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排序方式: 共有324条查询结果,搜索用时 305 毫秒
121.
Hoischen A van Bon BW Rodríguez-Santiago B Gilissen C Vissers LE de Vries P Janssen I van Lier B Hastings R Smithson SF Newbury-Ecob R Kjaergaard S Goodship J McGowan R Bartholdi D Rauch A Peippo M Cobben JM Wieczorek D Gillessen-Kaesbach G Veltman JA Brunner HG de Vries BB 《Nature genetics》2011,43(8):729-731
Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous. 相似文献
122.
O'Roak BJ Deriziotis P Lee C Vives L Schwartz JJ Girirajan S Karakoc E Mackenzie AP Ng SB Baker C Rieder MJ Nickerson DA Bernier R Fisher SE Shendure J Eichler EE 《Nature genetics》2011,43(6):585-589
Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs. 相似文献
123.
Shi Y Li Z Xu Q Wang T Li T Shen J Zhang F Chen J Zhou G Ji W Li B Xu Y Liu D Wang P Yang P Liu B Sun W Wan C Qin S He G Steinberg S Cichon S Werge T Sigurdsson E Tosato S Palotie A Nöthen MM Rietschel M Ophoff RA Collier DA Rujescu D Clair DS Stefansson H Stefansson K Ji J Wang Q Li W Zheng L Zhang H Feng G He L 《Nature genetics》2011,43(12):1224-1227
Schizophrenia is a severe mental disorder affecting ~1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 individuals with schizophrenia and 6,468 healthy controls (1,578 cases and 1,592 controls from northern Han Chinese, 1,238 cases and 2,856 controls from central Han Chinese, and 934 cases and 2,020 controls from the southern Han Chinese). We further analyzed the strongest association signals in an additional independent cohort of 4,383 cases and 4,539 controls from the Han Chinese population. Meta-analysis identified common SNPs that associated with schizophrenia with genome-wide significance on 8p12 (rs16887244, P = 1.27 × 10(-10)) and 1q24.2 (rs10489202, P = 9.50 × 10(-9)). Our findings provide new insights into the pathogenesis of schizophrenia. 相似文献
124.
Ford CB Lin PL Chase MR Shah RR Iartchouk O Galagan J Mohaideen N Ioerger TR Sacchettini JC Lipsitch M Flynn JL Fortune SM 《Nature genetics》2011,43(5):482-486
Tuberculosis poses a global health emergency, which has been compounded by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. We used whole-genome sequencing to compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent or reactivated disease. We sequenced 33 Mtb isolates from nine macaques with an average genome coverage of 93% and an average read depth of 117×. Based on the distribution of SNPs observed, we calculated the mutation rates for these disease states. We found a similar mutation rate during latency as during active disease or in a logarithmically growing culture over the same period of time. The pattern of polymorphisms suggests that the mutational burden in vivo is because of oxidative DNA damage. We show that Mtb continues to acquire mutations during disease latency, which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance. 相似文献
125.
126.
Sarah Easterby-Smith 《Studies in history and philosophy of science》2012,43(1):208-212
127.
Myosin-7a participates in auditory and visual processes. Defects in MYO7A, the gene encoding the myosin-7a heavy chain, are causative for Usher syndrome 1B, the most frequent cause of deaf-blindness
in humans. In the present study, we performed a detailed kinetic and functional characterization of the isolated human myosin-7a
motor domain to elucidate the details of chemomechanical coupling and the regulation of motor function. A rate-limiting, slow
ADP release step causes long lifetimes of strong actin-binding intermediates and results in a high duty ratio. Moreover, our
results reveal a Mg2+-sensitive regulatory mechanism tuning the kinetic and mechanical properties of the myosin-7a motor domain. We obtained direct
evidence that changes in the concentration of free Mg2+ ions affect the motor properties of human myosin-7a using an in vitro motility assay system. Our results suggest that in
a cellular environment, compartment-specific fluctuations in free Mg2+ ions can mediate the conditional switching of myosin-7a between cargo moving and tension bearing modes. 相似文献
128.
Sarah?N.?Fontaine Jonathan?J.?Sabbagh Jeremy?Baker Carlos?R.?Martinez-Licha April?Darling Chad?A.?DickeyEmail author 《Cellular and molecular life sciences : CMLS》2015,72(10):1863-1879
Pathological accumulation of the microtubule-associated protein tau, in the form of neurofibrillary tangles, is a major hallmark of Alzheimer’s disease, the most prevalent neurodegenerative condition worldwide. In addition to Alzheimer’s disease, a number of neurodegenerative diseases, called tauopathies, are characterized by the accumulation of aggregated tau in a variety of brain regions. While tau normally plays an important role in stabilizing the microtubule network of the cytoskeleton, its dissociation from microtubules and eventual aggregation into pathological deposits is an area of intense focus for therapeutic development. Here we discuss the known cellular factors that affect tau aggregation, from post-translational modifications to molecular chaperones. 相似文献
129.
Dibbens LM Tarpey PS Hynes K Bayly MