosomal region 7q11.23 and a resultant predilection toward hypersociability, non-social anxiety, impaired visuospatial construction, and often intellectual impairment. Structural and functional neuroimaging studies have begun not only to map these well-defined genetic alterations to systems-level brain abnormalities, but also to identify relationships between neural phenotypes and particular genes within the critical deletion regions. Though neuroimaging of both VCFS and WS presents specific, formidable methodological challenges, including comparison subject selection and accounting for neuroanatomical and vascular anomalies in patients, and many questions remain, the literature to date on these syndromes, reviewed herein, constitutes a fruitful “bottom-up” approach to defining gene-brain relationships. PMID:20206275

  18. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome.

    Science.gov (United States)

    Frank, Valeska; den Hollander, Anneke I; Brüchle, Nadina Ortiz; Zonneveld, Marijke N; Nürnberg, Gudrun; Becker, Christian; Du Bois, Gabriele; Kendziorra, Heide; Roosing, Susanne; Senderek, Jan; Nürnberg, Peter; Cremers, Frans P M; Zerres, Klaus; Bergmann, Carsten

    2008-01-01

    Meckel-Gruber syndrome (MKS) is an autosomal recessive, lethal multisystemic disorder characterized by meningooccipital encephalocele, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Recently, genes for MKS1 and MKS3 were identified, putting MKS on the list of ciliary disorders (ciliopathies). By positional cloning in a distantly related multiplex family, we mapped a novel locus for MKS to a 3-Mb interval on 12q21. Sequencing of the CEP290 gene located in the minimal critical region showed a homozygous 1-bp deletion supposed to lead to loss of function of the encoded centrosomal protein CEP290/nephrocystin-6. CEP290 is thought to be involved in chromosome segregation and localizes to cilia, centrosomes, and the nucleus. Subsequent analysis of another consanguineous multiplex family revealed homozygous haplotypes and the same frameshift mutation. Our findings add to the increasing body of evidence that ciliopathies can cause a broad spectrum of disease phenotypes, and pleiotropic effects of CEP290 mutations range from single organ involvement with isolated Leber congenital amaurosis to Joubert syndrome and lethal early embryonic multisystemic malformations in Meckel-Gruber syndrome. We compiled clinical and genetic data of all patients with CEP290 mutations described so far. No clear-cut genotype-phenotype correlations were apparent as almost all mutations are nonsense, frameshift, or splice-site changes and scattered throughout the gene irrespective of the patients' phenotypes. Conclusively, other factors than the type and location of CEP290 mutations may underlie phenotypic variability. (c) 2007 Wiley-Liss, Inc.

  19. A ceRNA analysis on LMNA gene focusing on the Hutchinson-Gilford progeria syndrome

    Science.gov (United States)

    2013-01-01

    Background Hutchinson-Gilford progeria syndrome is a rare dominant human disease of genetic origin. The average life expectancy is about 20 years, patients’ life quality is still very poor and no efficient therapy has yet been developed. It is caused by mutation of the LMNA gene, which results in accumulation in the nuclear membrane of a particular splicing form of Lamin-A called progerin. The mechanism by which progerin perturbs cellular homeostasis and leads to the symptoms is still under debate. Micro-RNAs are able to negatively regulate transcription by coupling with the 3’ UnTranslated Region of messenger RNAs. Several Micro-RNAs recognize the same 3’ UnTranslated Region and each Micro-RNA can recognize multiple 3’ UnTranslated Regions of different messenger RNAs. When different messenger RNAs are co-regulated via a similar panel of micro-RNAs, these messengers are called Competing Endogenous RNAs, or ceRNAs. The 3’ UnTranslated Region of the longest LMNA transcript was analysed looking for its ceRNAs. The aim of this study was to search for candidate genes and gene ontology functions possibly influenced by LMNA mutations that may exert a role in progeria development. Results 11 miRNAs were isolated as potential LMNA regulators. By computational analysis, the miRNAs pointed to 17 putative LMNA ceRNAs. Gene ontology analysis of isolated ceRNAs showed an enrichment in RNA interference and control of cell cycle functions. Conclusion This study isolated novel genes and functions potentially involved in LMNA network of regulation that could be involved in laminopathies such as the Hutchinson-Gilford progeria syndrome. PMID:23317481

  20. Unusual presentation of Kallmannn syndrome with contiguous gene deletion in three siblings of a family.

    Science.gov (United States)

    Madhu, Sri Venkat; Kant, Saket; Holla, Vikram Venkappayya; Arora, Rakesh; Rathi, Sahaj

    2012-12-01

    We report the case of 3 brothers aged 34, 24, and 22 years, unmarried, who presented to our endocrinology clinic with absence of secondary sexual characters. There was no such history in other siblings, but their maternal uncle had similar complaints. On examination, all 3 had pre-pubertal appearance, voice, and genitalia along with anosmia and bimanual synkinesia. Cryptorchidism was noticed in 2 while third person had small hypoplastic testes. It was also noted that all 3 patients had icthyosis mainly involving trunk, back, and limbs. The hormonal assays were consistent with isolated hypogonadotrophic hypogonadism. IQ testing revealed mental retardation in the 2 patients. Ultrasound showed ectopic right kidney in one patient, atrophic right kidney in the second patient while the third patient had normal kidneys. MRI brain of all the patients showed poorly visualized olfactory tract and bulb. Kallmann syndrome (KS) was diagnosed based on hormonal evaluation and MRI results. Of the four types of KS: Synkinesia, renal anomaly, and X-linked pedigree pattern in our patients pointed towards X-linked type 1 KS as the possible cause. But, icthyosis and mental retardation are not usual presentation of type 1 KS. They are usually seen as a result of contiguous gene deletion of KAL1, steroid sulfatase (STS), and mental retardation (MRX) gene on X chromosome. Hence, the possible gene defect in our cases is inherited defect in contiguous gene deletion. The contiguous gene deletion as the cause of KS in 3 patients of same family is very rare and worth reporting. Also, the significance of phenotype-genotypic association in Kallmann syndrome is discussed.

  1. Neonatal Dubin-Johnson syndrome: novel compound heterozygous mutation in the ABCC2 gene.

    Science.gov (United States)

    Okada, Hitoshi; Kusaka, Takashi; Fuke, Noriko; Kunikata, Jun; Kondo, Sonoko; Iwase, Takashi; Nan, Wang; Hirota, Takeshi; Ieiri, Ichiro; Itoh, Susumu

    2014-10-01

    Dubin-Johnson syndrome (DJS) is an autosomal recessive inherited disorder characterized by conjugated hyperbilirubinemia. Neonatal-onset DJS is rare. It is caused by dysfunction of adenosine triphosphate-binding cassette, sub-family C, member 2 (ABCC2). We found a novel compound heterozygous mutation of DJS-related gene: W709R (T2145C): a missense mutation in exon 17, and R768W (C2302T), a missense mutation in exon 18. Serum diglucuronosyl bilirubin/monoglucuronosyl bilirubin ratio was high. ABCC2 may excrete diglucuronosyl bilirubin preferentially over monoglucuronosyl bilirubin.

  2. When chromatin organisation floats astray: the Srcap gene and Floating-Harbor syndrome.

    Science.gov (United States)

    Messina, Giovanni; Atterrato, Maria Teresa; Dimitri, Patrizio

    2016-12-01

    Floating-Harbor syndrome (FHS) is a rare human disease characterised by delayed bone mineralisation and growth deficiency, often associated with mental retardation and skeletal and craniofacial abnormalities. FHS was first described at Boston's Floating Hospital 42 years ago, but the causative gene, called Srcap, was identified only recently. Truncated SRCAP protein variants have been implicated in the mechanism of FHS, but the molecular bases underlying the disease must still be elucidated and investigating the molecular defects leading to the onset of FHS remains a challenge. Here we comprehensively review recent work and provide alterative hypotheses to explain how the Srcap truncating mutations lead to the onset of FHS.

  3. Severe myoclonus-dystonia syndrome associated with a novel epsilon-sarcoglycan gene truncating mutation.

    Science.gov (United States)

    Maréchal, Lucie; Raux, Grégory; Dumanchin, Cécile; Lefebvre, Guillaume; Deslandre, Emmanuelle; Girard, Carole; Campion, Dominique; Parain, Dominique; Frebourg, Thierry; Hannequin, Didier

    2003-05-15

    Myoclonus-dystonia syndrome (MDS) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions, associated with psychiatric manifestations. MDS is usually considered as a benign disease. In most of the families, MDS is linked to chromosome 7q21 and mutations within epsilon-sarcoglycan (SGCE) gene have been recently described. We report a MDS family with a severe and heterogeneous phenotype, including myoclonus with important functional impact and several psychiatric features, characterized by obsessive-compulsive disorder, depression, and anxiety. This phenotype was shown to be associated with a novel truncating mutation located within exon 4 of SGCE.

  4. Genetic variation in the oxytocin receptor (OXTR) gene is associated with Asperger Syndrome.

    Science.gov (United States)

    Di Napoli, Agnese; Warrier, Varun; Baron-Cohen, Simon; Chakrabarti, Bhismadev

    2014-01-01

    Autism Spectrum Conditions (ASC) are a group of neurodevelopmental conditions characterized by impairments in communication and social interaction, alongside unusually repetitive behaviors and narrow interests. ASC are highly heritable and have complex patterns of inheritance where multiple genes are involved, alongside environmental and epigenetic factors. Asperger Syndrome (AS) is a subgroup of these conditions, where there is no history of language or cognitive delay. Animal models suggest a role for oxytocin (OXT) and oxytocin receptor (OXTR) genes in social-emotional behaviors, and several studies indicate that the oxytocin/oxytocin receptor system is altered in individuals with ASC. Previous studies have reported associations between genetic variations in the OXTR gene and ASC. The present study tested for an association between nine single nucleotide polymorphisms (SNPs) in the OXTR gene and AS in 530 individuals of Caucasian origin, using SNP association test and haplotype analysis. There was a significant association between rs2268493 in OXTR and AS. Multiple haplotypes that include this SNP (rs2268493-rs2254298, rs2268490-rs2268493-rs2254298, rs2268493-rs2254298-rs53576, rs237885-rs2268490-rs2268493-rs2254298, rs2268490-rs2268493-rs2254298-rs53576) were also associated with AS. rs2268493 has been previously associated with ASC and putatively alters several transcription factor-binding sites and regulates chromatin states, either directly or through other variants in linkage disequilibrium (LD). This study reports a significant association of the sequence variant rs2268493 in the OXTR gene and associated haplotypes with AS.

  5. Integration of gene expression, clinical, and epidemiologic data to characterize Chronic Fatigue Syndrome

    Directory of Open Access Journals (Sweden)

    Vernon Suzanne D

    2003-12-01

    Full Text Available Abstract Background Chronic fatigue syndrome (CFS has no diagnostic clinical signs or diagnostic laboratory abnormalities and it is unclear if it represents a single illness. The CFS research case definition recommends stratifying subjects by co-morbid conditions, fatigue level and duration, or functional impairment. But to date, this analysis approach has not yielded any further insight into CFS pathogenesis. This study used the integration of peripheral blood gene expression results with epidemiologic and clinical data to determine whether CFS is a single or heterogeneous illness. Results CFS subjects were grouped by several clinical and epidemiological variables thought to be important in defining the illness. Statistical tests and cluster analysis were used to distinguish CFS subjects and identify differentially expressed genes. These genes were identified only when CFS subjects were grouped according to illness onset and the majority of genes were involved in pathways of purine and pyrimidine metabolism, glycolysis, oxidative phosphorylation, and glucose metabolism. Conclusion These results provide a physiologic basis that suggests CFS is a heterogeneous illness. The differentially expressed genes imply fundamental metabolic perturbations that will be further investigated and illustrates the power of microarray technology for furthering our understanding CFS.

  6. Association of polymorphisms of interleukin-18 gene promoter region with polycystic ovary syndrome in chinese population

    Directory of Open Access Journals (Sweden)

    Li Mei-zhi

    2010-10-01

    Full Text Available Abstract Background Recent research shows that polycystic ovary syndrome (PCOS may have an association with low-grade chronic inflammation, and that PCOS may induce an increase in serum interleukin-18 (IL-18 levels. Methods To investigate the polymorphisms of the IL-18 gene promoters with PCOS, two single nucleotide polymorphisms (SNPs in the promoter of the IL-18 gene (at positions -607C/A and -137G/C in 118 Chinese women with PCOS and 79 controls were evaluated using polymerase chain reaction (PCR. Results No significant differences were found in the genotype distribution, allele frequency and haplotype frequency between the PCOS and control groups. Further analysis demonstrated a relationship between IL-18 gene promoter polymorphisms and PCOS insulin resistance (IR. Regarding the -137 allele frequency, G and C allele frequencies were 93.5% and 6.5%, respectively, in the PCOS with IR patients; G and C allele frequencies were 85.4% and 14.6%, respectively, in PCOS patients without IR (chi2 = 3.601, P = 0.048. Conclusions The presence of a polymorphism in the IL-18 gene was found to have no correlation with the occurrence of PCOS. Carriage of the C allele at position -137 in the promoter of the IL-18 gene may play a protective role from the development of PCOS IR.

  7. Lentivirus-based Gene Therapy of Hematopoietic Stem Cells in Wiskott-Aldrich Syndrome

    Science.gov (United States)

    Aiuti, Alessandro; Biasco, Luca; Scaramuzza, Samantha; Ferrua, Francesca; Cicalese, Maria Pia; Baricordi, Cristina; Dionisio, Francesca; Calabria, Andrea; Giannelli, Stefania; Castiello, Maria Carmina; Bosticardo, Marita; Evangelio, Costanza; Assanelli, Andrea; Casiraghi, Miriam; Di Nunzio, Sara; Callegaro, Luciano; Benati, Claudia; Rizzardi, Paolo; Pellin, Danilo; Di Serio, Clelia; Schmidt, Manfred; Von Kalle, Christof; Gardner, Jason; Mehta, Nalini; Neduva, Victor; Dow, David J.; Galy, Anne; Miniero, Roberto; Finocchi, Andrea; Metin, Ayse; Banerjee, Pinaki; Orange, Jordan; Galimberti, Stefania; Valsecchi, Maria Grazia; Biffi, Alessandra; Montini, Eugenio; Villa, Anna; Ciceri, Fabio; Roncarolo, Maria Grazia; Naldini, Luigi

    2015-01-01

    Wiskott-Aldrich Syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and re-infused the cells after reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical score. Vector integration analyses revealed highly polyclonal and multi-lineage haematopoiesis resulting from the gene corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes and no aberrant clonal expansion was observed after 20–32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS. PMID:23845947

  8. ALK7 Gene Polymorphism is Associated with Metabolic Syndrome Risk and Cardiovascular Remodeling

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Wenchao; Wang, Hui; Zhang, Wei [Key Laboratory of Cardiovascular Remodeling and Function Research Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan (China); Lv, Ruijuan [Department of Emergency, Qilu Hospital of Shandong University, Jinan (China); Wang, Zhihao [Key Laboratory of Cardiovascular Remodeling and Function Research Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan (China); Department of Geriatrics, Qilu Hospital of Shandong University, Jinan (China); Shang, Yuanyuan; Zhang, Yun; Zhong, Ming [Key Laboratory of Cardiovascular Remodeling and Function Research Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan (China); Chen, Yuguo; Tang, Mengxiong, E-mail: tangmengxiongsdu8@163.com [Key Laboratory of Cardiovascular Remodeling and Function Research Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan (China); Department of Emergency, Qilu Hospital of Shandong University, Jinan (China)

    2013-08-15

    Activin receptor-like kinase 7 (ALK7) is a type I receptor for the TGF-β superfamily and has recently been demonstrated to play an important role in the maintenance of metabolic homeostasis. To investigate the association of the ALK7 gene polymorphism with metabolic syndrome (MetS) and cardiovascular remodeling in MetS patients. The single nucleotide polymorphism rs13010956 in the ALK7 gene was genotyped in 351 Chinese subjects undergoing carotid and cardiac ultrasonography. The associations of the ALK7 gene polymorphism with the MetS phenotype, MetS parameters, and cardiovascular ultrasonic features were analyzed. The rs13010956 polymorphism in the ALK7 gene was found to be significantly associated with the MetS phenotype in females (p < 0.05) and was also significantly associated with blood pressure in the total (p < 0.05) and female populations (p < 0.01). Further analysis revealed that rs13010956 was associated with mean intima-media thickness of the carotid arteries in females (p < 0.05). After control for body mass index, blood pressure, fasting blood glucose, and triglycerides, rs13010956 was also found to be significantly associated with left ventricular mass index in the total (p < 0.05) and female populations (p < 0.05). Our findings suggested that the ALK7 gene polymorphism rs13010956 was significantly associated with MetS risk in females and may be involved in cardiovascular remodeling in MetS patients.

  9. Large contiguous gene deletions in Sjögren-Larsson syndrome.

    Science.gov (United States)

    Engelstad, Holly; Carney, Gael; S'aulis, Dana; Rise, Janae; Sanger, Warren G; Rudd, M Katharine; Richard, Gabriele; Carr, Christopher W; Abdul-Rahman, Omar A; Rizzo, William B

    2011-11-01

    Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis.

  10. Sequence analysis of 21 genes located in the Kartagener syndrome linkage region on chromosome 15q.

    Science.gov (United States)

    Geremek, Maciej; Schoenmaker, Frederieke; Zietkiewicz, Ewa; Pogorzelski, Andrzej; Diehl, Scott; Wijmenga, Cisca; Witt, Michal

    2008-06-01

    Primary ciliary dyskinesia (PCD) is a rare genetic disorder, which shows extensive genetic heterogeneity and is mostly inherited in an autosomal recessive fashion. There are four genes with a proven pathogenetic role in PCD. DNAH5 and DNAI1 are involved in 28 and 10% of PCD cases, respectively, while two other genes, DNAH11 and TXNDC3, have been identified as causal in one PCD family each. We have previously identified a 3.5 cM (2.82 Mb) region on chromosome 15q linked to Kartagener syndrome (KS), a subtype of PCD characterized by the randomization of body organ positioning. We have now refined the KS candidate region to a 1.8 Mb segment containing 18 known genes. The coding regions of these genes and three neighboring genes were subjected to sequence analysis in seven KS probands, and we were able to identify 60 single nucleotide sequence variants, 35 of which resided in mRNA coding sequences. However, none of the variations alone could explain the occurrence of the disease in these patients.

  11. Is catechol-o-methyltransferase gene polymorphism a risk factor in the development of premenstrual syndrome?

    Science.gov (United States)

    Deveci, Esma Ozturk; Selek, Salih; Camuzcuoglu, Aysun; Hilali, Nese Gul; Camuzcuoglu, Hakan; Erdal, Mehmet Emin; Vural, Mehmet

    2014-01-01

    Objective The objective of this study was to investigate whether there was a correlation between catechol-o-methyltransferase (COMT) gene polymorphism, which is believed to play a role in the etiology of psychotic disorders, and premenstrual syndrome (PMS). Methods Fifty-three women with regular menstrual cycles, aged between 18 and 46 years and diagnosed with PMS according to the American Congress of Obstetrics and Gynecology criteria were included in this study as the study group, and 53 healthy women having no health problems were selected as the controls. Venous blood was collected from all patients included in the study and kept at -18℃ prior to analysis. Results There was no significant difference between the groups in terms of demographic features such as age, body mass index, number of pregnancies, parity, and number of children. No statistically significant difference was observed in terms of COMT gene polymorphism (p=0.61) between women in the PMS and the control groups. However, a significant difference was found between arthralgia, which is an indicator of PMS, and low-enzyme activity COMT gene (Met/Met) polymorphism (p=0.04). Conclusion These results suggested that there was no significant relationship between PMS and COMT gene polymorphism. Since we could not find a direct correlation between the COMT gene polymorphism and PMS, further studies including alternative neurotransmitter pathways are needed to find an effective treatment for this disease. PMID:25045629

  12. The 21-cm signature of the first stars during the Lyman-Werner feedback era

    CERN Document Server

    Fialkov, Anastasia; Visbal, Eli; Tseliakhovich, Dmitriy; Hirata, Christopher M

    2012-01-01

    The formation of the first stars is an exciting frontier area in astronomy. Early redshifts z ~ 20 have become observationally promising as a result of a recently recognized effect of a supersonic relative velocity between the dark matter and gas. This effect produces prominent structure on 100 comoving Mpc scales, which makes it much more feasible to detect 21-cm fluctuations from the epoch of first heating. We use semi-numerical hybrid methods to follow for the first time the joint evolution of the X-ray and Lyman-Werner radiative backgrounds, including the effect of the supersonic streaming velocity on the cosmic distribution of stars. We incorporate self-consistently the negative feedback on star formation induced by the Lyman-Werner radiation, which dissociates molecular hydrogen and thus suppresses gas cooling. We find that the feedback delays the X-ray heating transition by a Delta z ~ 2, but leaves a promisingly large fluctuation signal over a broad redshift range. The large-scale power spectrum is pr...

  13. Analysis of Ellis van Creveld syndrome gene products: implications for cardiovascular development and disease.

    Science.gov (United States)

    Sund, Kristen Lipscomb; Roelker, Stephanie; Ramachandran, Vijaya; Durbin, Lisa; Benson, D Woodrow

    2009-05-15

    Mutations identified in a cohort of patients with atrioventricular septal defects as a part of Ellis van Creveld syndrome (EvC syndrome) led us to study the role of two non-homologous genes, EVC and LBN, in heart development and disease pathogenesis. To address the cause of locus heterogeneity resulting in an indistinguishable heart-hand phenotype, we carried out in situ hybridization and immunofluorescence and identified co-localization of Evc and Lbn mRNA and protein. In the heart, expression was identified to be strongest in the secondary heart field, including both the outflow tract and the dorsal mesenchymal protrusion, but was also found in mesenchymal structures of the atrial septum and the atrioventricular cushions. Finally, we studied the transcriptional hierarchy of EVC and LBN but did not find any evidence of direct transcriptional interregulation between the two. Due to the locus heterogeneity of human mutations predicted to result in a loss of protein function, a bidirectional genomic organization and overlapping expression patterns, we speculate that these proteins function coordinately in cardiac development and that loss of this coordinate function results in the characteristics of EvC syndrome.

  14. Gene expression of adipose tissue, endothelial cells and platelets in subjects with metabolic syndrome (Review).

    Science.gov (United States)

    Pérez, Pablo M; Moore-Carrasco, Rodrigo; González, Daniel R; Fuentes, Eduardo Q; Palomo, Iván G

    2012-05-01

    Metabolic syndrome is a combination of medical disorders including hypertension, dyslipidemia, hyperglycemia, insulin resistance and increased waist circumference, and is associated with a higher risk of cardiovascular disease. An increase in adipose tissue mass is associated with the augmented secretion of certain adipokines, such as interleukin-6, tumor necrosis factor-α and resistin, which cause endothelial dysfunction (an increase in vasoconstrictor molecules and in the expression of adhesion molecules as well as a decrease of vasodilator molecules, amongst other features) and hemostasis alterations that also favor a prothrombotic state (increased fibrinogen and plasminogen activator inhibitor-1 concentrations and platelet activation/aggregation). This interaction between adipose tissue, endothelial cells and platelets is associated with an increase or decrease in the expression of several transcription factors (peroxisome proliferator-activated receptors, CCAAT-enhancer-binding proteins, carbohydrate responsive element-binding proteins and sterol regulatory element-binding proteins) that play a crucial role in the regulation of distinct metabolic pathways related to the metabolic syndrome. In the present review, we present the primary changes in adipose tissue, endothelial cells and platelets in subjects with metabolic syndrome and their possible target sites at the gene expression level.

  15. Clinical phenotype and candidate genes for the 5q31.3 microdeletion syndrome.

    Science.gov (United States)

    Hosoki, Kana; Ohta, Tohru; Natsume, Jun; Imai, Sumiko; Okumura, Akihisa; Matsui, Takeshi; Harada, Naoki; Bacino, Carlos A; Scaglia, Fernando; Jones, Jeremy Y; Niikawa, Norio; Saitoh, Shinji

    2012-08-01

    Array-based technologies have led to the identification of many novel microdeletion and microduplication syndromes demonstrating multiple congenital anomalies and intellectual disability (MCA/ID). We have used chromosomal microarray analysis for the evaluation of patients with MCA/ID and/or neonatal hypotonia. Three overlapping de novo microdeletions at 5q31.3 with the shortest region of overlap (SRO) of 370 kb were detected in three unrelated patients. These patients showed similar clinical features including severe neonatal hypotonia, neonatal feeding difficulties, respiratory distress, characteristic facial features, and severe developmental delay. These features are consistent with the 5q31.3 microdeletion syndrome originally proposed by Shimojima et al., providing further evidence that this syndrome is clinically discernible. The 370 kb SRO encompasses only four RefSeq genes including neuregulin 2 (NRG2) and purine-rich element binding protein A (PURA). NRG2 is one of the members of the neuregulin family related to neuronal and glial cell growth and differentiation, thus making NRG2 a good candidate for the observed phenotype. Moreover, PURA is also a good candidate because Pura-deficient mice demonstrate postnatal neurological manifestations.

  16. Sodium Channel Gene Mutations in Children with GEFS+ and Dravet Syndrome: A Cross Sectional Study

    Directory of Open Access Journals (Sweden)

    Seyed Hassan TONEKABONI

    2013-06-01

    Full Text Available  How to Cite This Article: Tonekaboni SH, Ebrahimi A, Bakhshandeh Bali MK, Houshmand M, Moghaddasi M, Taghdiri MM, Nasehi MM. Sodium Channel Gene Mutations in Children with GEFS+ and Dravet Syndrome: A Cross Sectional Study. Iran J Child Neurol. 2013 Winter; 7 (1:25-29. Objective Dravet syndrome or severe myoclonic epilepsy of infancy (SMEI is a baleful epileptic encephalopathy that begins in the first year of life. This syndrome specified by febrile seizures followed by intractable epilepsy, disturbed psychomotor development, and ataxia. Clinical similarities between Dravet syndrome and generalized epilepsy with febrile seizure plus (GEFS+ includes occurrence of febrile seizures and joint molecular genetic etiology. Shared features of these two diseases support the idea that these two disorders represent a severity spectrum of the same illness. Nowadays, more than 60 heterozygous pattern SCN1A mutations, which many are de novo mutations, have been detected in Dravet syndrome. Materials & Methods From May 2008 to August 2012, 35 patients who referred to Pediatric Neurology Clinic of Mofid Children Hospital in Tehran were enrolled in this study. Entrance criterion of this study was having equal or more than four criteria for Dravet syndrome. We compared clinical features and genetic findings of the patients diagnosed as Dravet syndrome or GEFS+. Results 35 patients (15 girls and 20 boys underwent genetic testing. Mean age of them was 7.7 years (a range of 13 months to 15 years. Three criteria that were best evident in SCN1A mutation positive patients are as follows: Normal development before the onset of seizures, onset of seizure before age of one year, and psychomotor retardation after onset of seizures. Our genetic testing showed that 1 of 3 (33.3% patients with clinical Dravet syndrome and 3 of 20 (15% patients that diagnosed as GEFS+, had SCN1A mutation. Conclusion In this study, normal development before seizure onset, seizures beginning

  17. A Newly-Discovered Mutation in the RFX6 Gene of the Rare Mitchell-Riley Syndrome

    Science.gov (United States)

    Khan, Nusrat; Dandan, Waleed; Al Hassani, Noura; Hadi, Suha

    2016-01-01

    Mitchell-Riley syndrome is a genetic disorder characterized by neonatal diabetes, pancreatic hypoplasia, intestinal atresia and/or malrotation, biliary atresia, and gallbladder aplasia or hypoplasia. It was considered a variant of the Martinez-Frias syndrome with similar phenotypic characteristics, except for neonatal diabetes and tracheoesophageal fistula. However, the genetic mutation in (regulatory factor X on chromosome 6) RFX6 was only detected in babies who had diabetes, making it different from the previously known mutations for the disease. This is the first reported case of a classical Mitchell-Riley syndrome in the Arab peninsula along with additional features and novel mutations in the RFX6 gene. PMID:26761945

  18. Identification of novel mutation in cathepsin C gene causing Papillon-Lefèvre Syndrome in Mexican patients

    OpenAIRE

    2013-01-01

    Abstract Background Papillon-Lefèvre Syndrome (PLS) is a type IV genodermatosis caused by mutations in cathepsin C (CTSC), with a worldwide prevalence of 1–4 cases per million in the general population. In México, the prevalence of this syndrome is unknown, and there are few case reports. The diagnosis of twenty patients in the state of Sinaloa highlights the need to characterize this syndrome in Mexicans. Methods To understand the basis of PLS in Mexicans, the gene expression, enzymatic acti...

  19. Identification of novel mutation in cathepsin C gene causing Papillon-Lefèvre Syndrome in Mexican patients

    OpenAIRE

    2013-01-01

    Background Papillon-Lefèvre Syndrome (PLS) is a type IV genodermatosis caused by mutations in cathepsin C (CTSC), with a worldwide prevalence of 1–4 cases per million in the general population. In México, the prevalence of this syndrome is unknown, and there are few case reports. The diagnosis of twenty patients in the state of Sinaloa highlights the need to characterize this syndrome in Mexicans. Methods To understand the basis of PLS in Mexicans, the gene expression, enzymatic activity and ...

  20. A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family.

    Science.gov (United States)

    Sher, Gulab; Naeem, Muhammad

    2014-01-01

    Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive rare disorder characterized by hyperphalangism of digits, facial dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor and mental development, and growth retardation. Loss of function mutations have been recently reported in the CHSY1 gene to cause the TPBS. Here, we report a novel missense mutation (c.1897 G > A) in the CHSY1 gene in two TPBS patients from a consanguineous Pakistani family. The mutation predicted substitution of a highly conserved aspartate amino acid residue to asparagine at position 633 in the protein (D633N). Polyphen analysis supported the pathogenicity of D36N mutation. Our finding extends the body of recent evidence that supports the role of CHSY1 as a potential mediator of BMP signaling.

  1. 657del5 mutation of the NBS1 gene in myelodysplastic syndrome

    Directory of Open Access Journals (Sweden)

    Bunjevacki Vera

    2014-01-01

    Full Text Available Myelodysplastic syndromes (MDS are clonal hematologic stem cell disorders with an as yet unknown molecular pathology. Genetic instability has been proposed as a cause of MDS. Mutations in the NBS1 gene, whose product nibrin (p95 is involved in DNA damage repair and cell-cycle control, might be associated with an elevated predisposition to the development of MDS. The aim of the study was to examine truncating 5 bp deletion (657del5, the most frequent NBS1 gene mutation in Slavic populations, in MDS patients. Among 71 MDS patients, we found one case that was heterozygous for the NBS1 657del5 mutation. To the best of our knowledge, this is the first report of a NBS1 mutation in MDS. [Projekat Ministarstva nauke Republike Srbije, br. 175091

  2. Relatively common mutations of the Bloom syndrome gene in the Japanese population.

    Science.gov (United States)

    Kaneko, Hideo; Isogai, Kouji; Fukao, Toshiyuki; Matsui, Eiko; Kasahara, Kimiko; Yachie, Akihiro; Seki, Hidetoshi; Koizumi, Shoichi; Arai, Masami; Utunomiya, Joji; Miki, Yoshio; Kondo, Naomi

    2004-09-01

    Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by lupus-like erythematous facial telangiectasia, sun sensitivity, infertility, stunted growth and a high predisposition to various types of cancer. Chromosomal abnormalities are hallmarks of this disorder, and high frequencies of sister chromatid exchanges and quadriradial configurations in lymphocytes and fibroblasts are diagnostic features. BLM is the causative gene for BS. We investigated the mutation in the BLM gene in 4 Japanese BS kindreds. Taken together with previously documented mutations, 2 kindreds were homozygous for 631delCAA and 2 were compound heterozygous for 631delCAA. The silent mutation of A1055C (Thr to Thr) was detected in control Japanese individuals. The 6-bp deletion/7-bp insertion at position 2,281, which most Askenazi Jewish BS patients carry, was not detected in 200 Japanese alleles. These results suggest that 631delCAA is a relatively common mutation among the Japanese BS patients.

  3. Angelman syndrome due to a termination codon mutation of the UBE3A gene.

    Science.gov (United States)

    Al-Maawali, Almundher; Machado, Jerry; Fang, Ping; Dupuis, Lucie; Faghfoury, Hannaneh; Mendoza-Londono, Roberto

    2013-03-01

    Angelman syndrome is a neurodevelopmental disorder characterized by global developmental delay, mental retardation, seizures, microcephaly, and severe speech delay. It may be caused by deletion of chromosome region 15q11.2 of the maternally inherited chromosome, mutations in the UBE3A gene, uniparental disomy, or imprinting defects. Most patients with this diagnosis have a severe phenotype, and a few have a mild form of the disease. We report a patient with a novel mutation in the UBE3A gene that consists of a deletion of the termination codon (c.2556-*+6del GTAAAACAAA) and results in an elongated protein E3 ubiquitin-protein ligase. Our patient has a mild phenotype compared with other patients in general and specifically to patients with UBE3A mutations. He has mild developmental delay, moderate speech delay, and no seizures. Recognition of this genotype-phenotype correlation will allow better genetic counseling to other patients with similar stop codon mutations.

  4. Gene localisation for Wilson-Turner syndrome (WTS:MIM 309585)

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-07-12

    The gene for this syndrome of X-linked mental retardation with gynecomastia, obesity, speech difficulties, tapering fingers and small feet was mapped between Xp21.1 and Xq22. Linkage to DXS255 at Xp11 was firmly established, with no recombination. Subsequent characterization of numerous microsatellite markers and development of the background genetic map in this region of the X chromosome has enabled significant reduction to the localization of the gene for WTS in the one family so far reported. The new linkage data were obtained as described previously and are presented in Table I. The closest flanking markers are DXS426 at Xp11.3 and DXS990 at Xq21.3. The regional localization is significantly reduced from the previous interval of 66 cM to an interval of 25 cM. The maximum two-point lod score is now 6.07 at AR. 6 refs., 1 tab.

  5. Tyrosinemia type II (Richner-Hanhart syndrome): a new mutation in the TAT gene.

    Science.gov (United States)

    Culic, Vida; Betz, Regina C; Refke, Melanie; Fumic, Ksenija; Pavelic, Jasminka

    2011-01-01

    In the present study we report the clinical features and the molecular genetic investigation of the tyrosine aminotransferase (TAT) gene in a young girl from Croatia with Richner-Hanhart syndrome, mainly suffering from photophobia, hyperkeratosis of the palmes and soles and slight neurological abnormalities. Sequencing analysis of the TAT gene revealed a novel homozygous missense mutation c.1250G>A (p.R417Q) in exon 12, and herewith confirmed the clinical diagnosis. Showing the first symptoms in babyhood, at the age of 8 years it was for the first time clinically diagnosed that the patient suffers from tyrosinemia type II and a therapy with tyrosine and phenylalanine reduced diet has been started successfully. All symptoms disappeared within 2-4 weeks. Since that time, we have been following the girl until today for more than ten years. She is in a good condition, and attends the normal high school program.

  6. VPA alleviates neurological deficits and restores gene expression in a mouse model of Rett syndrome.

    Directory of Open Access Journals (Sweden)

    Weixiang Guo

    Full Text Available Rett syndrome (RTT is a devastating neurodevelopmental disorder that occurs once in every 10,000-15,000 live female births. Despite intensive research, no effective cure is yet available. Valproic acid (VPA has been used widely to treat mood disorder, epilepsy, and a growing number of other disorders. In limited clinical studies, VPA has also been used to control seizure in RTT patients with promising albeit somewhat unclear efficacy. In this study we tested the effect of VPA on the neurological symptoms of RTT and discovered that short-term VPA treatment during the symptomatic period could reduce neurological symptoms in RTT mice. We found that VPA restores the expression of a subset of genes in RTT mouse brains, and these genes clustered in neurological disease and developmental disorder networks. Our data suggest that VPA could be used as a drug to alleviate RTT symptoms.

  7. RAS gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes

    Energy Technology Data Exchange (ETDEWEB)

    Janssen, J.W.G.; Steenvoorden, A.C.M.; Lyons, J.; Anger, B.; Boehlke, J.U.; Bos, J.L.; Seliger, H.; Bartram, C.R.

    1987-12-01

    The authors report on investigations aimed at detecting mutated RAS genes in a variety of preleukemic disorders and leukemias of myeloid origin. DNA transfection analyses (tumorigenicity assay) and hybridization to mutation-specific oligonucleotide probes established NRAS mutations in codon 12 or 61 of 4/9 acute myelocytic leukemias (AML) and three AML lines. Leukemic cells of another AML patient showed HRAS gene activation. By using a rapid and sensitive dot-blot screening procedure based on the combination of in vitro amplification of RAS-specific sequences and oligonucleotide hybridization they additionally screened 15 myelodysplastic syndromes, 26 Philadelphia chromosome-positive chronic myelocytic leukemias in chronic or acute phase, and 19 other chronic myeloproliferative disorders. A mutation within NRAS codon 12 could thus be demonstrated in a patient with idiopathic myelofibrosis and in another with chronic myelomonocytic leukemia. Moreover, mutated NRAS sequences were detected in lymphocytes, in granulocytes, as well as in monocytes/macrophages of the latter case.

  8. MECP2 gene mutation analysis in Chinese patients with Rett syndrome

    Institute of Scientific and Technical Information of China (English)

    PanH; WangYP; BaoXH; MengHD; ZhangY; WuXR; ShenY

    2005-01-01

    Rett syndrome (RTT) is a progressive neurodevelopmental disorder that affects almost exclusively girls. Mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) have been found to be a cause. In order to study the spectrum of MECP2 mutations in Chinese patients, we employed PCR and sequencing of the coding region of MECP2 gene in 31 Chinese cases of classical sporadic RTT. Mutations in MECP2 were found in about 55%. Twelve different mutations in exon 3 were identified in 17 of these 31 patients; two of these are novel. A novel missense variant was detected in the C-terminal region in a patient and her father who was normal. In addition, there was a single nucleotide variant in the 3'UTR.

  9. Effect of angiotensin converting enzyme gene I/D polymorphism in patients with metabolic syndrome in North Indian population

    Institute of Scientific and Technical Information of China (English)

    Gaurav Mittal; Vibhanshu Gupta; Shahzad F Haque; Anwer S Khan

    2011-01-01

    Background Numerous studies have investigated the effect of angiotensin converting enzyme (ACE) gene I/D polymorphism and various cardiovascular risk factors in different populations with varied results. Currently, the association of ACE gene polymorphism with metabolic syndrome has not been studied in North Indians. While studies assessing the effect with polymorphism on each of the components of metabolic syndrome separately are present, data regarding the metabolic syndrome per se are sparse. The present study evaluated the effect of ACE gene I/D polymorphism in patients with metabolic syndrome in North Indian population at a tertiary care centre.Methods Fifty subjects, with thirty cases of metabolic syndrome (NCEP/ATP Ⅲ guidelines, 2004) and twenty age and gender matched healthy controls were chosen. Detailed history was reviewed and clinical examination of the subjects was carried out. Relevant investigations including blood glucose (fasting and post prandial), blood urea, serum creatinine and serum lipids were done. DNA of cases and controls was analysed for I/D polymorphism using polymerase chain reaction.Results D/D genotype was more frequent in patients with metabolic syndrome as compared with healthy controls (P<0.05). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) was significantly higher in the D/D genotype than I/D and I/I genotypes (P <0.05). Our study also showed positive association between obesity, fasting blood glucose and ACE gene polymorphism while no association was found with triglycerides and high density lipoprotein cholesterol.The I/I group was significantly associated with waist circumference and fasting blood glucose (P <0.05).Conclusion Our study clearly showed that metabolic syndrome was associated with ACE gene polymorphism.However due to less number of subjects in the study further studies are needed to corroborate our results.

  10. Otitis media in a new mouse model for CHARGE syndrome with a deletion in the Chd7 gene.

    Directory of Open Access Journals (Sweden)

    Cong Tian

    Full Text Available Otitis media is a middle ear disease common in children under three years old. Otitis media can occur in normal individuals with no other symptoms or syndromes, but it is often seen in individuals clinically diagnosed with genetic diseases such as CHARGE syndrome, a complex genetic disease caused by mutation in the Chd7 gene and characterized by multiple birth defects. Although otitis media is common in human CHARGE syndrome patients, it has not been reported in mouse models of CHARGE syndrome. In this study, we report a mouse model with a spontaneous deletion mutation in the Chd7 gene and with chronic otitis media of early onset age accompanied by hearing loss. These mice also exhibit morphological alteration in the Eustachian tubes, dysregulation of epithelial proliferation, and decreased density of middle ear cilia. Gene expression profiling revealed up-regulation of Muc5ac, Muc5b and Tgf-β1 transcripts, the products of which are involved in mucin production and TGF pathway regulation. This is the first mouse model of CHARGE syndrome reported to show otitis media with effusion and it will be valuable for studying the etiology of otitis media and other symptoms in CHARGE syndrome.

  11. Sudden infant death syndrome (SIDS) and polymorphisms in Monoamine oxidase A gene (MAOA): a revisit.

    Science.gov (United States)

    Groß, Maximilian; Bajanowski, Thomas; Vennemann, Mechtild; Poetsch, Micaela

    2014-01-01

    Literature describes multiple possible links between genetic variations in the neuroadrenergic system and the occurrence of sudden infant death syndrome. The X-chromosomal Monoamine oxidase A (MAOA) is one of the genes with regulatory activity in the noradrenergic and serotonergic neuronal systems and a polymorphism of the promoter which affects the activity of this gene has been proclaimed to contribute significantly to the prevalence of sudden infant death syndrome (SIDS) in three studies from 2009, 2012 and 2013. However, these studies described different significant correlations regarding gender or age of children. Since several studies, suggesting associations between genetic variations and SIDS, were disproved by follow-up analysis, this study was conducted to take a closer look at the MAOA gene and its polymorphisms. The functional MAOA promoter length polymorphism was investigated in 261 SIDS cases and 93 control subjects. Moreover, the allele distribution of 12 coding and non-coding single nucleotide polymorphisms (SNPs) of the MAOA gene was examined in 285 SIDS cases and 93 controls by a minisequencing technique. In contrast to prior studies with fewer individuals, no significant correlations between the occurrence of SIDS and the frequency of allele variants of the promoter polymorphism could be demonstrated, even including the results from the abovementioned previous studies. Regarding the SNPs, three statistically significant associations were observed which had not been described before. This study clearly disproves interactions between MAOA promoter polymorphisms and SIDS, even if variations in single nucleotide polymorphisms of MAOA should be subjected to further analysis to clarify their impact on SIDS.

  12. Three novel FOXL2 gene mutations in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    @@ Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES, OMIM # 110100) is a rare autosomal dominant disorder affecting the eyelid and ovarian development. When co-occurred together, it is type I and when only the eyelid abnormalities are present, it is type II. Both types had been mapped to the same locus 3q23 on the basis of cytogenetic rearrangements 1-3 and linkage analyses. 4-6 Subsequently, haploinsufficiency of the FOXL2 gene (OMIM# 605597) was identified as the cause for both types. 7 This FOXL2 gene is a small gene consisting of a single exon of 2.7 kb. It belongs to the family of winged helix/forkhead transcription factors. The predicted protein of 376 amino acids contains the characteristic 100 amino acids (from amino acid position 52 to 152) DNA binding forkhead domain. Downstream of the forkhead is an alanine rich domain, consisting of 14 alanines (from amino acid position 221 to 234). This protein has been shown to express in the developing mouse eyelids, in both the fetal and adult ovarian follicular and stromal cells. 7, 8 Since the identification of the gene, increasing number of mutations are being described. Recently, a database (http://medgen.ugent.be/foxl2/) has been created to facilitate tracking of all the known FOXL2 intragenic mutations and variants. 9 Whether it is type I or II BPES depends on the FOXL2 genotype plus other unknown mechanism because for the same genotype, there is inter and intra-familial phenotypic variability.10 Furthermore, FOXL2 mutation might be associated with non-syndromic premature ovarian failure. In this work, we screened for FOXL2 mutations in our Chinese patients using multiplex ligation-dependent probe amplification (MLPA) and direct sequencing techniques.

  13. Germline variants in Hamartomatous Polyposis Syndrome-associated genes from patients with one or few hamartomatous polyps

    DEFF Research Database (Denmark)

    Jelsig, Anne Marie; Brusgaard, Klaus; Hansen, Tine Plato;

    2016-01-01

    Sequencing, DNA samples from 77 patients with 84 hamartomatous polyps were sequenced. The detected germline variants were classified into pathogenicity classes. RESULTS: We detected several germline variants, among them three in ENG, two in BMPR1A, one in PTEN, and one in SMAD4. Although some of the detected......OBJECTIVE: A subgroup of patients with hamartomatous polyps in the GI tract has a hereditary Hamartomatous Polyposis Syndrome with an increased risk of cancer. The distinction between patients with one or few polyps and patients with a syndrome can be difficult. A pathogenic germline mutation can...... be detected in a majority of HPS patients. This study investigates whether patients with one or few hamartomatous polyps could have a syndrome based on genetic screening of relevant genes. METHODS: We designed a gene panel including 26 hamartomatous polyposis-associated genes. Using targeted Next Generation...

  14. A novel mutation in the NOD2 gene associated with Blau syndrome: a Norwegian family with four affected members

    DEFF Research Database (Denmark)

    Milman, N; Ursin, K; Rødevand, E

    2009-01-01

    BACKGROUND: Blau syndrome is a chronic granulomatous disease with an autosomal dominant trait characterized by the triad granulomatous dermatitis, arthritis, and uveitis. It is caused by mutations in the NOD2 gene, also termed the CARD15 gene. OBJECTIVE: To report a novel mutation in the NOD2 gene...... associated with Blau syndrome. METHODS AND RESULTS: The proband was a 68-year-old ethnic Norwegian male who had uveitis and arthritis since 10 years of age followed by lifelong recurrent arthritis and chronic eye involvement. Genetic analysis showed a heterozygous c.1814 C>A, T605N mutation in NOD2 that has...... not previously been described. All of his three children had Blau syndrome and had inherited the NOD2 mutation. The proband's first son had exanthema, arthritis, and uveitis from 10 years of age and later presented with granulomatous lymphadenopathy, granulomatous parotitis, and granulomatous intestinal...

  15. The association between HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia.

    Science.gov (United States)

    Mulder, Hans; Franke, Barbara; van der-Beek van der, Annemarie Aart; Arends, Johan; Wilmink, Frederik W; Scheffer, Hans; Egberts, Antoine C G

    2007-08-01

    The use of antipsychotics is associated with metabolic side effects, which put patients with schizophrenia or related disorders at risk for cardiovascular morbidity. The high interindividual variability in antipsychotic-induced metabolic abnormalities suggests that genetic makeup is a possible determinant. In this cross-sectional study, we investigated whether genotypes of the HTR2C receptor are associated with the metabolic syndrome in patients using antipsychotics. Patients were identified from a schizophrenia disease management program. In this program, patients' blood pressure, triglycerides, high-density lipoprotein-cholesterol, and waist circumference are measured regularly during follow-up. The primary end point of our study was the prevalence of the metabolic syndrome as classified by a modified version of the National Cholesterol Education Program's Adult Treatment Panel III. Primary determinants were polymorphisms in the HTR2C receptor gene (HTR2C:c.1-142948[GT]n, rs3813928 [-997 G/A], rs3813929 [-759 C/T], rs518147 [-697 G/C], and rs1414334 [C > G]). The included patients (n = 112) mainly (>80%) used atypical antipsychotics (clozapine, olanzapine, and risperidone). Carriership of the variant alleles of the HTR2C polymorphisms rs518147, rs1414334, and HTR2C:c.1-142948(GT)n was associated with an increased risk of the metabolic syndrome (adjusted odds ratio [OR], 2.62 [95% confidence interval {CI}, 1.00-6.85]; OR, 4.09 [95% CI, 1.41-11.89]; and OR, 3.12 [95% CI, 1.13-8.16]), respectively. Our findings suggest that HTR2C genotypes are associated with antincreased risk of metabolic syndrome in patients taking antipsychotics.

  16. Identification of Polycystic Ovary Syndrome (PCOS) Specific Genes in Cumulus and Mural Granulosa Cells

    Science.gov (United States)

    Aydos, Alp; Gurel, Aykut; Oztemur Islakoglu, Yasemin; Noyan, Senem; Gokce, Bagdagul; Ecemis, Tolga; Kaya, Cemil; Aksu, Arif Tarik

    2016-01-01

    Polycystic ovary syndrome (PCOS) is a metabolic and endocrine disorder which affects women of reproductive age with prevalence of 8–18%. The oocyte within the follicle is surrounded by cumulus cells (CCs), which connect with mural granulosa cells (MGCs) that are responsible for secreting steroid hormones. The main aim of this study is comparing gene expression profiles of MGCs and CCs in PCOS and control samples to identify PCOS-specific differentially expressed genes (DEGs). In this study, two microarray databases were searched for mRNA expression microarray studies performed with CCs and MGCs obtained from PCOS patients and control samples. Three independent studies were selected to be integrated with naive meta-analysis since raw meta-data from these studies were found to be highly correlated. DEGs in these somatic cells were identified for PCOS and control groups. This study enabled us to reveal dysregulation in MAPK (mitogen activated protein kinase), insulin and Wnt signaling pathways between CCs and MGCs in PCOS. The meta-analysis results together with qRT-PCR validations provide evidence that molecular signaling is dysregulated through MGCs and CCs in PCOS, which is important for follicle and oocyte maturation and may contribute to the pathogenesis of the syndrome. PMID:27997581

  17. Genetic mapping of the gene for Usher syndrome: Linkage analysis in a large Samaritan kindred

    Energy Technology Data Exchange (ETDEWEB)

    Bonne-Tamir, B.; Korostishevsky, M.; Kalinsky, H.; Seroussi, E.; Beker, R.; Weiss, S. (Sackler Faculty of Medicine, Ramat-Aviv (Israel)); Godel, V. (Ichilov Hospital, Tel-Aviv (Israel))

    1994-03-01

    Usher syndrome is a group of autosomal recessive disorders associated with congenital sensorineural deafness and progressive visual loss due to retinitis pigmentosa. Sixteen members of the small inbred Samaritan isolate with autosomal recessive deafness from 59 individuals including parents and affected and nonaffected sibs were typed for markers on chromosomes 1q and 11q for which linkage has recently been established for Usher syndrome types II and I. Statistically significant linkage was observed with four markers on 11q (D11S533, D11S527, OMP, and INT2) with a maximum six-point location score of 11.61 at the D11S533 locus. Analysis of haplotypes supports the notion that the mutation arose only once in an ancestral chromosome carrying a specific haplotype. The availability of markers closely linked to the disease locus allows indirect genotype analysis and identifies all carriers of the gene within the community. Furthermore, the detection of complete linkage disequilibrium between the D11S533 marker and the Usher gene suggests that these loci are either identical or adjacent and narrows the critical region to which physical mapping efforts are currently directed. 35 refs., 2 figs., 6 tabs.

  18. Selection of Suitable Reference Genes for Analysis of Salivary Transcriptome in Non-Syndromic Autistic Male Children

    Directory of Open Access Journals (Sweden)

    Yasin Panahi

    2016-10-01

    Full Text Available Childhood autism is a severe form of complex genetically heterogeneous and behaviorally defined set of neurodevelopmental diseases, collectively termed as autism spectrum disorders (ASD. Reverse transcriptase quantitative real-time PCR (RT-qPCR is a highly sensitive technique for transcriptome analysis, and it has been frequently used in ASD gene expression studies. However, normalization to stably expressed reference gene(s is necessary to validate any alteration reported at the mRNA level for target genes. The main goal of the present study was to find the most stable reference genes in the salivary transcriptome for RT-qPCR analysis in non-syndromic male childhood autism. Saliva samples were obtained from nine drug naïve non-syndromic male children with autism and also sex-, age-, and location-matched healthy controls using the RNA-stabilizer kit from DNA Genotek. A systematic two-phased measurement of whole saliva mRNA levels for eight common housekeeping genes (HKGs was carried out by RT-qPCR, and the stability of expression for each candidate gene was analyzed using two specialized algorithms, geNorm and NormFinder, in parallel. Our analysis shows that while the frequently used HKG ACTB is not a suitable reference gene, the combination of GAPDH and YWHAZ could be recommended for normalization of RT-qPCR analysis of salivary transcriptome in non-syndromic autistic male children.

  19. Selection of Suitable Reference Genes for Analysis of Salivary Transcriptome in Non-Syndromic Autistic Male Children.

    Science.gov (United States)

    Panahi, Yasin; Salasar Moghaddam, Fahimeh; Ghasemi, Zahra; Hadi Jafari, Mandana; Shervin Badv, Reza; Eskandari, Mohamad Reza; Pedram, Mehrdad

    2016-10-12

    Childhood autism is a severe form of complex genetically heterogeneous and behaviorally defined set of neurodevelopmental diseases, collectively termed as autism spectrum disorders (ASD). Reverse transcriptase quantitative real-time PCR (RT-qPCR) is a highly sensitive technique for transcriptome analysis, and it has been frequently used in ASD gene expression studies. However, normalization to stably expressed reference gene(s) is necessary to validate any alteration reported at the mRNA level for target genes. The main goal of the present study was to find the most stable reference genes in the salivary transcriptome for RT-qPCR analysis in non-syndromic male childhood autism. Saliva samples were obtained from nine drug naïve non-syndromic male children with autism and also sex-, age-, and location-matched healthy controls using the RNA-stabilizer kit from DNA Genotek. A systematic two-phased measurement of whole saliva mRNA levels for eight common housekeeping genes (HKGs) was carried out by RT-qPCR, and the stability of expression for each candidate gene was analyzed using two specialized algorithms, geNorm and NormFinder, in parallel. Our analysis shows that while the frequently used HKG ACTB is not a suitable reference gene, the combination of GAPDH and YWHAZ could be recommended for normalization of RT-qPCR analysis of salivary transcriptome in non-syndromic autistic male children.

  20. Regenerating Gene Protein as a Novel Autoantigen in the Pathogenesis of Sjögren’s Syndrome

    Directory of Open Access Journals (Sweden)

    Takashi Fujimoto

    2015-12-01

    Full Text Available Sjögren’s syndrome, an autoimmune disease characterized by exocrine gland dysfunction leading to dry mouth and dry eye diseases, is typified by lymphoplasmacytic infiltrations and a progressive destruction of the salivary and lacrimal glands. Despite an ever-increasing focus on identifying the underlying etiology of Sjögren’s syndrome, the factors that initiate this autoimmune disease and the mechanisms that cause the subsequent exocrine gland dysfunction remain a mystery. The original explanatory concept for the pathogenesis of Sjögren’s syndrome proposed a specific, self-perpetuating, immune-mediated loss of acinar and ductal cells as the principal cause of salivary gland dysfunction. We highlight the possible involvement of regenerating gene (Reg in the regeneration and destruction of salivary gland acinar and ductal cells in Sjögren’s syndrome. The Reg gene was originally isolated as a gene specifically overexpressed in regenerating pancreatic islets and constitutes a growth factor family (Reg family. We describe how salivary gland dysfunction is initiated and maintained and how it can be regenerated or progressed, mediated by the Reg gene, Reg protein, and anti-REG autoantibodies in Sjögren’s syndrome.

  1. Nelson`s syndrome associated with a somatic frame shift mutation in the glucocorticoid recepter gene

    Energy Technology Data Exchange (ETDEWEB)

    Karl, M.; Stratakis, C.A.; Chrousos, G.P.; Katz, D.A.; Ali, I.U.; Oldfield, E.H. [National Inst. of Neurological Disorders and Stroke, Bethesda, MD (United States)] [and others

    1996-01-01

    Nelson`s syndrome is the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for Cushing`s disease. Extremely high plasma ACTH levels and aggressive neoplastic growth might be explained by the lack of appropriate glucocorticoid negative feedback due to defective glucocorticoid signal transduction. To study the glucocorticoid receptor (GR) gene in Nelson`s syndrome, DNA was extracted from pituitary adenomas and leukocytes of four patients with this condition and amplified by PCR for direct sequence analysis. In one of the tumors, a heterozygous mutation, consisting of an insertion of a thymine between complementary DNA nucleotides 1188 and 1189, was found in exon 2. This frame-shift mutation led to premature termination at amino acid residue 366 of the world-type coding sequence, excluding the expression of a functioning receptor protein from the defective allele. The mutation was not detected in the sequence of the GR gene in the patient`s leukocyte DNA, indicating a somatic origin. By lowering the receptor number in tumorous cells, this defect might have caused local resistance to negative glucocorticoid feedback similar to that caused by the presence of a null allele in a kindred with the generalized glucocorticoid resistance syndrome. P53 protein accumulation, previously reported in 60% of corticotropinomas, could not be detected in any of the four pituitary tumors examined by immunohistochemistry. We suggest that a somatic GR defect might have played a pathophysiological role in the tumorigenesis of the corticotropinoma bearing this mutation. 35 refs., 3 figs., 1 tab.

  2. A novel mutation in the sodium channel α1 subunit gene in a child with Dravet syndrome in Turkey

    Institute of Scientific and Technical Information of China (English)

    Mutluay Arslan; Ulu(c) Yi(s); Hande (C)a(g)layan; R1dvan Akin

    2013-01-01

    Dravet syndrome is a rare epileptic encephalopathy characterized by frequent seizures beginning in the first year of life and behavioral disorders. Mutations in the sodium channel α1 subunit gene are the main cause of this disease. We report two patients with refractory seizures and psychomotor retardation in whom the final diagnosis was Dravet syndrome with confirmed mutations in the sodium channel α1 subunit gene. The mutation identified in the second patient was a novel frame shift mutation, which resulted from the deletion of five nucleotides in exon 24.

  3. Identification of a novel mutation in the human growth hormone receptor gene (GHR) in a patient with Laron syndrome.

    Science.gov (United States)

    Gennero, Isabelle; Edouard, Thomas; Rashad, Mona; Bieth, Eric; Conte-Aurio, Françoise; Marin, Françoise; Tauber, Maithé; Salles, Jean Pierre; El Kholy, Mohamed

    2007-07-01

    Deletions and mutations in the growth hormone receptor (GHR) gene are the underlying etiology of Laron syndrome (LS) or growth hormone (GH) insensitivity syndrome (GHIS), an autosomal recessive disease. Most patients are distributed in or originate from Mediterranean and Middle-Eastern countries. Sixty mutations have been described so far. We report a novel mutation in the GHR gene in a patient with LS. Genomic DNA sequencing of exon 5 revealed a TT insertion at nucleotide 422 after codon 122. The insertion resulted in a frameshift introducing a premature termination codon that led to a truncated receptor. We present clinical, biochemical and molecular evidence of LS as the result of this homozygous insertion.

  4. Gene editing as applied to prevention of reproductive porcine reproductive and respiratory syndrome.

    Science.gov (United States)

    Whitworth, Kristin M; Prather, Randall S

    2017-04-08

    Porcine Reproductive and Respiratory Syndrome (PRRS) causes severe reproductive failure in sows, as well as transplacental transfer of PRRS virus (PRRSV) to late-gestation fetuses, resulting in abortions, early farrowing, increased number of stillborn piglets, and weak neonatal piglets. PRRSV-infected boars present with anorexia and lethargy, and have decreased sperm quality. The gene for the cellular receptor that the PRRSV uses, Cluster of differentiation 163 (CD163), was edited using Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene-editing technology to create biallelic DNA edits to the CD163 gene in 100% of the offspring. CD163-null pigs challenged with virus were completely resistant to both Type 1 and Type 2 PRRSV isolates, as measured by clinical signs, viremia, antibody response, and lung histopathology. In vitro studies showed that CD163-null alveolar macrophages were also not permissive to infection by a panel of six Type 1 and nine Type 2 viral isolates. Thus, DNA editing of the CD163 gene prevented PRRSV infection and reproductive losses associated with infection. This article is protected by copyright. All rights reserved.

  5. Deleterious Mutations in the Zinc-Finger 469 Gene Cause Brittle Cornea Syndrome

    Science.gov (United States)

    Abu, Almogit; Frydman, Moshe; Marek, Dina; Pras, Eran; Nir, Uri; Reznik-Wolf, Haike; Pras, Elon

    2008-01-01

    Brittle cornea syndrome (BCS) is an autosomal-recessive disorder characterized by a thin cornea that tends to perforate, causing progressive visual loss and blindness. Additional systemic symptoms such as joint hypermotility, hyperlaxity of the skin, and kyphoscoliosis place BCS among the connective-tissue disorders. Previously, we assigned the disease gene to a 4.7 Mb interval on chromosome 16q24. In order to clone the BCS gene, we first narrowed the disease locus to a 2.8 Mb interval and systematically sequenced genes expressed in connective tissue in this chromosomal segment. We have identified two frameshift mutations in the Zinc-Finger 469 gene (ZNF469). In five unrelated patients of Tunisian Jewish ancestry, we found a 1 bp deletion at position 5943 (5943 delA), and in an inbred Palestinian family we detected a single-nucleotide deletion at position 9527 (9527 delG). The function of ZNF469 is unknown. However, a 30% homology to a number of collagens suggests that it could act as a transcription factor involved in the synthesis and/or organization of collagen fibers. PMID:18452888

  6. Insulin gene polymorphisms in type 1 diabetes, Addison's disease and the polyglandular autoimmune syndrome type II

    Directory of Open Access Journals (Sweden)

    Hahner Stefanie

    2008-07-01

    Full Text Available Abstract Background Polymorphisms within the insulin gene can influence insulin expression in the pancreas and especially in the thymus, where self-antigens are processed, shaping the T cell repertoire into selftolerance, a process that protects from β-cell autoimmunity. Methods We investigated the role of the -2221Msp(C/T and -23HphI(A/T polymorphisms within the insulin gene in patients with a monoglandular autoimmune endocrine disease [patients with isolated type 1 diabetes (T1D, n = 317, Addison's disease (AD, n = 107 or Hashimoto's thyroiditis (HT, n = 61], those with a polyglandular autoimmune syndrome type II (combination of T1D and/or AD with HT or GD, n = 62 as well as in healthy controls (HC, n = 275. Results T1D patients carried significantly more often the homozygous genotype "CC" -2221Msp(C/T and "AA" -23HphI(A/T polymorphisms than the HC (78.5% vs. 66.2%, p = 0.0027 and 75.4% vs. 52.4%, p = 3.7 × 10-8, respectively. The distribution of insulin gene polymorphisms did not show significant differences between patients with AD, HT, or APS-II and HC. Conclusion We demonstrate that the allele "C" of the -2221Msp(C/T and "A" -23HphI(A/T insulin gene polymorphisms confer susceptibility to T1D but not to isolated AD, HT or as a part of the APS-II.

  7. Mutations of the TWIST gene in the Saethre-Chotzen syndrome.

    Science.gov (United States)

    el Ghouzzi, V; Le Merrer, M; Perrin-Schmitt, F; Lajeunie, E; Benit, P; Renier, D; Bourgeois, P; Bolcato-Bellemin, A L; Munnich, A; Bonaventure, J

    1997-01-01

    Saethre-Chotzen syndrome (acrocephalo-syndactyly type III, ACS III) is an autosomal dominant craniosynostosis with brachydactyly, soft tissue syndactyly and facial dysmorphism including ptosis, facial asymmetry and prominent ear crura. ACS III has been mapped to chromosome 7p21-22. Of interest, TWIST, the human counterpart of the murine Twist gene, has been localized on chromosome 7p21 as well. The Twist gene product is a transcription factor containing a basic helix-loop-helix (b-HLH) domain, required in head mesenchyme for cranial neural tube morphogenesis in mice. The co-localisation of ACS III and TWIST prompted us to screen ACS III patients for TWIST gene mutations especially as mice heterozygous for Twist null mutations displayed skull defects and duplication of hind leg digits. Here, we report 21-bp insertions and nonsense mutations of the TWIST gene (S127X, E130X) in seven ACS III probands and describe impairment of head mesenchyme induction by TWIST as a novel pathophysiological mechanism in human craniosynostoses.

  8. Composition analysis of A, C, G, T nucleotides in genes responsible for the Long QT Syndrome

    Directory of Open Access Journals (Sweden)

    Vamsidhar Enireddy,

    2010-06-01

    Full Text Available Long QT syndrome (LQTS is a congenital disorder characterized by a prolongation of the QT interval on ECG and a propensity to ventricular tachyarrhythmia, which may lead to syncope, cardiac arrest, or sudden death. LQTS is caused by mutations of the genes for cardiac potassium and sodium or calcium ion channels. 8 genes have been identified.LQT1 (KCNQ1, LQT2 (KCNH2, and LQT3 (SCN5A account for most cases of LQTS, with estimated prevalence of 45%, 45%, and 7%, respectively. We have used the analogy of genome analysis and VIRUS (vital information recourse under siege and analyzed Since KCNQ1, KCNH2 and SCN5A genes are playing an important role in LQTS disease, we have taken their nucleotide sequences in FASTA format and submitted them in Geneboy(www.dnai.org.And studied their composition of nucleic acids (A,C,T,G,and we have received results for genes KCNQ1,KCNH2 such that their nucleic acid composition approximately same, being their prevalence percentage is same.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1994-09-01

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

  10. Polymorphism analysis of the ABCA3 gene: association with neonatal respiratory distress syndrome in preterm infants

    Institute of Scientific and Technical Information of China (English)

    JIANG Lin; WU Yi-dong; XU Xue-feng; DU Li-zhong

    2012-01-01

    Background Previous reports indicated that mutations in the adenosine triphosphate (ATP)-binding cassette transporter A3 (ABCA3) cause fatal respiratory failure in term infants,and common ABCA3 gene polymorphisms have been characterized at the population level in Caucasians.But the role of ABCA3 in relation to respiratory distress syndrome (RDS) in newborns has not been evaluated within a Chinese population.The aim of this study was to analyze eight single-nucleotide polymorphisms (SNPs) of the ABCA3 gene,and to assess the ABCA3 gene as a candidate gene for susceptibility to RDS in newborns.Methods Eight SNPs were selected and genotyped in 203 newborns.The data analysis and statistical tests were used for allele frequencies,haplotype and Hardy-Weinberg equilibrium pairwise linkage disequilibrium measures.Results There was a haplotype association with SNP rs313909 and SNP rs170447,but no haplotype association was observed among the newborns with and without RDS (P >0.05).The minor allele frequency (G) of the coding SNP (cSNP) rs323043 (P585P) was significantly increased in preterm infants with RDS.Conclusion There is an association between a synonymous cSNP rs323043 and the development of RDS.

  11. Gene expression in response to exercise in patients with chronic fatigue syndrome: a pilot study.

    Directory of Open Access Journals (Sweden)

    Andrew Keech

    2016-09-01

    Full Text Available Chronic fatigue syndrome (CFS is a debilitating disorder of unknown pathogenesis, characterised by fatigue, which is exacerbated after minimal exercise. We examined the effect of a single bout of aerobic exercise on leucocyte mRNA expression of genes putatively linked to exaggerated afferent signalling as an under-pinning of the fatigue state. A carefully-characterised sample of patients with CFS (N = 10 and healthy matched control participants (N = 12 were included. Participant ratings of fatigue and other symptoms, as well as blood samples, were obtained at baseline, and five other time-points up to 72 hours after 25 minutes of moderate-intensity cycling exercise. Leucocyte mRNA of 19 metabolite-sensing, adrenergic, immune and neurotransmission genes was examined using quantitative polymerase chain reaction. Patients with CFS reported substantial fatigue, functional impairment and poor sleep at baseline (all p < 0.02, and exercise immediately induced worsened patients’ fatigue (effect size, ES = 1.17. There were no significant changes in gene expression after exercise and patients did not differ from control participants at any time point. Higher levels of expression of ficolin (FCN1 and a purinergic receptor (P2RX4 in patients with CFS were found when all time points were combined. Patients with CFS did not show significant exercise-induced changes in leucocyte mRNA of 19 metabolite-sensing, adrenergic, immune and neurotransmission genes despite a prominent exacerbation of fatigue.

  12. Germinal mosaicism for a deletion of the FMR1 gene leading to fragile X syndrome.

    Science.gov (United States)

    Jiraanont, P; Hagerman, R J; Neri, G; Zollino, M; Murdolo, M; Tassone, F

    2016-09-01

    Aberrant CGG trinucleotide amplification within the FMR1 gene, which spans approximately 38 Kb of genomic DNA is almost always what leads to fragile X syndrome (FXS). However, deletions of part or the entire FMR1 gene can also cause FXS. Both CGG amplification-induced silencing and deletions result in the absence of the FMR1 gene product, FMRP. Here, we report a rare case of germinal mosaicism of a deletion encompassing approximately 300 Kb of DNA, which by removing the entire FMR1 gene led to FXS. The male proband, carrying the deletion, presented in clinic with the typical features of FXS. His mother was analyzed by FISH on metaphase chromosomes with cosmid probe c22.3 spanning the FMR1 locus, and she was found not to carry the deletion on 30 analyzed cells from peripheral blood lymphocytes. Prenatal examination of the mother's third pregnancy showed that the male fetus also had the same deletion as the proband. Following this prenatal diagnosis, FISH analysis in the mother was expanded to 400 metaphases from peripheral lymphocytes, and a heterozygous FMR1 deletion was found in three. Although this result could be considered questionable from a diagnostic point of view, it indicates that the deletion is in the ovary's germinal cells.

  13. Nephrogenic diabetes insipidus in a patient with L1 syndrome: a new report of a contiguous gene deletion syndrome including L1CAM and AVPR2.

    Science.gov (United States)

    Knops, Noël B B; Bos, Krista K; Kerstjens, Mieke; van Dael, Karin; Vos, Yvonne J

    2008-07-15

    We report on an infant boy with congenital hydrocephalus due to L1 syndrome and polyuria due to diabetes insipidus. We initially believed his excessive urine loss was from central diabetes insipidus and that the cerebral malformation caused a secondary insufficient pituitary vasopressin release. However, he failed to respond to treatment with a vasopressin analogue, which pointed to nephrogenic diabetes insipidus (NDI). L1 syndrome and X-linked NDI are distinct clinical disorders caused by mutations in the L1CAM and AVPR2 genes, respectively, located in adjacent positions in Xq28. In this boy we found a deletion of 61,577 basepairs encompassing the entire L1CAM and AVPR2 genes and extending into intron 7 of the ARHGAP4 gene. To our knowledge this is the first description of a patient with a deletion of these three genes. He is the second patient to be described with L1 syndrome and NDI. During follow-up he manifested complications from the hydrocephalus and NDI including global developmental delay and growth failure with low IGF-1 and hypothyroidism.

  14. Gene expression profile exploration of a large dataset on chronic fatigue syndrome.

    Science.gov (United States)

    Fang, Hong; Xie, Qian; Boneva, Roumiana; Fostel, Jennifer; Perkins, Roger; Tong, Weida

    2006-04-01

    To gain understanding of the molecular basis of chronic fatigue syndrome (CFS) through gene expression analysis using a large microarray data set in conjunction with clinically administrated questionnaires. Data from the Wichita (KS, USA) CFS Surveillance Study was used, comprising 167 participants with two self-report questionnaires (multidimensional fatigue inventory [MFI] and Zung depression scale [Zung]), microarray data, empiric classification, and others. Microarray data was analyzed using bioinformatics tools from ArrayTrack. Correspondence analysis was applied to the MFI questionnaire to select the 23 samples having either the most or the least fatigue, and to the Zung questionnaire to select the 26 samples having either the most or least depression; ten samples were common, resulting in a total of 39 samples. The MFI and Zung-based CFS/non-CFS (NF) classifications on the 39 samples were consistent with the empiric classification. Two differentially-expressed gene lists were determined, 188 fatigue-related genes and 164 depression-related genes, which shared 24 common genes and involved 11 common pathways. Principal component analysis based on 24 genes clearly separates 39 samples with respect to their likelihood to be CFS. Most of the 24 genes are not previously reported for CFS, yet their functions are consistent with the prevailing model of CFS, such as immune response, apoptosis, ion channel activity, signal transduction, cell-cell signaling, regulation of cell growth and neuronal activity. Hierarchical cluster analysis was performed based on 24 genes to classify 128 (=167-39) unassigned samples. Several of the 11 identified common pathways are supported by earlier findings for CFS, such as cytokine-cytokine receptor interaction and neuroactive ligand-receptor interaction. Importantly, most of the 11 common pathways are interrelated, suggesting complex biological mechanisms associated with CFS. Bioinformatics is critical in this study to select

  15. Rapid Mutation Scanning of Genes Associated with Familial Cancer Syndromes Using Denaturing High-Performance Liquid Chromatography

    Directory of Open Access Journals (Sweden)

    Deborah J. Marsh

    2001-01-01

    Full Text Available Germline mutations in tumor suppressor genes, or less frequently oncogenes, have been identified in up to 19 familial cancer syndromes including Li-Fraumeni syndrome, familial paraganglioma, familial adenomatous polyposis coli and breast and ovarian cancers. Multiple genes have been associated with some syndromes as approximately 26 genes have been linked to the development of these familial cancers. With this increased knowledge of the molecular determinants of familial cancer comes an equal expectation for efficient genetic screening programs. We have trialled denaturing highperformance liquid chromatography (dHPLC as a tool for rapid germline mutation scanning of genes implicated in three familial cancer syndromes - Cowden syndrome (PTEN mutation, multiple endocrine neoplasia type 2 (RET mutation and von Hippel-Lindau disease (VHL mutation. Thirty-two mutations, including 21 in PTEN, 9 in RET plus a polymorphism, and 2 in VHL, were analyzed using the WAVE DNA fragment analysis system with 100% detection efficiency. In the case of the tumor suppressor gene PTEN, mutations were scattered along most of the gene. However, mutations in the RET proto-oncogene associated with multiple endocrine neoplasia type 2 were limited to specific clusters or “hot spots”. The use of GC-clamped primers to scan for mutations scattered along PTEN exons was shown to greatly enhance the sensitivity of detection of mutant hetero- and homoduplex peaks at a single denaturation temperature compared to fragments generated using non-GC-clamped primers. Thus, when scanning tumor suppressor genes for germline mutation using dHPLC, the incorporation of appropriate GCclamped primers will likely increase the efficiency of mutation detection.

  16. Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome.

    Science.gov (United States)

    Woollard, Wesley J; Pullabhatla, Venu; Lorenc, Anna; Patel, Varsha M; Butler, Rosie M; Bayega, Anthony; Begum, Nelema; Bakr, Farrah; Dedhia, Kiran; Fisher, Joshua; Aguilar-Duran, Silvia; Flanagan, Charlotte; Ghasemi, Aria A; Hoffmann, Ricarda M; Castillo-Mosquera, Nubia; Nuttall, Elisabeth A; Paul, Arisa; Roberts, Ceri A; Solomonidis, Emmanouil G; Tarrant, Rebecca; Yoxall, Antoinette; Beyers, Carl Z; Ferreira, Silvia; Tosi, Isabella; Simpson, Michael A; de Rinaldis, Emanuele; Mitchell, Tracey J; Whittaker, Sean J

    2016-06-30

    Sézary syndrome (SS) is a leukemic variant of cutaneous T-cell lymphoma (CTCL) and represents an ideal model for study of T-cell transformation. We describe whole-exome and single-nucleotide polymorphism array-based copy number analyses of CD4(+) tumor cells from untreated patients at diagnosis and targeted resequencing of 101 SS cases. A total of 824 somatic nonsynonymous gene variants were identified including indels, stop-gain/loss, splice variants, and recurrent gene variants indicative of considerable molecular heterogeneity. Driver genes identified using MutSigCV include POT1, which has not been previously reported in CTCL; and TP53 and DNMT3A, which were also identified consistent with previous reports. Mutations in PLCG1 were detected in 11% of tumors including novel variants not previously described in SS. This study is also the first to show BRCA2 defects in a significant proportion (14%) of SS tumors. Aberrations in PRKCQ were found to occur in 20% of tumors highlighting selection for activation of T-cell receptor/NF-κB signaling. A complex but consistent pattern of copy number variants (CNVs) was detected and many CNVs involved genes identified as putative drivers. Frequent defects involving the POT1 and ATM genes responsible for telomere maintenance were detected and may contribute to genomic instability in SS. Genomic aberrations identified were enriched for genes implicated in cell survival and fate, specifically PDGFR, ERK, JAK STAT, MAPK, and TCR/NF-κB signaling; epigenetic regulation (DNMT3A, ASLX3, TET1-3); and homologous recombination (RAD51C, BRCA2, POLD1). This study now provides the basis for a detailed functional analysis of malignant transformation of mature T cells and improved patient stratification and treatment.

  17. Upregulation of skeletal muscle inflammatory genes links inflammation with insulin resistance in women with the metabolic syndrome.

    Science.gov (United States)

    Poelkens, Fleur; Lammers, Gerwen; Pardoel, Elisabeth M; Tack, Cees J; Hopman, Maria T E

    2013-10-01

    The metabolic syndrome, a combination of interrelated metabolic risk factors, is associated with insulin resistance and promotes the development of cardiovascular diseases and type 2 diabetes mellitus. There is a close link between inflammation and metabolic disease, but the responsible mechanisms remain elusive. The aim of this study was to identify differentially expressed genes in insulin-resistant skeletal muscle tissue of women with the metabolic syndrome compared with healthy control women. Women with the metabolic syndrome (n = 19) and healthy control women (n = 20) were extensively phenotyped, insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp, and a skeletal muscle biopsy was obtained. Gene expression levels were compared between the two groups by microarrays. The upregulated genes in skeletal muscle of the women with the metabolic syndrome were primarily enriched for inflammatory response-associated genes. The three most significantly upregulated of this group, interleukin 6 receptor (IL6R), histone deacetylase 9 (HDAC9) and CD97 molecule (CD97), were significantly correlated with insulin resistance. Taken together, these findings suggest an important role for a number of inflammatory-related genes in the development of skeletal muscle insulin resistance.

  18. Majewski osteodysplastic primordial dwarfism type II (MOPD II) syndrome previously diagnosed as Seckel syndrome: report of a novel mutation of the PCNT gene.

    Science.gov (United States)

    Piane, Maria; Della Monica, Matteo; Piatelli, Gianluca; Lulli, Patrizia; Lonardo, Fortunato; Chessa, Luciana; Scarano, Gioacchino

    2009-11-01

    We report on a 3-year-old boy with prenatal onset of proportionate dwarfism, postnatal severe microcephaly, high forehead with receded hairline, sparse scalp hair, beaked nose, mild retrognathia and hypotonia diagnosed at birth as Seckel syndrome. At age 3 years, he became paralyzed due to a cerebrovascular malformation. Based on the clinical and radiological features showing evidence of skeletal dysplasia, the diagnosis was revised to Majewski osteodysplastic primordial dwarfism type II (MOPD II) syndrome. Western blot analysis of the patient's lymphoblastoid cell line lysate showed the absence of the protein pericentrin. Subsequent molecular analysis identified a novel homozygous single base insertion (c.1527_1528insA) in exon 10 of the PCNT gene, which leads to a frameshift (Treo510fs) and to premature protein truncation. PCNT mutations must be considered diagnostic of MOPD II syndrome. A possible role of pericentrin in the development of cerebral vessels is suggested. Copyright 2009 Wiley-Liss, Inc.

  19. Diagnosing Smith-Magenis syndrome and duplication 17p11.2 syndrome by RAI1 gene copy number variation using quantitative real-time PCR.

    Science.gov (United States)

    Truong, Hoa T; Solaymani-Kohal, Sara; Baker, Kevin R; Girirajan, Santhosh; Williams, Stephen R; Vlangos, Christopher N; Smith, Ann C M; Bunyan, David J; Roffey, Paul E; Blanchard, Christopher L; Elsea, Sarah H

    2008-03-01

    Smith-Magenis syndrome (SMS) and duplication 17p11.2 (dup17p11.2) syndrome are multiple congenital anomalies/mental retardation disorders resulting from either a deletion or duplication of the 17p11.2 region, respectively. The retinoic acid induced 1 (RAI1) gene is the causative gene for SMS and is included in the 17p11.2 region of dup17p11.2 syndrome. Currently SMS and dup17p11.2 syndrome are diagnosed using a combination of clinically recognized phenotypes and molecular cytogenetic analyses such as fluorescent in situ hybridization (FISH). However, these methods have proven to be highly expensive, time consuming, and dependent upon the low resolving capabilities of the assay. To address the need for improved diagnostic methods for SMS and dup17p11.2 syndrome, we designed a quantitative real-time PCR (Q-PCR) assay that measures RAI1 copy number using the comparative C(t) method, DeltaDeltaC(t). We tested our assay with samples blinded to their previous SMS or dup17p11.2 syndrome status. In all cases, we were able to determine RAI1 copy number status and render a correct diagnosis accordingly. We validated these results by both FISH and multiplex ligation-dependent probe amplification (MLPA). We conclude that Q-PCR is an accurate, reproducible, low-cost, and reliable assay that can be employed for routine use in SMS and dup17p11.2 diagnosis.

  20. Metal Vector Manipulated Molecular Self-Assembly from Werner System to Cotton System

    Institute of Scientific and Technical Information of China (English)

    YU Shu-Yan; ZHANG Zhong-Xing; HUANG Hui; LI Sheng-Hui; HUANG Hai-Ping

    2004-01-01

    A definition of metal vector was given to coordinatively unsaturated metals or asymmetrically coordinated metal complexes in which the metal center is partly blocked by inert chelating ligand(s), thus possess specific reactivity and directionality, such as cis-coordinated square Pd(Ⅱ) or Pt(Ⅱ) complexes. Metal vectors have been extensively used in coordination catalysis and molecular assembly. In 1990, Fujita [ 1 ] first demonstrated the utility of cis-coordinated square Pd(Ⅱ)or Pt(Ⅱ) complexes as a right angular 2D metal vector in the formation of molecular square, a cyclic tetramer with nano-cavity and unique molecular recognition. So far, much attention has been paid to the use of the mononuclear coordination centers (Werner-type metal vectors) in molecular assembly.As late as 1999, Cotton et al. [2] reported the use of cis-coordinated metal-metal bonded dimetal units (Cotton-type metal vectors) to direct assembly of molecular squares.This presentation includes two parts: 1) Werner-type metal vector directed molecular assembly; [3]2) Cotton-type metal vector directed molecular assembly.[4]Firstly, the Werner-type metal vector, cis-coordinated Pd(Ⅱ) nitrate, was used to direct a 6-component self-assembly. This leads to the formation of a molecular bowl or crown with syn,syn,syn conformation. These structures are analogues of calix[3]arenes and can function as anion receptors. Interestingly, an nitrate is found to distort from a trigonal plane into a trigonal pyramid when binding to the bottom of the molecular bowl.Secondly, the Cotton-type metal vector, cis-diRh(Ⅱ, Ⅱ), was used to assemble di- or poly-carboxylate anions into neutral supermolecules. Most interestingly, a calixarene-based carceplex with four cis-diRh(Ⅱ, Ⅱ) fastners was obtained[5].All self-assembling entities were studied by both X-ray crystallographic analysis and solution NMR spectra, which are consistent with the presence of assembling structures even in solution.

  1. Homozygous c.1160C>T (P38L) in the MECP2 gene in a female Rett syndrome patient.

    Science.gov (United States)

    Bhanushali, Aparna A; Mandsaurwala, A; Das, Bibhu R

    2016-03-01

    Rett syndrome is a severe X-linked dominant neurodevelopmental disorder. Mutations in the MECP2 gene on chromosome Xq28 have been shown to be the cause of Rett syndrome. Sequencing of the MECP2 gene in a patient with clinical suspicion of Rett syndrome revealed c.1160C>T (P387L) in exon 4 of the MECP2 gene homozygously. Females with Rett syndrome are usually heterozygous for a mutation in MECP2. Uniparental disomy as a probable cause for the homozygous presence of this mutation was ruled out by quantitative fluorescence-polymerase chain reaction. Moreover to our knowledge this mutation has only been reported in males with X-linked mental retardation (MRX). We hypothesize that the presence of this mutation c.1160C>T (P387L) in the homozygous form is responsible for the Rett syndrome-like phenotype seen in this patient. This novel report reveals for the first time the homozygous presence of a mutation which has hitherto only been reported in males with MRX.

  2. Protein causes hyperinsulinemia: a Chinese patient with hyperinsulinism/hyperammonaemia syndrome due to a glutamate dehydrogenase gene mutation

    Institute of Scientific and Technical Information of China (English)

    CHEN Shi; XIAO Xin-hua; DIAO Cheng-ming; TONG An-li; WANG Ou; QIU Zheng-qing; YU Kang; WANG Tong

    2010-01-01

    @@ Glucose is derived from three sources: intestinal absorption, glycogenolysis, and gluconeogenesis. Hypoglycemia in child is often attributed to depletion of glycogen stores. However, recently, congenital hyperinsulinism becomes an important cause of hypoglycaemia in early infancy. Mutations in the genes encoding SUR1 and KIR6.2 are the most frequent genetic causes of hyperinsulinism followed by mutations in the glutamate dehydrogenase (GDH) gene which encodes hyperinsulinism/hyperammonaemia (HI/HA) syndrome.

  3. PCOSKB: A KnowledgeBase on genes, diseases, ontology terms and biochemical pathways associated with PolyCystic Ovary Syndrome

    OpenAIRE

    Joseph, Shaini; Barai, Ram Shankar; Bhujbalrao, Rasika; Idicula-Thomas, Susan

    2015-01-01

    Polycystic ovary syndrome (PCOS) is one of the major causes of female subfertility worldwide and ≈7–10% of women in reproductive age are affected by it. The affected individuals exhibit varying types and levels of comorbid conditions, along with the classical PCOS symptoms. Extensive studies on PCOS across diverse ethnic populations have resulted in a plethora of information on dysregulated genes, gene polymorphisms and diseases linked to PCOS. However, efforts have not been taken to collate ...

  4. 15 years of research on Oral-Facial-Digital syndromes: from 1 to 16 causal genes

    Science.gov (United States)

    Bruel, Ange-Line; Franco, Brunella; Duffourd, Yannis; Thevenon, Julien; Jego, Laurence; Lopez, Estelle; Deleuze, Jean-François; Doummar, Diane; Giles, Rachel H.; Johnson, Colin A.; Huynen, Martijn A.; Chevrier, Véronique; Burglen, Lydie; Morleo, Manuela; Desguerres, Isabelle; Pierquin, Geneviève; Doray, Bérénice; Gilbert-Dussardier, Brigitte; Reversade, Bruno; Steichen-Gersdorf, Elisabeth; Baumann, Clarisse; Panigrahi, Inusha; Fargeot-Espaliat, Anne; Dieux, Anne; David, Albert; Goldenberg, Alice; Bongers, Ernie; Gaillard, Dominique; Argente, Jesús; Aral, Bernard; Gigot, Nadège; St-Onge, Judith; Birnbaum, Daniel; Phadke, Shubha R.; Cormier-Daire, Valérie; Eguether, Thibaut; Pazour, Gregory J.; Herranz-Pérez, Vicente; Lee, Jaclyn S.; Pasquier, Laurent; Loget, Philippe; Saunier, Sophie; Mégarbané, André; Rosnet, Olivier; Leroux, Michel R.; Wallingford, John B.; Blacque, Oliver E.; Nachury, Maxence V.; Attie-Bitach, Tania; Rivière, Jean-Baptiste; Faivre, Laurence; Thauvin-Robinet, Christel

    2017-01-01

    Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterized by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFD subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 OFDS cases. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753, IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231, WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterizing three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the MKS module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these 3 main subtypes, a further classification could be based on the genotype. PMID:28289185

  5. Genetic variant rs17225178 in the ARNT2 gene is associated with Asperger Syndrome.

    Science.gov (United States)

    Di Napoli, Agnese; Warrier, Varun; Baron-Cohen, Simon; Chakrabarti, Bhismadev

    2015-01-01

    Autism Spectrum Conditions (ASC) are neurodevelopmental conditions characterized by difficulties in communication and social interaction, alongside unusually repetitive behaviours and narrow interests. Asperger Syndrome (AS) is one subgroup of ASC and differs from classic autism in that in AS there is no language or general cognitive delay. Genetic, epigenetic and environmental factors are implicated in ASC and genes involved in neural connectivity and neurodevelopment are good candidates for studying the susceptibility to ASC. The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) gene encodes a transcription factor involved in neurodevelopmental processes, neuronal connectivity and cellular responses to hypoxia. A mutation in this gene has been identified in individuals with ASC and single nucleotide polymorphisms (SNPs) have been nominally associated with AS and autistic traits in previous studies. In this study, we tested 34 SNPs in ARNT2 for association with AS in 118 cases and 412 controls of Caucasian origin. P values were adjusted for multiple comparisons, and linkage disequilibrium (LD) among the SNPs analysed was calculated in our sample. Finally, SNP annotation allowed functional and structural analyses of the genetic variants in ARNT2. We tested the replicability of our result using the genome-wide association studies (GWAS) database of the Psychiatric Genomics Consortium (PGC). We report statistically significant association of rs17225178 with AS. This SNP modifies transcription factor binding sites and regions that regulate the chromatin state in neural cell lines. It is also included in a LD block in our sample, alongside other genetic variants that alter chromatin regulatory regions in neural cells. These findings demonstrate that rs17225178 in the ARNT2 gene is associated with AS and support previous studies that pointed out an involvement of this gene in the predisposition to ASC.

  6. Adiponectin gene polymorphism is selectively associated with the concomitant presence of metabolic syndrome and essential hypertension.

    Directory of Open Access Journals (Sweden)

    Hsin-Bang Leu

    Full Text Available OBJECTIVE: Cardiovascular risk increases with the presence of both metabolic syndrome (MetS and hypertension (HTN. Although the adiponectin (ADIPOQ gene has been reported to be involved in MetS, its association with HTN remained undetermined. This study aimed to investigate the association of ADIPOQ gene with the phenotypes of HTN and MetS. METHODS: A total of 962 participants from 302 families from the Taiwan young-onset hypertension genetic study were enrolled. Plasma adiponectin were measured, and association analysis was conducted by using GEE regression-based method. Another study, of 1448 unrelated participants, was conducted to replicate the association between ADIPOQ gene and variable phenotypes of MetS with or without HTN. RESULTS: Among 962 subjects from family samples, the lowest plasma adiponectin value was observed in MetS with HTN component (9.3±0.47 µg/ml compared with hypertensives (13.4±0.74 µg /ml or MetS without HTN (11.9±0.60 µg/ml, P<0.05. The SNP rs1501299 (G276T in ADIPOQ gene was found associated with the presence of HTN in MetS (odds ratio for GG+GT vs. TT = 2.46; 95% CI: 1.14-5.3, p = 0.02, but not rs2241766 (T45G. No association of ADIPOQ gene with HTN alone or MetS without HTN was observed. The significant association of the SNP rs1501299 (G276T with the phenotype of presence of HTN in MetS was confirmed (odds ratio for GG+GT vs. TT = 2.15; 95% CI: 1.1-4.3 in the replication study. CONCLUSIONS: ADIPOQ genetic variants were selectively and specifically associated with the concomitant presence of MetS and HTN, suggesting potential genetic linkage between MetS and HTN.

  7. Barth syndrome associated with compound hemizygosity and heterozygosity of the TAZ and LDB3 genes.

    Science.gov (United States)

    Marziliano, Nicola; Mannarino, Savina; Nespoli, Luisa; Diegoli, Marta; Pasotti, Michele; Malattia, Clara; Grasso, Maurizia; Pilotto, Andrea; Porcu, Emanuele; Raisaro, Arturo; Raineri, Claudia; Dore, Roberto; Maggio, Pietro Paolo; Brega, Agnese; Arbustini, Eloisa

    2007-05-01

    Barth syndrome is an X-linked recessive disorder caused by the tafazzin (TAZ) gene mutations and includes dilated cardiomyopathy (DCM) with left ventricular non-compaction, neutropenia, skeletal myopathy, abnormal mitochondria and 3-methylglutaconic aciduria. Dilated cardiomyopathy with left ventricular non-compaction transmitted as an autosomal dominant condition has also been associated with LIM domain-binding 3 (LDB3) gene defects. We describe a family in which the 12-year-old proband had left ventricular non-compaction and DCM. His mother had five miscarriages, two other sons who died in infancy, and a healthy son and daughter. The proband showed left ventricular non-compaction-DCM, skeletal myopathy, recurrent oral aphthous ulcers and cyclic neutropenia. The DCM progressively improved with age; medical therapy was discontinued at 5 years of age. At present, left ventricular function is normal and arrhythmias are absent. Magnetic resonance imaging documented left ventricular non-compaction. However, oral aphthous ulcers and cyclic neutropenia have recurred. In the proband we identified two novel mutations, one of maternal origin in the TAZ gene (p.[Glu202ValfsX15]) and one of paternal origin in the LDB3 gene (p.[Thr350Ile]). The mother, brother and father are healthy; although the latter two show prominent left ventricle trabeculation without dysfunction. Expression studies of TAZ and LDB3 genes were conducted in family members and controls. In the proband, brother and father, LDB3 expression was similar to control cases. TAZ and LDB3 expression progressively declined with age in control both blood and myocardial samples. However, an endomyocardial biopsy performed in the proband at 6 months of age, showed significantly lower TAZ and LDB3 expression than in age-matched myocardial controls. We believe that the clinical, genetic and expression data support the hypothesis that tafazzins are essential during fetal and early post-natal life.

  8. Gene expression profiling provides insights into pathways of oxaliplatin-related sinusoidal obstruction syndrome in humans.

    Science.gov (United States)

    Rubbia-Brandt, Laura; Tauzin, Sébastien; Brezault, Catherine; Delucinge-Vivier, Céline; Descombes, Patrick; Dousset, Bertand; Majno, Pietro E; Mentha, Gilles; Terris, Benoit

    2011-04-01

    Sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) is a well-established complication of hematopoietic stem cell transplantation, pyrrolizidine alkaloid intoxication, and widely used chemotherapeutic agents such as oxaliplatin. It is associated with substantial morbidity and mortality. Pathogenesis of SOS in humans is poorly understood. To explore its molecular mechanisms, we used Affymetrix U133 Plus 2.0 microarrays to investigate the gene expression profile of 11 human livers with oxaliplatin-related SOS and compared it to 12 matched controls. Hierarchical clustering analysis showed that profiles from SOS and controls formed distinct clusters. To identify functional networks and gene ontologies, data were analyzed by the Ingenuity Pathway Analysis Tool. A total of 913 genes were differentially expressed in SOS: 613 being upregulated and 300 downregulated. Reverse transcriptase-PCR results showed excellent concordance with microarray data. Pathway analysis showed major gene upregulation in six pathways in SOS compared with controls: acute phase response (notably interleukin 6), coagulation system (Serpine1, THBD, and VWF), hepatic fibrosis/hepatic stellate cell activation (COL3a1, COL3a2, PDGF-A, TIMP1, and MMP2), and oxidative stress. Angiogenic factors (VEGF-C) and hypoxic factors (HIF1A) were upregulated. The most significant increase was seen in CCL20 mRNA. In conclusion, oxaliplatin-related SOS can be readily distinguished according to morphologic characteristics but also by a molecular signature. Global gene analysis provides new insights into mechanisms underlying chemotherapy-related hepatotoxicity in humans and potential targets relating to its diagnosis, prevention, and treatment. Activation of VEGF and coagulation (vWF) pathways could partially explain at a molecular level the clinical observations that bevacizumab and aspirin have a preventive effect in SOS.

  9. Novel germline mutations in FLCN gene identified in two Chinese patients with Birt-Hogg-Dubé syndrome.

    Science.gov (United States)

    Li, Teng; Ning, Xianghui; He, Qun; Gong, Kan

    2017-01-09

    Birt-Hogg-Dubé (BHD) syndrome, a hereditary renal cancer syndrome caused by mutations in the folliculin (FLCN) gene, is characterized by the presence of fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal cell carcinoma (RCC). Few BHD syndrome cases have been reported in Asian countries, and cutaneous presentations are relatively rare in Asian patients. Asian BHD patients may be misdiagnosed due to their atypical manifestations. Here, we report two Chinese BHD patients with novel FLCN mutations (c.946-947delAG in exon 9 and c.770-772delCCT in exon 7). Both of them had RCC and spontaneous pneumothorax without fibrofolliculomas. In patients with RCC and pulmonary cysts but without cutaneous lesions, screening for mutations in the FLCN gene should be performed, especially for those with a family history of RCC or pulmonary cysts (pneumothorax).

  10. A novel and de novo deletion in the OCRL1 gene associated with a severe form of Lowe syndrome.

    Science.gov (United States)

    Peces, Ramón; Peces, Carlos; de Sousa, Erika; Vega, Cristina; Selgas, Rafael; Nevado, Julián

    2013-12-01

    The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder. The mutation of the gene OCRL1 localized at Xq26.1, coding for the enzyme phosphatidylinositol (4,5) bisphosphate (PIP2P) 5-phosphatase, is responsible for the phenotypic characteristics of the disease. We report a 22-year-old male with a severe form of OCRL syndrome, diagnosed on the basis of congenital cataracts, severe psychomotor and cognitive deficits, and renal tubular dysfunction without Fanconi syndrome. The patient presented low molecular weight proteinuria, nephrocalcinosis, nephrolithiasis, rickets, and growth retardation and developed progressive renal failure. Genetic analysis showed a novel and de novo deletion of exons 10-13 in the OCRL1 gene.

  11. ANGIOTENSIN CONVERTING ENZIME GENE I/D POLYMORPHISM AND PROMISSING OF RENOPROTECTIVE AND IMMUNOSUPRESSIVE THERAPY IN CHILDREN WITH NEPHROTIC SYNDROME

    Directory of Open Access Journals (Sweden)

    Zh.P. Sharnova

    2007-01-01

    Full Text Available To investigate the role of i/d polymorphism gene angiotensin converting enzyme (ACE in promissing of renoprotective and immunosupressive therapy in children with nephrotic syndrome syndrome (NS we determined the genotypes of ACE in 76 children with ns including 22 children with chronic renal failure (CRF. the analysis of treatment effect with inhibitor ace in patients with steroid resistant ns (SRNS demonstrated decreasing of renoprotective effect of these drugs in patients with DD genotype compared with ii and id genotypes (р = 0,033 by similar degree of the glomerular filtration rate (GFR, proteinuria and blood pressure decrease in these patients. Percentage of DD genotype in patients with ns refractory to therapy of cyclosporin a were height compared with patients, sensitive to this therapy.Key words: nephrotic syndrome, chronic renal failure, polymorphism of genes, renin-angiotensin system.

  12. Un'estrema solitudine la vita e l'opera di Werner Heisenberg

    CERN Document Server

    Cassidy, David C

    1996-01-01

    Il genio di Werner Heisenberg attraversa l'orizzonte della fisica del nostro secolo come una meteora. Testimoniano della fecondità e dell'originalità del suo pensiero non solo il Nobel che gli fu assegnato a soli 32 anni, ma soprattutto i decisivi impulsi da lui dati alla fisica quantistica, alla teoria delle particelle elementari, alla teoria del nucleo. Si deve a Heisenberg quel "principio di indeterminazione" che ha rivoluzionato non solo il corso della fisica ma il modo di concepire la posizione dell'uomo nell'universo. L'interesse del libro, però, vuole andare oltre la fisica, giacché il curriculum del "ragazzo di campagna dei biondi capelli" rispecchia in forma emblematica l'ambiguo rapporto della scienza col potere.

  13. Robustness measure of hybrid intra-particle entanglement, discord, and classical correlation with initial Werner state

    Science.gov (United States)

    Saha, P.; Sarkar, D.

    2016-02-01

    Quantum information processing is largely dependent on the robustness of non-classical correlations, such as entanglement and quantum discord. However, all the realistic quantum systems are thermodynamically open and lose their coherence with time through environmental interaction. The time evolution of quantum entanglement, discord, and the respective classical correlation for a single, spin-1/2 particle under spin and energy degrees of freedom, with an initial Werner state, has been investigated in the present study. The present intra-particle system is considered to be easier to produce than its inter-particle counterpart. Experimentally, this type of system may be realized in the well-known Penning trap. The most stable correlation was identified through maximization of a system-specific global objective function. Quantum discord was found to be the most stable, followed by the classical correlation. Moreover, all the correlations were observed to attain highest robustness under initial Bell state, with minimum possible dephasing and decoherence parameters.

  14. High-Redshift Star Formation in a Time-Dependent Lyman-Werner Background

    CERN Document Server

    Visbal, Eli; Terrazas, Bryan; Bryan, Greg L; Barkana, Rennan

    2014-01-01

    The first generation of stars produces a background of Lyman-Werner (LW) radiation which can photo-dissociate molecular hydrogen, increasing the mass of dark matter halos required to host star formation. Previous studies have determined the critical mass required for efficient molecular cooling with a constant LW background. However, the true background is expected to increase rapidly at early times. Neglecting this evolution could underestimate star formation in small halos that may have started to cool in the past when the LW intensity was much lower. Background evolution is a large source of uncertainty in pre-reionization predictions of the cosmological 21cm signal, which can be observed with future radio telescopes. To address this, we perform zero-dimentional one-zone calculations that follow the density, chemical abundances, and temperature of gas in the central regions of dark matter halos, including hierarchical growth and an evolving LW background. We begin by studying the physics of halos subjected...

  15. Transcriptional analysis of the ribonucleotide reductase genes of shrimp white spot syndrome virus.

    Science.gov (United States)

    Tsai, M F; Lo, C F; van Hulten, M C; Tzeng, H F; Chou, C M; Huang, C J; Wang, C H; Lin, J Y; Vlak, J M; Kou, G H

    2000-11-10

    The causative agent of white spot syndrome (WSS) is a large double-stranded DNA virus, WSSV, which is probably a representative of a new genus, provisionally called Whispovirus. From previously constructed WSSV genomic libraries of a Taiwan WSSV isolate, clones with open reading frames (ORFs) that encode proteins with significant homology to the class I ribonucleotide reductase large (RR1) and small (RR2) subunits were identified. WSSV rr1 and rr2 potentially encode 848 and 413 amino acids, respectively. RNA was isolated from WSSV-infected shrimp at different times after infection and Northern blot analysis with rr1- and rr2-specific riboprobes found major transcripts of 2.8 and 1.4 kb, respectively. 5' RACE showed that the major rr1 transcript started at a position of -84 (C) relative to the ATG translational start, while transcription of the rr2 gene started at nucleotide residue -68 (T). A consensus motif containing the transcriptional start sites for rr1 and rr2 was observed (TCAc/tTC). Northern blotting and RT-PCR showed that the transcription of rr1 and rr2 started 4-6 h after infection and continued for at least 60 h. The rr1 and rr2 genes thus appear to be WSSV "early genes."

  16. Transcriptional analysis of the DNA polymerase gene of shrimp white spot syndrome virus.

    Science.gov (United States)

    Chen, Li-Li; Wang, Han-Ching; Huang, Chiu-Jung; Peng, Shao-En; Chen, Yen-Gu; Lin, Shin-Jen; Chen, Wei-Yu; Dai, Chang-Feng; Yu, Hon-Tsen; Wang, Chung-Hsiung; Lo, Chu-Fang; Kou, Guang-Hsiung

    2002-09-15

    The white spot syndrome virus DNA polymerase (DNA pol) gene (WSSV dnapol) has already been tentatively identified based on the presence of highly conserved motifs, but it shows low overall homology with other DNA pols and is also much larger (2351 amino acid residues vs 913-1244 aa). In the present study we perform a transcriptional analysis of the WSSV dnapol gene using the total RNA isolated from WSSV-infected shrimp at different times after infection. Northern blot analysis with a WSSV dnapol-specific riboprobe found a major transcript of 7.5 kb. 5'-RACE revealed that the major transcription start point is located 27 nucleotides downstream of the TATA box, at the nucleotide residue A within a CAGT motif, one of the initiator (Inr) motifs of arthropods. In a temporal expression analysis using differential RT-PCR, WSSV dnapol transcripts were detected at low levels at 2-4 h.p.i., increased at 6 h.p.i., and remained fairly constant thereafter. This is similar to the previously reported transcription patterns for genes encoding the key enzyme of nucleotide metabolism, ribonucleotide reductase. Phylogenetic analysis showed that the DNA pols from three different WSSV isolates form an extremely tight cluster. In addition, similar to an earlier phylogenetic analysis of WSSV protein kinase, the phylogenetic tree of viral DNA pols further supports the suggestion that WSSV is a distinct virus (likely at the family level) that does not belong to any of the virus families that are currently recognized.

  17. Novel mutations of TCOF1 gene in European patients with treacher Collins syndrome

    Directory of Open Access Journals (Sweden)

    Rinaldi Fabrizio

    2011-09-01

    Full Text Available Abstract Background Treacher Collins syndrome (TCS is one of the most severe autosomal dominant congenital disorders of craniofacial development and shows variable phenotypic expression. TCS is extremely rare, occurring with an incidence of 1 in 50.000 live births. The TCS distinguishing characteristics are represented by down slanting palpebral fissures, coloboma of the eyelid, micrognathia, microtia and other deformity of the ears, hypoplastic zygomatic arches, and macrostomia. Conductive hearing loss and cleft palate are often present. TCS results from mutations in the TCOF1 gene located on chromosome 5, which encodes a serine/alanine-rich nucleolar phospho-protein called Treacle. However, alterations in the TCOF1 gene have been implicated in only 81-93% of TCS cases. Methods In this study, the entire coding regions of the TCOF1 gene, including newly described exons 6A and 16A, were sequenced in 46 unrelated subjects suspected of TCS clinical indication. Results Fifteen mutations were reported, including twelve novel and three already described in 14 sporadic patients and in 3 familial cases. Moreover, seven novel polymorphisms were also described. Most of the mutations characterised were microdeletions spanning one or more nucleotides, in addition to an insertion of one nucleotide in exon 18 and a stop mutation. The deletions and the insertion described cause a premature termination of translation, resulting in a truncated protein. Conclusion This study confirms that almost all the TCOF1 pathogenic mutations fall in the coding region and lead to an aberrant protein.

  18. Growth hormone receptor gene mutations in two Italian patients with Laron Syndrome.

    Science.gov (United States)

    Fassone, L; Corneli, G; Bellone, S; Camacho-Hübner, C; Aimaretti, G; Cappa, M; Ubertini, G; Bona, G

    2007-05-01

    Laron Syndrome (LS) represents a condition characterized by GH insensitivity caused by molecular defects in the GH receptor (GHR) gene or in the post-receptor signalling pathway. We report the molecular characterization of two unrelated Italian girls from Sicily diagnosed with LS. The DNA sequencing of the GHR gene revealed the presence of different nonsense mutations, occurring in the same background haplotype. The molecular defects occurred in the extracellular domain of the GHR leading to a premature termination signal and to a truncated non-functional receptor. In one patient, a homozygous G to T transversion, in exon 6, led to the mutation GAA to TAA at codon 180 (E180X), while in the second patient a homozygous C to T transition in exon 7 was detected, causing the CGA to TAA substitution at codon 217 (R217X). Both probands presented the polymorphisms Gly168Gly and Ile544Leu in a homozygous state in exons 6 and 10, respectively. The E180X represents a novel defect of the GHR gene, while the R217X mutation has been previously reported in several patients from different ethnic backgrounds but all from countries located in the Mediterranean and Middle Eastern region.

  19. A new mutation site in the AIRE gene causes autoimmune polyendocrine syndrome type 1.

    Science.gov (United States)

    Zhu, Wufei; Hu, Zhen; Liao, Xiangyu; Chen, Xing; Huang, Wenrong; Zhong, Yu; Zeng, Zhaoyang

    2017-05-24

    Autoimmune polyendocrine syndrome type 1 (APS-1, OMIM 2403000) is a rare autosomal recessive disease that is caused by autoimmune regulator (AIRE). The main symptoms of APS-1 are chronic mucocutaneous candidiasis, autoimmune adrenocortical insufficiency (Addison's disease) and hypoparathyroidism. We collected APS-1 cases and analysed them. The AIRE genes of the patient and his family members were sequenced to identify whether the APS-1 patient had an AIRE mutation. We discovered a mutation site (c.206A>C) that had never before been reported in the AIRE gene located in exon 2 of the AIRE gene. This homogyzous mutation caused a substitution of the 69th amino acid of the AIRE protein from glutamine to proline (p.Q69P). A yeast two-hybrid assay, which was used to analyse the homodimerization properties of the mutant AIRE protein, showed that the mutant AIRE protein could not interact with the normal AIRE protein. Flow cytometry and RT-qPCR analyses indicated that the new mutation site could decrease the expression levels of the AIRE, glutamic acid decarboxylase 65 (GAD65) and tryptophan hydroxylase-1 (TPH1) proteins to affect central immune tolerance. In conclusion, our research has shown that the new mutation site (c.206A>C) may influence the homodimerization and expression levels and other aspects of the AIRE protein. It may also impact the expression levels of tissue-restricted antigens (TRAs), leading to a series of autoimmune diseases.

  20. Sudden infant death syndrome caused by cardiac arrhythmias: only a matter of genes encoding ion channels?

    Science.gov (United States)

    Sarquella-Brugada, Georgia; Campuzano, Oscar; Cesar, Sergi; Iglesias, Anna; Fernandez, Anna; Brugada, Josep; Brugada, Ramon

    2016-03-01

    Sudden infant death syndrome is the unexpected demise of a child younger than 1 year of age which remains unexplained after a complete autopsy investigation. Usually, it occurs during sleep, in males, and during the first 12 weeks of life. The pathophysiological mechanism underlying the death is unknown, and the lethal episode is considered multifactorial. However, in cases without a conclusive post-mortem diagnosis, suspicious of cardiac arrhythmias may also be considered as a cause of death, especially in families suffering from any cardiac disease associated with sudden cardiac death. Here, we review current understanding of sudden infant death, focusing on genetic causes leading to lethal cardiac arrhythmias, considering both genes encoding ion channels as well as structural proteins due to recent association of channelopathies and desmosomal genes. We support a comprehensive analysis of all genes associated with sudden cardiac death in families suffering of infant death. It allows the identification of the most plausible cause of death but also of family members at risk, providing cardiologists with essential data to adopt therapeutic preventive measures in families affected with this lethal entity.

  1. Mutation analysis of GJB2 gene and prenatal diagnosis in a non-syndromic deafness family

    Directory of Open Access Journals (Sweden)

    Xiao-hua CHEN

    2014-08-01

    Full Text Available Objective To identify the pathogenic gene in a non-syndromic deafness family, provide an accurate genetic consultation and early intervention for deaf family to reduce the incidence of congenital deafness. Methods Mutation analysis was carried out by polymerase chain reaction followed by DNA sequencing of coding region of GJB2 gene. The fetal DNA was extracted from the amniotic fluid cells by amniocentesis at 20 weeks during pregnancy. The genotype of the fetus was characterized for predicting the status of hearing. Results Complex heterozygous mutations 235delC and 176-191del16bp were detected in the proband of the family, heterozygous mutation 176-191del16bp was detected in the father, and 235delC was detected in the mother. Fetus carried 235delC heterozygous mutation inherited from his mother. Conclusions The proband's hearing loss is resulted from the complex heterozygous mutations 235delC and 176-191del16bp in GJB2 gene. Fetus is a heterozygous mutation 235delC carrier. Prenatal diagnosis for deafness assisted by genetic test can provide efficient guidance about offspring's hearing condition, and prevent another deaf-mute member from birth. DOI: 10.11855/j.issn.0577-7402.2014.07.09

  2. Autoimmune lymphoproliferative syndrome in a patient with a new minimal deletion in the death domain of the FAS gene

    NARCIS (Netherlands)

    Gualco, Gabrieta; van den Berg, Anke; Koopmans, Sicco; Bacchi, Livia M.; Carneiro, Siderley S.; Ruiz, Everaldo; Vecchi, Ana Paula; Chan, John K. C.

    2008-01-01

    We present a case of autoimmune lymphoproliferative syndrome (ALPS) caused by a previously undescribed minimal deletion in the death domain of the FAS gene. ALPS is an uncommon disease associated with an impaired Fas-mediated apoptosis. The patient presented with a history of splenomegaly since 4 mo

  3. Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome.

    NARCIS (Netherlands)

    Ruiz-Perez, V.L.; Tompson, S.W.; Blair, H.J.; Espinoza-Valdez, C.; Lapunzina, P.; Silva, E.O.; Hamel, B.C.J.; Gibbs, J.L.; Young, I.D.; Wright, M.J.; Goodship, J.A.

    2003-01-01

    Ellis-van Creveld syndrome (EvC) is an autosomal recessive skeletal dysplasia. Elsewhere, we described mutations in EVC in patients with this condition (Ruiz-Perez et al. 2000). We now report that mutations in EVC2 also cause EvC. These two genes lie in a head-to-head configuration that is conserved

  4. A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene

    DEFF Research Database (Denmark)

    Højlund, Kurt; Hansen, Torben; Lajer, Maria

    2004-01-01

    a missense mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene that cosegregated with the disease phenotype (logarithm of odds [LOD] score 3.21). In conclusion, we report a novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia. The findings demonstrate...

  5. Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified

    DEFF Research Database (Denmark)

    Hansen, Lars; Eiberg, Hans Rudolf Lytchoff; Barrett, Timothy

    2005-01-01

    Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing...

  6. Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome

    NARCIS (Netherlands)

    Jaeken, J.; Martens, K.; Francois, I.; Eyskens, F.; Lecointre, C.; Derua, R.; Meulemans, S.; Slootstra, J.W.; Waelkens, E.; Zegher, de F.; Creemers, J.W.M.; Matthijs, G.

    2006-01-01

    In 11 patients with a recessive congenital disorder, which we refer to as ¿the hypotonia-cystinuria syndrome,¿ microdeletion of part of the SLC3A1 and PREPL genes on chromosome 2p21 was found. Patients present with generalized hypotonia at birth, nephrolithiasis, growth hormone deficiency, minor fac

  7. Mutations in the codon for a conserved arginine-1563 in the COL4A5 collagen gene in Alport syndrome

    DEFF Research Database (Denmark)

    Zhou, J; Gregory, M C; Hertz, Jens Michael

    1993-01-01

    We have screened 110 unrelated Alport syndrome kindreds for mutations in the exon 48 region of the COL4A5 collagen gene. Denaturing gradient gel electrophoresis (DGGE) of the PCR-amplified region of exon 48 revealed sequence variants in DNA from affected males and carriers of three unrelated kind...

  8. Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome

    NARCIS (Netherlands)

    Jaeken, J.; Martens, K.; Francois, I.; Eyskens, F.; Lecointre, C.; Derua, R.; Meulemans, S.; Slootstra, J.W.; Waelkens, E.; Zegher, de F.; Creemers, J.W.M.; Matthijs, G.

    2006-01-01

    In 11 patients with a recessive congenital disorder, which we refer to as ¿the hypotonia-cystinuria syndrome,¿ microdeletion of part of the SLC3A1 and PREPL genes on chromosome 2p21 was found. Patients present with generalized hypotonia at birth, nephrolithiasis, growth hormone deficiency, minor fac

  9. Association between HTR2C gene polymorphisms and the metabolic syndrome in patients Using Antipsychotics: A Replication Study

    NARCIS (Netherlands)

    Risselada, Arne; Vehof, Jelle; Bruggeman, Richard; Wilffert, Bob; Cohen, Dan; Al Hadithy, Asmar; Arends, Johan; Mulder, Hans

    2010-01-01

    Background: In two previous studies we investigated the association between the rs1414334 C/G and 759 C/T polymorphisms in the HTR2C gene, coding for the 5HT2c-receptor, and prevalence of the metabolic syndrome in a schizophrenic population. In both studies we found an association between the varian

  10. [The influence of GPIIIA gene polymorphism on the variability of standard electrocardiogram in patients with acute coronary syndrome].

    Science.gov (United States)

    Komarova, A G; Zotova, T Iu; Miandina, G I; Kasapova, E N; Zotov, A K; Tarasova, E S; Frolov, V A

    2010-01-01

    The authors analyse effect of GPIIIA gene (PI a allele) polymorphism on the frequency of complicated coronary heart disease in patients with dyslipidemia and hypertensive disease. Specific features of ventricular repolarization (T-wave variability) in patients with acute coronary syndrome are described.

  11. Association study of single nucleotide polymorphism of dopamine D2 receptor gene and Tourette syndrome therapeutic effects

    Institute of Scientific and Technical Information of China (English)

    黄环环

    2013-01-01

    Objective To explore the difference of rs1800497 of single nucleotide polymorphism (SNP) of dopamine D2 receptor (DRD2) gene genotype and allele frequency in Tourette syndrome (TS) patients with different therapeutic effect in Chinese Han population.Methods The

  12. The relationship between tumor necrosis factor-α gene promoter polymorphism and obstructive sleep apnea-hypopnea syndrome

    Institute of Scientific and Technical Information of China (English)

    刘辉国

    2006-01-01

    Objective To investigate the relationship between tumor necrosis factor-α(TNF-α) gene promoter polymorphism and obstructive sleep apnea-hypopnea syndrome (OSAHS). Methods The plasma TNF-αlevel of OSAHS group and non-OSAHS group was detected by enzyme-linked immunosorbent assay (ELISA). Eighteen patients with severe OSAHS were treated with continuous

  13. Association between HTR2C gene polymorphisms and the metabolic syndrome in patients Using Antipsychotics: A Replication Study

    NARCIS (Netherlands)

    Risselada, Arne; Vehof, Jelle; Bruggeman, Richard; Wilffert, Bob; Cohen, Dan; Al Hadithy, Asmar; Arends, Johan; Mulder, Hans

    2010-01-01

    Background: In two previous studies we investigated the association between the rs1414334 C/G and 759 C/T polymorphisms in the HTR2C gene, coding for the 5HT2c-receptor, and prevalence of the metabolic syndrome in a schizophrenic population. In both studies we found an association between the varian

  14. The 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is not associated with HELLP syndrome.

    Science.gov (United States)

    Muetze, Sabine; Eggermann, Thomas; Leeners, Brigitte; Birke, Cornelia; Kuse, Sabine; Ortlepp, Jan Rudolf; Rudnik-Schoeneborn, Sabine; Zerres, Klaus; Rath, Werner

    2009-02-01

    Plasminogen activator inhibitor-1 (PAI-1) is a major inhibitor of fibrinolysis, and a single nucleotide insertion/deletion (4G/5G) polymorphism in the promoter region of the PAI-1 gene has been identified. Subjects homozygous for the 4G allele have the highest PAI-levels due to increased PAI-1 gene transcription. Pre-eclampsia, and one of its most severe forms, the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, are characterized by increased placental thrombosis based on a procoagulatory state in the mother. Several studies have investigated the role of the PAI-1 4G/5G polymorphism in pre-eclampsia, but no study has focused especially on HELLP syndrome. Therefore we aimed to assess the association between HELLP syndrome and the 4G/5G polymorphism in the PAI-1 gene. Genotyping of the PAI-1 4G/5G promoter polymorphism was performed in 102 Caucasian women with HELLP syndrome and 102 Caucasian women with uncomplicated pregnancies. The 4G/4G genotype was more frequent in women with HELLP syndrome than in controls (35.3% vs. 22.5%, respectively) but this difference was not significantly different (P = 0.129). The frequency of the 4G allele was 0.588 in patients and 0.515 in controls. These data suggest that women carrying a 4G/4G genotype of the PAI-1 gene are not at increased risk for developing HELLP syndrome and are thus in line with the majority of previous studies on the association between the PAI-1 4G/5G polymorphism and pre-eclampsia.

  15. A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene

    Science.gov (United States)

    Meunier, Isabelle; Bocquet, Béatrice; Labesse, Gilles; Zeitz, Christina; Defoort-Dhellemmes, Sabine; Lacroux, Annie; Mauget-Faysse, Martine; Drumare, Isabelle; Gamez, Anne-Sophie; Mathieu, Cyril; Marquette, Virginie; Sagot, Lola; Dhaenens, Claire-Marie; Arndt, Carl; Carroll, Patrick; Remy-Jardin, Martine; Cohen, Salomon Yves; Sahel, José-Alain; Puech, Bernard; Audo, Isabelle; Mrejen, Sarah; Hamel, Christian P.

    2016-01-01

    To revisit the autosomal dominant Sorsby fundus dystrophy (SFD) as a syndromic condition including late-onset pulmonary disease. We report clinical and imaging data of ten affected individuals from 2 unrelated families with SFD and carrying heterozygous TIMP3 mutations (c.572A > G, p.Y191C, exon 5, in family 1 and c.113C > G, p.S38C, exon 1, in family 2). In family 1, all SFD patients older than 50 (two generations) had also a severe emphysema, despite no history of smoking or asthma. In the preceding generation, the mother died of pulmonary emphysema and she was blind after the age of 50. Her two great-grandsons (<20 years), had abnormal Bruch Membrane thickness, a sign of eye disease. In family 2, eye and lung diseases were also associated in two generations, both occurred later, and lung disease was moderate (bronchiectasis). This is the first report of a syndromic SFD in line with the mouse model uncovering the role of TIMP3 in human lung morphogenesis and functions. The TIMP3 gene should be screened in familial pulmonary diseases with bronchiectasis, associated with a medical history of visual loss. In addition, SFD patients should be advised to avoid tobacco consumption, to practice sports, and to undergo regular pulmonary examinations. PMID:27601084

  16. [Mutation screening of MITF gene in patients with Waardenburg syndrome type 2].

    Science.gov (United States)

    Chen, Jing; Yang, Shu-Zhi; Liu, Jun; Han, Bing; Wang, Guo-Jian; Zhang, Xin; Kang, Dong-Yang; Dai, Pu; Young, Wie-Yen; Yuan, Hui-Jun

    2008-04-01

    Warrgenburg syndrome type 2 (WS2) is the most common autosomal dominantly-inherited syndrome with hearing loss. MITF (microphthalmia associated transcription factor)is a basic-helix-loop-helix-luecine zipper (bHLHZip) factor which regulates expression of tyrosinase, and is involved in melanocyte differentiation. Mutations in MITF associated with WS2 have been identified in some but not all affected families. Here, we report a three-generation Chinese family with a point mutation in the MITF gene causing WS2. The proband exhibits congenital severe sensorineural hearing loss, heterochromia iridis and facial freckles. One of family members manifests sensorineural deafness, and the other patients show premature greying or/and freckles. This mutation, heterozygous deletion c.639delA, creates a stop codon in exon 7 and is predicted to result in a truncated protein lacking normal interaction with its target DNA motif. This mutation is a novel mutation and the third case identified in exon 7 of MITF in WS2. Though there is only one base pair distance between this novel mutation and the other two documented cases and similar amino acids change, significant difference is seen in clinical phenotype, which suggests genetic background may play an important role.

  17. The Tourette International Collaborative Genetics (TIC Genetics) study, finding the genes causing Tourette syndrome

    DEFF Research Database (Denmark)

    Dietrich, Andrea; Fernandez, Thomas V; King, Robert A

    2015-01-01

    Tourette syndrome (TS) is a neuropsychiatric disorder characterized by recurrent motor and vocal tics, often accompanied by obsessive-compulsive disorder and/or attention-deficit/hyperactivity disorder. While the evidence for a genetic contribution is strong, its exact nature has yet to be clarif......Tourette syndrome (TS) is a neuropsychiatric disorder characterized by recurrent motor and vocal tics, often accompanied by obsessive-compulsive disorder and/or attention-deficit/hyperactivity disorder. While the evidence for a genetic contribution is strong, its exact nature has yet......, it is clear that large patient cohorts and open-access repositories will be essential to further advance the field. To that end, the large multicenter Tourette International Collaborative Genetics (TIC Genetics) study was established. The goal of the TIC Genetics study is to undertake a comprehensive gene...... discovery effort, focusing both on familial genetic variants with large effects within multiply affected pedigrees and on de novo mutations ascertained through the analysis of apparently simplex parent-child trios with non-familial tics. The clinical data and biomaterials (DNA, transformed cell lines, RNA...

  18. Rare Syndromes and Common Variants of the Brain-Derived Neurotrophic Factor Gene in Human Obesity.

    Science.gov (United States)

    Han, J C

    2016-01-01

    Rare genetic disorders that cause BDNF haploinsufficiency, such as WAGR syndrome, 11p deletion, and 11p inversion, serve as models for understanding the role of BDNF in human energy balance and neurocognition. Patients with BDNF haploinsufficiency or inactivating mutations of the BDNF receptor exhibit hyperphagia, childhood-onset obesity, intellectual disability, and impaired nociception. Prader-Willi, Smith-Magenis, and ROHHAD syndromes are separate genetic disorders that do not directly affect the BDNF locus but share many similar clinical features with BDNF haploinsufficiency, and BDNF insufficiency is believed to possibly contribute to the pathophysiology of each of these conditions. In the general population, common variants of BDNF that affect BDNF gene expression or BDNF protein processing have also been associated with modest alterations in energy balance and cognitive functioning. Thus, variable degrees of BDNF insufficiency appear to contribute to a spectrum of excess weight gain and cognitive impairment that ranges in phenotypic severity. In this modern era of precision medicine, genotype-specific therapies aimed at increasing BDNF signaling in patients with rare and common disorders associated with BDNF insufficiency could serve as useful approaches for treating obesity and neurodevelopmental disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Searching for Tourette’s syndrome gene. Part 1. Heterogeneity of clinical phenotypes

    Directory of Open Access Journals (Sweden)

    Anna Kowalska

    2012-02-01

    Full Text Available The French neuropsychiatrist Georges Gilles de la Tourette described in 1885 the “Maladie des Tics” which later was named after him, as Gilles de la Tourette syndrome (GTS. Gilles de la Tourette syndrome is a neurodevelopmental disorder characterized by simple and complex motor and vocal tics with multiple neuropsychiatric comorbidities. GTS is often concurrent with obsessive-compulsive disorder (OCD and attention deficit hyperactivity disorder (ADHD. There are several clinical GTS subtypes: GTS only, GTS OCD, and GTS OCD ADHD. Additional clinical aspects of the disorder include occurrence of anger episodes, anxiety and mood disorders, and learning and sleeping disturbances. The genetics of GTS is complex and remains unclear. So far, no causative candidate genes have been identified. However, segregation studies in families and twins with GTS provide strong evidence for the existence of a genetic background associated with a multifactorial mode of inheritance. Progress in studies on genome variability among patients with GTS is necessary to improve pharmacotherapeutic strategies of the disorder.

  20. 5q14.3 deletion neurocutaneous syndrome: Contiguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C: A progressive disease.

    Science.gov (United States)

    Ilari, Rita; Agosta, Guillermo; Bacino, Carlos

    2016-03-01

    We report the case of a young girl who was presented with complex clinical symptoms caused by the deletion of contiguous genes: RASA1 and MEF2C, located on chromosome 5q14.3. Specifically, the diagnosis of her skin disorder and vascular malformations involving central nervous system is consistent with a RASopathy. The child's neurological manifestations are observed in most patients suffering from 5q14.3 by deletion or mutation of the MEF2C gene. A review of the literature allowed us to conclude that the contiguous deletion of genes RASA1 and MEF2C fulfills the criteria for the diagnosis of a Neurocutaneous syndrome as proposed by Carr et al. [2011]. We also assessed the penetrance of RASA1 and clinical manifestations of MEF2C according to the type of deletion. This child described presents the complete symptomatology of both deleted genes. We would also like to highlight the progression of the disorder.

  1. Sneddon Syndrome with Factor V Leiden, Methylene Tetrahydrofolate Reductase and FMF Gene Mutations

    Directory of Open Access Journals (Sweden)

    Murat Terzi

    2010-03-01

    Full Text Available Sneddon syndrome (SNS, characterized by livedo racemosa and stroke, is a rare disease, especially in young adults. Livedo racemosa are large lesions, widespread on the extremities and the body, that are violet-colored and have a good appearance and ambiguous limits. A 33-years-old female presented to our clinic for headache. She had a two-year history of blue-purple skin marks on her body and legs. The skin lesions were consistent with livedo racemosa. She had experienced right hemiparesis according to her medical history. Factor V Leiden (G1691A mutation was heterozygote-positive. Methylenetetrahydrofolate reductase (MTHFR C677T and FMF gene (MEFV V726A mutations were determined. SNS is the cause of stroke, rarely seen in young adults. We considered this case to be of value since it is the first SNS case having factor V Leiden, MTHFR and MEFV mutations concomitantly.

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

    Science.gov (United States)

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

    2014-01-01

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

  3. Analysis of unstable DNA sequence in FRM1 gene in Polish families with fragile X syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Milewski, Michal; Bal, Jerzy; Obersztyn, Ewa; Bocian, Ewa; Mazurczak, Tadeusz [Instytut Matki i Dziecka, Warsaw (Poland); Zygulska, Marta; Horst, Juergen [Institute of Human Genetics, Muenster (Germany); Deelen, Wout H.; Halley, Dicky J.J. [Erasmus Univ., Rotterdam (Netherlands)

    1996-12-31

    The unstable DNA sequence in the FMR1 gene was analyzed in 85 individuals from Polish families with fragile X syndrome in order to characterize mutations responsible for the disease in Poland. In all affected individuals classified on the basis of clinical features and expression of the fragile site at X(q27.3) a large expansion of the unstable sequence (full mutation) was detected. About 5% (2 of 43) of individuals with full mutation did not express the fragile site. Among normal alleles, ranging in size from 20 to 41 CGC repeats, allele with 29 repeats was the most frequent (37%). Transmission of premutated and fully mutated alleles to the offspring was always associated with size increase. No change in repeat number was found when normal alleles were transmitted. (author). 19 refs., 4 figs, 1 tab.

  4. Serotonin transporter gene polymorphisms: Relation with platelet serotonin level in patients with primary Sjogren's syndrome.

    Science.gov (United States)

    Markeljevic, J; Sarac, H; Bozina, N; Henigsberg, N; Simic, M; Cicin Sain, L

    2015-05-15

    Significantly lower platelet serotonin level (PSL) in patients with primary Sjogren's syndrome (pSS) than in healthy controls has been reported in our prior studies. In the present report, we demonstrated effect of functional polymorphisms in the serotonin transporter gene (5-HTT) on PSL. We describe a group of 61 pSS patients and 100 healthy individuals subjects, who received PSL measurement in our prior study. All subjects were genotyped for the promoter 5-HTTLPR (L/S), rs25531 (A/G) and intronic 5-HTTVNTRin2 (l/s) polymorphisms. Overall, the presence of 5-HTTVNTRin2 ss genotype was associated with significantly lower PSL in pSS patients, not in healthy controls. Reduced PSL in pSS patients is in line with hypothesis of association between chronic immunoinflammation and 5-HT system dysregulation, identifying additional mechanisms such as altered 5-HT transport as potential genetic factor contributing to PSL depletion.

  5. MAPT1 gene rs1052553 variant is unrelated with the risk for restless legs syndrome.

    Science.gov (United States)

    Roco, Angela; Jiménez-Jiménez, Félix Javier; Alonso-Navarro, Hortensia; Martínez, Carmen; Zurdo, Martín; Turpín-Fenoll, Laura; Millán, Jorge; Adeva-Bartolomé, Teresa; Cubo, Esther; Navacerrada, Francisco; Rojo-Sebastián, Ana; Rubio, Lluisa; Calleja, Marisol; Plaza-Nieto, José Francisco; Pilo-de-la-Fuente, Belén; Arroyo-Solera, Margarita; García-Martín, Elena; Agúndez, José A G

    2013-03-01

    Mutations in the microtubule-associated protein tau gene (MAPT) can cause frontotemporal dementia with Parkinsonism linked to the chromosome 17, and are associated with the risk for progressive supranuclear palsy, Parkinson's disease, corticobasal degeneration, and multiple system atrophy. We tried to establish, whether MAPT H1 discriminating haplotype single nucleotide polymorphisms (SNP) (rs1052553) is associated with the risk for restless legs syndrome (RLS). We studied the allelic and genotype frequencies of the SNP rs1052553 in 205 patients with RLS and 324 healthy controls using TaqMan genotyping. rs1052553 genotype and allelic frequencies did not differ significantly between patients with RLS and controls, and were unrelated with the age at onset of RLS, gender, family history of RLS, and severity of RLS. The results of the present study suggest that the SNP rs1052553 is not related with the risk for RLS.

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

    Science.gov (United States)

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

    2014-07-22

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

  7. Metabolic syndrome, diabetes and atherosclerosis: Influence of gene-environment interaction

    Energy Technology Data Exchange (ETDEWEB)

    Andreassi, Maria Grazia, E-mail: andreas@ifc.cnr.it [CNR Institute of Clinical Physiology, G. Pasquinucci Hospital, Via Aurelia Sud, Massa (Italy)

    2009-07-10

    Despite remarkable progress in diagnosis and understanding of risk factors, cardiovascular disease (CVD) remains still the leading cause of morbidity and mortality in the world's developed countries. The metabolic syndrome, a cluster of risk factors (visceral obesity, insulin resistance, dyslipidaemia, and hypertension), is increasingly being recognized as a new risk factor for type 2 diabetes and atherosclerotic cardiovascular disease. Nevertheless, there is wide variation in both the occurrence of disease and age of onset, even in individuals who display very similar risk profiles. There is now compelling evidence that a complex interplay between genetic determinants and environmental factors (still largely unknown) is the reason for this large inter-individual variation in disease susceptibility. The purpose of the present review is to describe the current status of our knowledge concerning the gene-environment interactions potentially implicated in the pathogenesis of metabolic syndrome, diabetes and cardiovascular disease. It focuses predominantly on studies of genes (peroxisome proliferator-activated receptor-gamma, alcohol dehydrogenase type 1C, apolipoprotein E, glutathione S-transferases T1 and M1) that are known to be modified by dietary and lifestyle habits (fat diet, intake of alcohol and smoking habit). It also describes the limited current understanding of the role of genetic variants of xenobiotic metabolizing enzymes and their interactions with environmental toxicants. Additional studies are needed in order to clarify whether inter-individual differences in detoxification of environmental toxicants may have an essential role in the development of CVD and contribute to the emerging field of 'environmental cardiology'. Such knowledge may be particularly relevant for improving cardiovascular risk stratification and conceiving the development of 'personalized intervention program'.

  8. Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome.

    Science.gov (United States)

    Ü Basmanav, F Buket; Cau, Laura; Tafazzoli, Aylar; Méchin, Marie-Claire; Wolf, Sabrina; Romano, Maria Teresa; Valentin, Frederic; Wiegmann, Henning; Huchenq, Anne; Kandil, Rima; Garcia Bartels, Natalie; Kilic, Arzu; George, Susannah; Ralser, Damian J; Bergner, Stefan; Ferguson, David J P; Oprisoreanu, Ana-Maria; Wehner, Maria; Thiele, Holger; Altmüller, Janine; Nürnberg, Peter; Swan, Daniel; Houniet, Darren; Büchner, Aline; Weibel, Lisa; Wagner, Nicola; Grimalt, Ramon; Bygum, Anette; Serre, Guy; Blume-Peytavi, Ulrike; Sprecher, Eli; Schoch, Susanne; Oji, Vinzenz; Hamm, Henning; Farrant, Paul; Simon, Michel; Betz, Regina C

    2016-12-01

    Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili trianguli et canaliculi," or "cheveux incoiffables" is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. Elucidation of the molecular outcomes of the disease-causing mutations by cell culture experiments and tridimensional protein models demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins. Scanning electron microscopy observations revealed morphological alterations in hair coat of Padi3 knockout mice. All together, these findings elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology in general. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  9. Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene.

    Science.gov (United States)

    Graul-Neumann, Luitgard M; Kienitz, Tina; Robinson, Peter N; Baasanjav, Sevjidmaa; Karow, Benjamin; Gillessen-Kaesbach, Gabriele; Fahsold, Raimund; Schmidt, Hartmut; Hoffmann, Katrin; Passarge, Eberhard

    2010-11-01

    We report on a 25-year-old woman with pronounced generalized lipodystrophy and a progeroid aspect since birth, who also had Marfan syndrome (MFS; fulfilling the Ghent criteria) with mild skeletal features, dilated aortic bulb, dural ectasia, bilateral subluxation of the lens, and severe myopia in addition to the severe generalized lipodystrophy. She lacked insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes. Mutation analysis in the gene encoding fibrillin 1 (FBN1) revealed a novel de novo heterozygous deletion, c.8155_8156del2 in exon 64. The severe generalized lipodystrophy in this patient with progeroid features has not previously been described in other patients with MFS and FBN1 mutations. We did not find a mutation in genes known to be associated with congenital lipodystrophy (APGAT2, BSCL2, CAV1, PTRF-CAVIN, PPARG, LMNB2) or with Hutchinson-Gilford progeria (ZMPSTE24, LMNA/C). Other progeria syndromes were considered unlikely because premature greying, hypogonadism, and scleroderma-like skin disease were not present. Our patient shows striking similarity to two patients who have been published in this journal by O'Neill et al. [O'Neill et al. (2007); Am J Med Genet Part A 143A:1421-1430] with the diagnosis of neonatal progeroid syndrome (NPS). This condition also known as Wiedemann-Rautenstrauch syndrome is a rare disorder characterized by accelerated aging and lipodystrophy from birth, poor postnatal weight gain, and characteristic facial features. The course is usually progressive with early lethality. However this entity seems heterogeneous. We suggest that our patient and the two similar cases described before represent a new entity, a subgroup of MFS with overlapping features to NPS syndrome.

  10. A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse)

    OpenAIRE

    Zhou, Yihua; Xu, Bixiong C.; Maheshwari, Hiralal G.; He, Li; Reed, Michael; Lozykowski, Maria; Okada, Shigeru; Cataldo, Lori; Coschigamo, Karen; Wagner, Thomas E.; Baumann, Gerhard; Kopchick, John J.

    1997-01-01

    Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach. Homozygous GHR/...

  11. Atypical Aicardi-Goutieres syndrome: is the WRN locus a modifier?

    Science.gov (United States)

    Lessel, Davor; Saha, Bidisha; Hisama, Fuki; Kaymakamzade, Bahar; Nurlu, Gulay; Gursoy-Özdemir, Yasemin; Thiele, Holger; Nürnberg, Peter; Martin, George M; Kubisch, Christian; Oshima, Junko

    2014-10-01

    We describe a 28-year-old Turkish man with consanguineous parents who presented with an aged appearance with prematurely gray hair and scleroderma-like skin, spastic paraplegia, and apparent disability. The proband and each of his parents were heterozygous for a mutation in WRN, which could not explain his symptoms. Exome sequencing of the proband's blood DNA showed a homozygous c.626-1G > C mutation in intron 5 of the SAMHD1 gene, which encodes a triphosphohydrolase involved in the regulation of intracellular dNTP pools and which is mutated in Aicardi-Goutieres syndrome. The RNA studies confirmed aberrant splicing of exon 6, and family studies showed that both parents are heterozygous for this mutation. We conclude that mutations in SAMHD1 - in addition to causing an early-onset form of encephalopathy in Aicardi-Goutieres syndrome - may present with modest signs of accelerated aging similar to Werner syndrome. The extent to which heterozygosity at the WRN locus may modify the effect of biallelic SAMHD1 mutations is unknown. It is conceivable that synergistic effects of these two mutations might be responsible for the unusual phenotype.

  12. Surfactant protein B gene polymorphism in preterm babies with respiratory distress syndrome

    Directory of Open Access Journals (Sweden)

    P.P.R. Lyra

    2011-01-01

    Full Text Available The etiology of respiratory distress syndrome (RDS is multifactorial and multigenic. Studies have suggested that polymorphisms and mutations in the surfactant protein B (SP-B gene are associated with the pathogenesis of RDS. The objectives of this study were to determine and compare the frequencies of SP-B gene polymorphisms in preterm babies with and without RDS. We studied 151 neonates: 79 preterm babies without RDS and 72 preterm newborns with RDS. The following four SP-B gene polymorphisms were analyzed: A/C at -18, C/T at 1580, A/G at 9306, and G/C at nucleotide 8714. The polymorphisms were detected by PCR amplification of genomic DNA and genotyping. The genotypes were determined using PCR-based converted restriction fragment length polymorphisms. The control group consisted of 42 (53% girls and 37 (47% boys. Weight ranged from 1170 to 3260 g and mean gestational age (GA was 33.9 weeks (range: 29 to 35 weeks and 6 days. The RDS group consisted of 31 (43% girls and 41 (57% boys. Weight ranged from 614 to 2410 g and mean GA was 32 weeks (range: 26 to 35 weeks. The logistic regression model showed that GA was the variable that most contributed to the occurrence of RDS. The AG genotype of the A/G polymorphism at position 9306 of the SP-B gene was a protective factor in this population (OR = 0.1681; 95%CI = 0.0426-0.6629. We did not detect differences in the frequencies of the other polymorphisms between the two groups of newborns.

  13. Translational implication of Kallmann syndrome-1 gene expression in hepatocellular carcinoma.

    Science.gov (United States)

    Tanaka, Yuri; Kanda, Mitsuro; Sugimoto, Hiroyuki; Shimizu, Dai; Sueoka, Satoshi; Takami, Hideki; Ezaka, Kazuhiro; Hashimoto, Ryoji; Okamura, Yukiyasu; Iwata, Naoki; Tanaka, Chie; Yamada, Suguru; Fujii, Tsutomu; Nakayama, Goro; Koike, Masahiko; Nomoto, Shuji; Fujiwara, Michitaka; Kodera, Yasuhiro

    2015-01-01

    Accumulation of epigenetic alterations causes inactivation of tumor suppressors and contributes to the initiation and progression of hepatocellular carcinoma (HCC). Identification of methylated genes is necessary to improve our understanding of the pathogenesis of HCC and develop novel biomarkers and therapeutic targets. The Kallmann syndrome-1 (KAL1) gene encodes an extracellular matrix-related protein with diverse oncological functions. However, the function of KAL1 in HCC has not been examined. We investigated the methylation status of the KAL1 promoter region in HCC cell lines, and evaluated KAL1 mRNA levels and those of genes encoding potential interacting cell adhesion factors. KAL1 mRNA expression level was heterogeneous in nine HCC cell lines, and reactivation of KAL1 mRNA expression was observed in cells with promoter hypermethylation of KAL1 gene after demethylation. In addition, KAL1 mRNA levels inversely correlated with those of ezrin in all nine HCC cell lines. KAL1 expression levels in 144 pairs of surgically-resected tissues were determined and correlated to clinicopathological parameters. KAL1 mRNA level was independent of the background liver status, whereas HCC tissues showed significantly lower KAL1 mRNA levels than corresponding noncancerous liver tissues. Downregulation of KAL1 mRNA in HCC was significantly associated with malignant phenotype characteristics, including elevated tumor markers, larger tumor size, vascular invasion, and hypermethylation of KAL1. Patients with downregulation of KAL1 were more likely to have a shorter overall survival than other patients, and multivariate analysis identified downregulation of KAL1 as an independent prognostic factor (hazard ratio 2.04, 95% confidence interval 1.11-3.90, P=0.022). Our results indicated that KAL1 may act as a putative tumor suppressor in HCC and is inactivated by promoter hypermethylation. KAL1 may serve as a biomarker of malignant phenotype of HCC.

  14. The expression of pregnancy-specific {beta}1-glycoprotein genes in Meckel-Gruber syndrome fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Shao-Ming; Cham, Wai-Yee [Georgetown Univ. Medical Center, Washington, DC (United States)

    1994-09-01

    Meckel-Gruber syndrome (MS) is an autosomal recessive disorder with multiple congenital malformations. The only available prenatal diagnostic marker for this disorder is the amniotic fluid level of pregnancy-specific {beta}1-glycoprotein (PSG). PSG is a family of proteins which are expressed at high levels during pregnancy. Increasing maternal serum PSG levels correlate with the progression of pregnancy and can be used as indicators for pregnancy outcome and fetal well-being. The amniotic fluid PSG level is about one-tenth of that of the maternal serum level in normal pregnancy, but are elevated in all cases of MS examined so far. On the other hand, the maternal serum PSG level and third trimester placental PSG content are normal in most cases of MS. This study aims at comparing the expression of PSG in fibroblasts derived from a fetus afflicted with MS. Total cellular RNA was extracted from two MS cultured fibroblast lines (M3206 and GM7817) and four age- and sex-matched control fibroblast lines obtained from the Human Genetic Mutant Cell Repository, Camden, NJ. The expression of eight PSG genes namely, PSG1, PSG2, PSG3, PSG4, PSG5, PSG6, PSG9 and PSG11, were examined with reverse transcription-polymerase chain reaction (RT-PCR). All PSG transcripts present in the cell were first amplified using universal primers in a 28-cycle PCR. Specific PSG gene products were then amplified with PSG gene-specific primers. Results showed that there is no significant difference in PSG expression between control and disease fibroblasts. In both cases, the most abundant transcript was the type II transcript of PSG5 followed by the type I transcripts of PSG1 and PG4. PSG9, PSG11 and PSG 3 were expressed at very low levels or not expressed at all in MS as well as in normal control fibroblasts. These results showed that PSG gene expression was not altered in MS fibroblasts.

  15. Association of obesity susceptibility gene variants with metabolic syndrome and related traits in 1,443 Czech adolescents.

    Science.gov (United States)

    Dušátková, L; Zamrazilová, H; Sedláčková, B; Včelák, J; Hlavatý, P; Aldhoon Hainerová, I; Korenková, V; Bradnová, O; Bendlová, B; Kunešová, M; Hainer, V

    2013-01-01

    Genome-wide association studies have revealed several gene variants associated with obesity; however, only a few studies have further investigated their association with metabolic syndrome. We performed a study of eleven variants in/near genes TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R, and FTO in Czech adolescents and analysed their association with obesity, metabolic syndrome and related traits. Genotyping was performed in 1,443 adolescents aged 13.0-17.9 years. Anthropometric parameters, biochemical parameters and blood pressure were assessed. Metabolic syndrome was defined according to the International Diabetes Federation. The FTO rs9939609 variant was associated with overweight/obesity (OR 1.40, 95% CI 1.21-1.63, P metabolic syndrome (OR 1.53, 95% CI 1.14-2.04, P = 0.005; 1.51, 95% CI 1.12-2.04, P = 0.009). The PCSK1 rs6235 variant was negatively related to increased blood glucose (OR 0.69, 95% CI 0.49-0.97, P = 0.040). In conclusion, the FTO variant was associated with overweight/obesity in Czech adolescents. Moreover, MC4R and BDNF variants increased the risk of metabolic syndrome, probably through their effect on abdominal obesity. The PCSK1 variant may have a protective role in the development of type 2 diabetes.

  16. Rothmund-Thomson syndrome

    Directory of Open Access Journals (Sweden)

    Roversi Gaia

    2010-01-01

    Full Text Available Abstract Rothmund-Thomson syndrome (RTS is a genodermatosis presenting with a characteristic facial rash (poikiloderma associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging and a predisposition to cancer. The prevalence is unknown but around 300 cases have been reported in the literature so far. The diagnostic hallmark is facial erythema, which spreads to the extremities but spares the trunk, and which manifests itself within the first year and then develops into poikiloderma. Two clinical subforms of RTS have been defined: RTSI characterised by poikiloderma, ectodermal dysplasia and juvenile cataracts, and RTSII characterised by poikiloderma, congenital bone defects and an increased risk of osteosarcoma in childhood and skin cancer later in life. The skeletal abnormalities may be overt (frontal bossing, saddle nose and congenital radial ray defects, and/or subtle (visible only by radiographic analysis. Gastrointestinal, respiratory and haematological signs have been reported in a few patients. RTS is transmitted in an autosomal recessive manner and is genetically heterogeneous: RTSII is caused by homozygous or compound heterozygous mutations in the RECQL4 helicase gene (detected in 60-65% of RTS patients, whereas the aetiology in RTSI remains unknown. Diagnosis is based on clinical findings (primarily on the age of onset, spreading and appearance of the poikiloderma and molecular analysis for RECQL4 mutations. Missense mutations are rare, while frameshift, nonsense mutations and splice-site mutations prevail. A fully informative test requires transcript analysis not to overlook intronic deletions causing missplicing. The diagnosis of RTS should be considered in all patients with osteosarcoma, particularly if associated with skin changes. The differential diagnosis should include other causes of childhood poikiloderma

  17. Novel mutations in PRG4 gene in two Indian families with camptodactyly-arthropathy- coxa vara- pericarditis (CACP syndrome

    Directory of Open Access Journals (Sweden)

    Rajashree S Nandagopalan

    2014-01-01

    Full Text Available Background & objectives: Camptodactyly - arthropathy- coxa vara- pericarditis (CACP syndrome is an autosomal recessive disorder caused by mutations in the PRG4 (proteoglycan 4 gene. Hallmarks of the syndrome include congenital or early-onset camptodactyly and arthropathy with synovial hyperplasia, progressive coxa vara deformity and non-inflammatory pericardial effusions. Till date only around 25 pathogenic mutations have been reported in this gene and none have been reported from India. We report here the mutations in the PRG4 gene in three patients of CACP from two unrelated families from India. Methods: Molecular genetic studies were done for the three patients with the CACP syndrome, from two unrelated Indian families, through sequence analysis of all coding exons and the exon-intron boundaries of the PRG4 gene. Results: Two novel frame-shift deletion mutations leading to premature protein termination were found. One patient was identified to be homozygous for a 2 base pair deletion in exon 6 (c.2645_2646delGA and the two affected siblings from the other family were found to be homozygous for a 4 base pair deletion in exon 6 (c.2883_2886delAAGA. Conclusions: This is perhaps the first report of PRG4 mutations from India. Further mutation studies in Indian CACP cases will help to determine the mutation spectrum of the PRG4 gene in the Indian population and also help to further elucidate the molecular pathology and the genotype-phenotype correlation of this rare disease.

  18. Imaging features of tuberous sclerosis complex with autosomal-dominant polycystic kidney disease: a contiguous gene syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Back, Susan J. [The Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); Andronikou, Savvas [University of the Witwatersrand, Radiology Department, Faculty of Health Sciences, Johannesburg (South Africa); Kilborn, Tracy [University of Cape Town, Red Cross War Memorial Children' s Hospital, Cape Town (South Africa); Kaplan, Bernard S. [The Children' s Hospital of Philadelphia, Division of Nephrology, Philadelphia, PA (United States); University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA (United States); Darge, Kassa [The Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA (United States)

    2015-03-01

    Genes for tuberous sclerosis complex (TSC) type 2 and autosomal-dominant polycystic kidney disease (ADPKD) type 1 are both encoded over a short segment of chromosome 16. When deletions involve both genes, an entity known as the TSC2/ADPKD1 contiguous gene syndrome, variable phenotypes of TSC and ADPKD are exhibited. This syndrome has not been reviewed in the radiology literature. Unlike renal cysts in TSC, cystic disease in TSC2/ADPKD1 contiguous gene syndrome results in hypertension and renal failure. A radiologist might demonstrate polycystic kidney disease before the patient develops other stigmata of TSC. Conversely, in patients with known TSC, enlarged and polycystic kidneys should signal the possibility of the TSC2/ADPKD1 contiguous gene syndrome and not simply TSC. Distinguishing these diagnoses has implications in prognosis, treatment and genetic counseling. To describe the clinical and imaging findings of tuberous sclerosis complex and polycystic kidney disease in seven pediatric patients. We retrospectively reviewed renal and brain imaging of children and young adults with genetically proven or high clinical suspicion for TSC2/ADPKD1 contiguous gene syndrome. We included seven pediatric patients from two referral institutions. Ages ranged from birth to 21 years over the course of imaging. The mean follow-up period was 9 years 8 months (4 years 6 months to 20 years 6 months). No child progressed to end-stage renal disease during this period. Three patients were initially imaged for stigmata of TSC, three for abdominal distension and one for elevated serum creatinine concentration. All patients developed enlarged, polycystic kidneys. The latest available imaging studies demonstrated that in 12 of the 14 kidneys 50% or more of the parenchyma was ultimately replaced by >15 cysts, resulting in significant cortical thinning. The largest cysts in each kidney ranged from 2.4 cm to 9.3 cm. Echogenic lesions were present in 13 of the 14 kidneys, in keeping with

  19. Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis.

    Science.gov (United States)

    Bagheri, Hani; Badduke, Chansonette; Qiao, Ying; Colnaghi, Rita; Abramowicz, Iga; Alcantara, Diana; Dunham, Christopher; Wen, Jiadi; Wildin, Robert S; Nowaczyk, Malgorzata J M; Eichmeyer, Jennifer; Lehman, Anna; Maranda, Bruno; Martell, Sally; Shan, Xianghong; Lewis, Suzanne M E; O'Driscoll, Mark; Gregory-Evans, Cheryl Y; Rajcan-Separovic, Evica

    2016-03-17

    The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1, USP34, BCL11A, and REL) that were included, alone or in combination, in the smallest deletions causing the syndrome. Here, we describe 8 new patients with the 2p15p16.1 deletion and review all published cases to date. We demonstrate functional deficits for the above 4 candidate genes using patients' lymphoblast cell lines (LCLs) and knockdown of their orthologs in zebrafish. All genes were dosage sensitive on the basis of reduced protein expression in LCLs. In addition, deletion of XPO1, a nuclear exporter, cosegregated with nuclear accumulation of one of its cargo molecules (rpS5) in patients' LCLs. Other pathways associated with these genes (e.g., NF-κB and Wnt signaling as well as the DNA damage response) were not impaired in patients' LCLs. Knockdown of xpo1a, rel, bcl11aa, and bcl11ab resulted in abnormal zebrafish embryonic development including microcephaly, dysmorphic body, hindered growth, and small fins as well as structural brain abnormalities. Our multifaceted analysis strongly implicates XPO1, REL, and BCL11A as candidate genes for 2p15p16.1 microdeletion syndrome.

  20. Novel mutation in forkhead box G1 (FOXG1) gene in an Indian patient with Rett syndrome.

    Science.gov (United States)

    Das, Dhanjit Kumar; Jadhav, Vaishali; Ghattargi, Vikas C; Udani, Vrajesh

    2014-03-15

    Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by the progressive loss of intellectual functioning, fine and gross motor skills and communicative abilities, deceleration of head growth, and the development of stereotypic hand movements, occurring after a period of normal development. The classic form of RTT involves mutation in MECP2 while the involvement of CDKL5 and FOXG1 genes has been identified in atypical RTT phenotype. FOXG1 gene encodes for a fork-head box protein G1, a transcription factor acting primarily as transcriptional repressor through DNA binding in the embryonic telencephalon as well as a number of other neurodevelopmental processes. In this report we have described the molecular analysis of FOXG1 gene in Indian patients with Rett syndrome. FOXG1 gene mutation analysis was done in a cohort of 34 MECP2/CDKL5 mutation negative RTT patients. We have identified a novel mutation (p. D263VfsX190) in FOXG1 gene in a patient with congenital variant of Rett syndrome. This mutation resulted into a frameshift, thereby causing an alteration in the reading frames of the entire coding sequence downstream of the mutation. The start position of the frameshift (Asp263) and amino acid towards the carboxyl terminal end of the protein was found to be well conserved across species using multiple sequence alignment. Since the mutation is located at forkhead binding domain, the resultant mutation disrupts the secondary structure of the protein making it non-functional. This is the first report from India showing mutation in FOXG1 gene in Rett syndrome.

  1. SPAG7 is a candidate gene for the periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome.

    Science.gov (United States)

    Bens, S; Zichner, T; Stütz, A M; Caliebe, A; Wagener, R; Hoff, K; Korbel, J O; von Bismarck, P; Siebert, R

    2014-01-01

    Periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome is an auto-inflammatory disease for which a genetic basis has been postulated. Nevertheless, in contrast to the other periodic fever syndromes, no candidate genes have yet been identified. By cloning, following long insert size paired-end sequencing, of a de novo chromosomal translocation t(10;17)(q11.2;p13) in a patient with typical PFAPA syndrome lacking mutations in genes associated with other periodic fever syndromes we identified SPAG7 as a candidate gene for PFAPA. SPAG7 protein is expressed in tissues affected by PFAPA and has been functionally linked to antiviral and inflammatory responses. Haploinsufficiency of SPAG7 due to a microdeletion at the translocation breakpoint leading to loss of exons 2-7 from one allele was associated with PFAPA in the index. Sequence analyses of SPAG7 in additional patients with PFAPA point to genetic heterogeneity or alternative mechanisms of SPAG7 deregulation, such as somatic or epigenetic changes.

  2. 9q33.3q34.11 microdeletion: new contiguous gene syndrome encompassing STXBP1, LMX1B and ENG genes assessed using reverse phenotyping.

    Science.gov (United States)

    Nambot, Sophie; Masurel, Alice; El Chehadeh, Salima; Mosca-Boidron, Anne-Laure; Thauvin-Robinet, Christel; Lefebvre, Mathilde; Marle, Nathalie; Thevenon, Julien; Perez-Martin, Stéphanie; Dulieu, Véronique; Huet, Frédéric; Plessis, Ghislaine; Andrieux, Joris; Jouk, Pierre-Simon; Billy-Lopez, Gipsy; Coutton, Charles; Morice-Picard, Fanny; Delrue, Marie-Ange; Heron, Delphine; Rooryck, Caroline; Goldenberg, Alice; Saugier-Veber, Pascale; Joly-Hélas, Géraldine; Calenda, Patricia; Kuentz, Paul; Manouvrier-Hanu, Sylvie; Dupuis-Girod, Sophie; Callier, Patrick; Faivre, Laurence

    2016-06-01

    The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneous-mucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.

  3. Johanson-Blizzard syndrome with mild phenotypic features confirmed by UBR1 gene testing

    Institute of Scientific and Technical Information of China (English)

    Naim Alkhouri; Barbara Kaplan; Marsha Kay; Amy Shealy; Carol Crowe; Susanne Bauhuber; Nartin Zenker

    2008-01-01

    Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive condition associated with exocrine pancreatic insufficiency, and is characterized by hypoplastic nasal alae, mental retardation, sensorineural hearing loss, short stature, scalp defects, dental abnormalities and abnormal hair patterns. Growth hormone deficiency, hypopituitarism, and impaired glucagon secretion response to insulin-induced hypoglycemia have been reported. Congenital heart defects have also been described in this condition. Mental retardation is typically moderate to severe in patients with JBS; however, normal intelligence can occur. In the pancreas, there is a selective defect of acinar tissue, whereas the islets of Langerhans and ducts are preserved. Diabetes has been reported in older children, suggesting the progressive nature of pancreatic disease. The molecular basis of JBS has recently been mapped to chromosome 15q15-q21 with identified mutations in the UBR1 gene. We report the case of a 7-year-old female with pancreatic insufficiency and mild phenotypic features, in whom the diagnosis of JBS was established using recently described molecular testing for the UBR1 gene.

  4. A case of familial paraganglioma syndrome type 4 caused by a mutation in the SDHB gene.

    Science.gov (United States)

    Drucker, Aaron M; Houlden, Robyn L

    2006-12-01

    A 40-year-old man was referred to our clinic with recurrent paragangliomas. He had undergone resection of a paraganglioma superior to the right adrenal gland at 19 years of age, resection of two para-aortic paragangliomas at 39 years of age, and resection of a paraganglioma in the interatrial septum at 40 years. The patient's mother had died at age 39 years of metastases from a carotid body tumor. MRI and CT scanning, 131I-labeled metaiodobenzylguanidine scanning, and genetic testing for a mutation in the succinate dehydrogenase complex, subunit B gene. Familial paraganglioma syndrome type 4 caused by a mutation in the succinate dehydrogenase complex, subunit B gene. The patient underwent two surgical procedures in our clinic. The first was to remove two para-aortic paragangliomas, and the second to remove a paraganglioma that involved both atria. The patient is at high risk for malignant disease and should undergo an annual monitoring program that consists of physical examination and measurement of his blood pressure and levels of urinary catecholamines and metanephrines. If these procedures suggest a recurrence of paraganglioma, 123I-labeled metaiodobenzylguanidine scanning should be performed. As he might develop nonfunctional tumors, however, he should also undergo CT scanning, MRI scanning, or both, of the neck, thorax, abdomen, and pelvis every 6-12 months. Genetic testing has been offered to family members.

  5. Diversity of the Genes Implicated in Algerian Patients Affected by Usher Syndrome.

    Science.gov (United States)

    Abdi, Samia; Bahloul, Amel; Behlouli, Asma; Hardelin, Jean-Pierre; Makrelouf, Mohamed; Boudjelida, Kamel; Louha, Malek; Cheknene, Ahmed; Belouni, Rachid; Rous, Yahia; Merad, Zahida; Selmane, Djamel; Hasbelaoui, Mokhtar; Bonnet, Crystel; Zenati, Akila; Petit, Christine

    2016-01-01

    Usher syndrome (USH) is an autosomal recessive disorder characterized by a dual sensory impairment affecting hearing and vision. USH is clinically and genetically heterogeneous. Ten different causal genes have been reported. We studied the molecular bases of the disease in 18 unrelated Algerian patients by targeted-exome sequencing, and identified the causal biallelic mutations in all of them: 16 patients carried the mutations at the homozygous state and 2 at the compound heterozygous state. Nine of the 17 different mutations detected in MYO7A (1 of 5 mutations), CDH23 (4 of 7 mutations), PCDH15 (1 mutation), USH1C (1 mutation), USH1G (1 mutation), and USH2A (1 of 2 mutations), had not been previously reported. The deleterious consequences of a missense mutation of CDH23 (p.Asp1501Asn) and the in-frame single codon deletion in USH1G (p.Ala397del) on the corresponding proteins were predicted from the solved 3D-structures of extracellular cadherin (EC) domains of cadherin-23 and the sterile alpha motif (SAM) domain of USH1G/sans, respectively. In addition, we were able to show that the USH1G mutation is likely to affect the binding interface between the SAM domain and USH1C/harmonin. This should spur the use of 3D-structures, not only of isolated protein domains, but also of protein-protein interaction interfaces, to predict the functional impact of mutations detected in the USH genes.

  6. Screening of UBE3A gene in patients referred for Angelman Syndrome.

    Science.gov (United States)

    Tzagkaraki, Evmorfia; Sofocleous, Christalena; Fryssira-Kanioura, Helen; Helen, Fryssira-Kanioura; Dinopoulos, Argyris; Goulielmos, Georgios; Mavrou, Ariadni; Kitsiou-Tzeli, Sofia; Sofia, Kitsiou-Tzeli; Kanavakis, Emmanuel

    2013-07-01

    Angelman Syndrome (AS) is a neurodevelopmental disorder characterized by severe developmental delay, speech impairment and unique behaviors including inappropriate laughter and happy disposition. AS is related to deficient maternal UBE3A gene expression caused either by chromosomal deletions, uniparental disomy, molecular defects of the imprinted 15q11-q13 critical region or by loss of function mutations in the maternally inherited UBE3A. In the present study, screening UBE3A was performed in 43 patients who were referred for AS but whom previous molecular diagnostic tests failed to provide a diagnosis. Two causative mutations--one of them novel--and four polymorphic variants one of which is also novel were revealed. Further investigation of 7 patients disclosed defects in other genes involved in clinical phenotypes mimicking AS. A typical EEG pattern and microcephaly in patients with developmental delay prompt for AS investigation while wide genetic screening should be applied to help resolution of the complex phenotypes characterized by developmental delay. Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  7. Baculovirus-mediated promoter assay and transcriptional analysis of white spot syndrome virus orf427 gene

    Directory of Open Access Journals (Sweden)

    Yu Li

    2005-08-01

    Full Text Available Abstract Background White spot syndrome virus (WSSV is an important pathogen of the penaeid shrimp with high mortalities. In previous reports, Orf427 of WSSV is characterized as one of the three major latency-associated genes of WSSV. Here, we were interested to analyze the promoter of orf427 and its expression during viral pathogenesis. Results in situ hybridization revealed that orf427 was transcribed in all the infected tissues during viral lytic infection and the translational product can be detected from the infected shrimp. A time-course RT-PCR analysis indicated that transcriptional products of orf427 could only be detected after 6 h post virus inoculation. Furthermore, a baculovirus-mediated promoter analysis indicated that the promoter of orf427 failed to express the EGFP reporter gene in both insect SF9 cells and primary shrimp cells. Conclusion Our data suggested that latency-related orf427 might not play an important role in activating virus replication from latent phase due to its late transcription during the lytic infection.

  8. Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome.

    Science.gov (United States)

    Fujii, Katsunori; Ohashi, Hirofumi; Suzuki, Maiko; Hatsuse, Hiromi; Shiohama, Tadashi; Uchikawa, Hideki; Miyashita, Toshiyuki

    2013-12-01

    Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1, encoding a receptor for the secreted protein, sonic hedgehog. Recently, a Chinese family with NBCCS carrying a missense mutation in PTCH2, a close homolog of PTCH1, was reported. However, the pathological significance of missense mutations should be discussed cautiously. Here, we report a 13-year-old girl diagnosed with NBCCS based on multiple keratocystic odontogenic tumors and rib anomalies carrying a frameshift mutation in the PTCH2 gene (c.1172_1173delCT). Considering the deleterious nature of the frameshift mutation, our study further confirmed a causative role for the PTCH2 mutation in NBCCS. The absence of typical phenotypes in this case such as palmar/plantar pits, macrocephaly, falx calcification, hypertelorism and coarse face, together with previously reported cases, suggested that individuals with NBCCS carrying a PTCH2 mutation may have a milder phenotype than those with a PTCH1 mutation.

  9. Two novel NIPBL gene mutations in Chinese patients with Cornelia de Lange syndrome.

    Science.gov (United States)

    Mei, Libin; Liang, Desheng; Huang, Yanru; Pan, Qian; Wu, Lingqian

    2015-01-25

    Cornelia de Lange syndrome (CdLS) is a dominantly inherited developmental disorder characterized by distinctive facial features, mental retardation, and upper limb defects, with the involvement of multiple organs and systems. To date, mutations have been identified in five genes responsible for CdLS: NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Here, we present a clinical and molecular characterization of five unrelated Chinese patients whose clinical presentation is consistent with that of CdLS. There were no chromosomal abnormalities in the five children. In three patients, DNA sequencing revealed a previously reported frameshift mutation c.2479delA (p.Arg827GlyfsX20), and two novel mutations including a heterozygous mutation c.6272 G>T (p.Cys2091Phe) and a frameshift mutation c.1672delA (p.Thr558LeufsX7) in NIPBL. For the remaining patients, large deletions and/or duplications within the NIPBL gene were excluded as playing a role in the pathogenesis, by Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. These findings broaden the mutation spectrum of NIPBL and further our understanding of the diverse and variable effects of NIPBL mutations on CdLS. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Nucleotide sequence analysis of NIPBL gene in Indian Cornelia de Lange syndrome cases.

    Science.gov (United States)

    Bajaj, Shailesh; Ranade, Suvidya; Gambhir, Prakash

    2013-01-01

    Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder in children. The disorder is caused mainly due to mutations in Nipped-B-like protein. The molecular data for CdLS is available from developed countries, but not available in developing countries like India. In the present study, the hotspot region of NIPBL gene was screened by Polymerase Chain Reaction which includes exon 2, 22, 42, and a biggest exon 10, in six CdLS patients and ten controls. The method adopted in present study was amplification of the target exon by using polymerase chain reaction, qualitative confirmation of amplicons by Agarose Gel Electrophoresis and use of amplicons for Conformation Sensitive Gel Electrophoresis to find heteroduplex formation followed by sequencing. We report two polymorphisms in the studied region of gene NIPBL. The polymorphisms are in the region of intron 1 and in exon 10. The polymorphism C/A is present in intron 1 region and polymorphism T/G in exon 10. The intronic region polymorphism may have a role in intron splicing whereas the polymorphism in exon 10 results in amino acid change (Val to Gly). These polymorphisms are disease associated as these are found in CdLS patients only and not in controls.

  11. A functional alternative splicing mutation in AIRE gene causes autoimmune polyendocrine syndrome type 1.

    Science.gov (United States)

    Zhang, Junyu; Liu, Hongbin; Liu, Zhiyuan; Liao, Yong; Guo, Luo; Wang, Honglian; He, Lin; Zhang, Xiaodong; Xing, Qinghe

    2013-01-01

    Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare autosomal recessive disease defined by the presence of two of the three conditions: mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Loss-of-function mutations of the autoimmune regulator (AIRE) gene have been linked to APS-1. Here we report mutational analysis and functional characterization of an AIRE mutation in a consanguineous Chinese family with APS-1. All exons of the AIRE gene and adjacent exon-intron sequences were amplified by PCR and subsequently sequenced. We identified a homozygous missense AIRE mutation c.463G>A (p.Gly155Ser) in two siblings with different clinical features of APS-1. In silico splice-site prediction and minigene analysis were carried out to study the potential pathological consequence. Minigene splicing analysis and subsequent cDNA sequencing revealed that the AIRE mutation potentially compromised the recognition of the splice donor of intron 3, causing alternative pre-mRNA splicing by intron 3 retention. Furthermore, the aberrant AIRE transcript was identified in a heterozygous carrier of the c.463G>A mutation. The aberrant intron 3-retaining transcript generated a truncated protein (p.G155fsX203) containing the first 154 AIRE amino acids and followed by 48 aberrant amino acids. Therefore, our study represents the first functional characterization of the alternatively spliced AIRE mutation that may explain the pathogenetic role in APS-1.

  12. Site-directed mutagenesis of long QT syndrome KCNQ1 gene in vitro

    Institute of Scientific and Technical Information of China (English)

    Wei LI; Junguo YANG; Rong DU; Li TIAN; Bin WANG; Qiumei XU; Qinmei KE; Qing WANG

    2008-01-01

    To construct a polymerase chain reaction (PCR) site-directed mutagenesis of the long QT syndrome KCNQ1 gene in vitro, two sets of primers were designed according to the sequence of KCNQ1 cDNA and a mismatch was introduced into primers. Mutagenesis was performed in a two-step PCR. The amplified fragments from the third PCR which contained the mutation site were sub-cloned into the T-vector pCR2.1. Then, the fragments containing the mutation site was obtained from pCR2.1 using restriction enzymes digestion and inserted into the same restriction site of plRES2-EGFP-KCNQ1. The sequencing analysis shows that the mutation site was correct. Mutation from A to G in site 983 of KCNQ1 cDNA was found. Using the Effectene transfection reagent, plRES2-EGFP-KCNQ1 (G983A) was transfected into HEK cells successfully. These results may shed light on further functional study of KCNQ1 gene.

  13. A functional alternative splicing mutation in AIRE gene causes autoimmune polyendocrine syndrome type 1.

    Directory of Open Access Journals (Sweden)

    Junyu Zhang

    Full Text Available Autoimmune polyendocrine syndrome type 1 (APS-1 is a rare autosomal recessive disease defined by the presence of two of the three conditions: mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Loss-of-function mutations of the autoimmune regulator (AIRE gene have been linked to APS-1. Here we report mutational analysis and functional characterization of an AIRE mutation in a consanguineous Chinese family with APS-1. All exons of the AIRE gene and adjacent exon-intron sequences were amplified by PCR and subsequently sequenced. We identified a homozygous missense AIRE mutation c.463G>A (p.Gly155Ser in two siblings with different clinical features of APS-1. In silico splice-site prediction and minigene analysis were carried out to study the potential pathological consequence. Minigene splicing analysis and subsequent cDNA sequencing revealed that the AIRE mutation potentially compromised the recognition of the splice donor of intron 3, causing alternative pre-mRNA splicing by intron 3 retention. Furthermore, the aberrant AIRE transcript was identified in a heterozygous carrier of the c.463G>A mutation. The aberrant intron 3-retaining transcript generated a truncated protein (p.G155fsX203 containing the first 154 AIRE amino acids and followed by 48 aberrant amino acids. Therefore, our study represents the first functional characterization of the alternatively spliced AIRE mutation that may explain the pathogenetic role in APS-1.

  14. Characterization of the porcine FBX07 gene: the first step towards generation of a pig model for Parkinsonian pyramidal syndrome

    DEFF Research Database (Denmark)

    Larsen, Knud; Bendixen, Christian

    2012-01-01

    Parkinsonian pyramidal syndrome, also named pallido-pyramidal syndrome (PKPS), is the combination of early-onset progressive Parkinsonism with pyramidal tract signs. FBXO7, an F-box protein, is a component of modular E3 ubiquitin protein ligases called SCFs (SKP1, cullin, F-box proteins), which f......). Using a radiation hybrid map the FBXO7 gene was mapped to pig chromosome 5. Real-time quantitative RT-PCR analysis revealed that FBXO7 mRNA is differentially expressed in many tissues and organs, and that FBXO7 transcript can be detected early in embryo development....

  15. Clinical features and growth hormone receptor gene mutations of patients with Laron syndrome from a Chinese family.

    Science.gov (United States)

    Ying, Yan-Qin; Wei, Hong; Cao, Li-Zhi; Lu, Juan-Juan; Luo, Xiao-Ping

    2007-08-01

    Laron syndrome is an autosomal recessive disorder caused by defects of growth hormone receptor (GHR) gene. It is characterized by severe postnatal growth retardation and characteristic facial features as well as high circulating levels of growth hormone (GH) and low levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3). This report described the clinical features and GHR gene mutations in 2 siblings with Laron syndrome in a Chinese family. Their heights and weights were in the normal range at birth, but the growth was retarded after birth. When they presented to the clinic, the heights of the boy (8 years old) and his sister (11 years old) were 80.0 cm (-8.2 SDS) and 96.6 cm (-6.8 SDS) respectively. They had typical appearance features of Laron syndrome such as short stature and obesity, with protruding forehead, saddle nose, large eyes, sparse and thin silky hair and high-pitched voice. They had higher basal serum GH levels and lower serum levels of IGF-I, IGFBP-3 and growth hormone binding protein (GHBP) than normal controls. The peak serum GH level after colonidine and insulin stimulations in the boy was over 350 ng/mL. After one-year rhGH treatment, the boy's height increased from 80.0 cm to 83.3 cm. The gene mutation analysis revealed that two patients had same homozygous mutation of S65H (TCA -->CCA) in exon 4, which is a novel gene mutation. It was concluded that a definite diagnosis of Laron syndrome can be made based on characteristic appearance features and serum levels of GH, IGF-I, IGFBP-3 and GHBP. The S65H mutation might be the cause of Laron syndrome in the two patients.

  16. Chromosomal protein HMG-14 gene maps to the Down syndrome region of human chromosome 21 and is overexpressed in mouse trisomy 16

    Energy Technology Data Exchange (ETDEWEB)

    Pash, J.; Popescu, N.; Matocha, M.; Rapoport, S.; Bustin, M. (National Institutes of Health, Bethesda, MD (USA))

    1990-05-01

    The gene for human high-mobility-group (HMG) chromosomal protein HMG-14 is located in region 21q22.3, a region associated with the pathogenesis of Down syndrome, one of the most prevalent human birth defects. The expression of this gene is analyzed in mouse embryos that are trisomic in chromosome 16 and are considered to be an animal model for Down syndrome. RNA blot-hybridization analysis and detailed analysis of HMG-14 protein levels indicate that mouse trisomy 16 embryos have approximately 1.5 times more HMG-14 mRNA and protein than their normal littermates, suggesting a direct gene dosage effect. The HMG-14 gene may be an additional marker for the Down syndrome. Chromosomal protein HMG-14 is a nucleosomal binding protein that may confer distinct properties to the chromatin structure of transcriptionally active genes and therefore may be a contributing factor in the etiology of the syndrome.

  17. Further localization of the gene for nevoid basal cell carcinoma syndrome (NBCCS) in 15 Australasian families: Linkage and loss of heterozygosity

    Energy Technology Data Exchange (ETDEWEB)

    Chenevix-Trench, G.; Wicking, C.; Berkman, J.; Sharpe, H.; Hockey, A.; Haan, E.; Oley, C.; Ravine, D.; Turner, A.; Searle, J. (and others)

    1993-09-01

    Nevoid basal cell carcinoma syndrome (NBCCS; basal cell nevus syndrome or Gorlin syndrome) is a cancer-predisposition syndrome characterized by multiple basal cell carcinomas (BCCs) and diverse developmental defects. The gene for NBCCS has been mapped to 9q23.1-q31 in North Americal and European families. In addition, loss of heterozygosity (LOH) for genetic markers in this region has been detected in sporadic BCCs, indicating that the NBCCs gene is probably a tumor-suppressor gene. In this study the authors have determined that the NBCCS gene is also linked to this region in Australasian pedigrees and that there is no significant evidence of heterogeneity. They have defined the localization of the gene by multipoint and haplotype analysis of 15 families, using four microsatellite markers. LOH at these loci was detected in 50% of sporadic BCCs, a rate that is significantly higher than that in other skin lesions used as controls. 21 refs., 3 figs., 2 tabs.

  18. ROR2 gene is associated with risk of non-syndromic cleft palate in an Asian population

    Institute of Scientific and Technical Information of China (English)

    WANG Hong; Vincent Yeow; Samuel S. Chong; Felicia SH Cheah; Ethylin Wang Jabs; Alan F. Scott; Terfi H. Beaty; Jacqueline B. Hetmanski; Ingo Ruczinski; Kung Yee Liang; M. Daniele Fallin; Richard J. Redett; Gerald V. Raymond; Yah-Huei Wu Chou; Philip Kuo-Ting Chen

    2012-01-01

    Background The receptor tyrosine kinase-like orphan receptor 2 (ROR2) gene has been recently shown to play important roles in palatal development in animal models and resides in the chromosomal region linked to non syndromic cleft lip with or without cleft palate in humans.The aim of this study was to investigate the possible association between ROR2 gene and non-syndromic oral clefts.Methods Here we tested 38 eligible single-nucleotide polymorphisms (SNPs) in ROR2 gene in 297 non-syndromic cleft lip with or without cleft palate and in 82 non-syndromic cleft palate case parent trios recruited from Asia and Maryland.Family Based Association Test was used to test for deviation from Mendelian inheritance.Plink software was used to test potential parent of origin effect.Possible maternally mediated in utero effects were assessed using the TRlad Multi-Marker approach under an assumption of mating symmetry in the population.Results Significant evidence of linkage and association was shown for 3 SNPs (rs7858435,rs10820914 and rs3905385) among 57 Asian non-syndromic cleft palate trios in Family Based Association Tests.P values for these 3 SNPs equaled to 0.000068,0.000115 and 0.000464 respectively which were all less than the significance level (0.05/38=0.0013) adjusted by strict Bonferroni correction.Relevant odds ratios for the risk allele were 3.42 (1.80-6.50),3.45 (1.75-6.67) and 2.94 (1.56-5.56),respectively.Statistical evidence of linkage and association was not shown for study groups other than non-syndromic cleft palate.Neither evidence for parent-of-origin nor maternal genotypic effect was shown for any of the ROR2 markers in our analysis for all study groups.Conclusion Our results provided evidence of linkage and association between the ROR2 gene and a gene controlling risk to non-syndromic cleft palate.

  19. In vivo exposures to particulate matter collected from Saudi Arabia or nickel chloride display similar dysregulation of metabolic syndrome genes

    Science.gov (United States)

    Brocato, Jason; Hernandez, Michelle; Laulicht, Freda; Sun, Hong; Shamy, Magdy; Alghamdi, Mansour A.; Khoder, Mamdouh I.; Kluz, Thomas; Chen, Lung-Chi; Costa, Max

    2016-01-01

    Particulate matter (PM) exposures have been linked to mortality, low birth weights, hospital admissions, and diseases associated with metabolic syndrome, including diabetes mellitus, cardiovascular disease, and obesity. In a previous in vitro and in vivo study, data demonstrated that PM10µm collected from Jeddah, Saudi Arabia (PMSA) altered expression of genes involved in lipid and cholesterol metabolism, as well as many other genes associated with metabolic disorders. PMSA contains a relatively high concentration of nickel (Ni), known to be linked to several metabolic disorders. In order to evaluate if Ni and PM exposures induce similar gene expression profiles, mice were exposed to 100µg/50µl PMSA (PM-100), 50µg/50µl nickel chloride (Ni-50), or 100µg/50µl nickel chloride (Ni-100) twice a week for 4 weeks and hepatic gene expression changes determined. Ultimately, 55 of the same genes were altered in all 3 exposures. However, where the two Ni groups differed markedly was in the regulation (up or down) of these genes. Ni-100 and PM-100 groups displayed similar regulations, whereby 104 of the 107 genes were similarly modulated. Many of the 107 genes involved in metabolic syndrome and include ALDH4A1, BCO2, CYP1A, CYP2U, TOP2A. In addition, the top affected pathways such as fatty acid α-oxidation, and lipid and carbohydrate metabolism, are involved in metabolic diseases. Most notably, the top diseased outcome affected by these changes in gene expression was cardiovascular disease. Given these data, it appears that Ni and PMSA exposures display similar gene expression profiles, modulating the expression of genes involved in metabolic disorders. PMID:26692068

  20. Mediterranean dietary pattern and VEGF +405 G/C gene polymorphisms in patients with metabolic syndrome: An aspect of gene-nutrient interaction

    Science.gov (United States)

    Hajiluian, Ghazaleh; Abbasalizad Farhangi, Mahdieh; Jahangiry, Leila

    2017-01-01

    Aims To evaluate the relationship between Mediterranean dietary pattern, anthropometric and metabolic biomarkers and vascular endothelial growth factor (VEGF) +405 G/C gene polymorphism in patient with metabolic syndrome (Mets). Materials and methods In this study 150 patients with Mets and 50 healthy subjects were enrolled. Dietary intakes were evaluated with a semi-quantitative food-frequency questionnaire (FFQ) and Mediterranean dietary quality index (Med-DQI) was assessed. Anthropometric assessments and blood pressure measurement were performed. Biochemical assays including fasting serum glucose (FSG), matrix metalloproteinase-3 (MMP-3), liver enzymes and lipid profiles were also assessed. Polymorphism of +405 G/C VEGF gene was determined utilizing polymerase chain reaction-restriction fragments length polymorphism (PCR-RFLP) method. Results Serum high density lipoprotein-cholesterol (HDL-C) was significantly lower and low density lipoprotein cholesterol (LDL-C), triglyceride (TG), total cholesterol (TC) concentrations and FSG were significantly higher in metabolic syndrome patients compared with control group (P LDL concentrations. In metabolic syndrome patients with CC genotype, mean score of “saturated fatty acid” subgroup was significantly higher compared with other genotypes; whereas, in healthy individuals, mean score of “fruit-vegetable” subgroup in individuals of CC and GG genotype was significantly higher (P<0.05). Conclusion Our findings indicated a significant relationship between Mediterranean dietary quality index and both anthropometric and metabolic risk factors. We also indicated a higher “saturated fatty acid” intake in CC genotype among metabolic syndrome patients. PMID:28212431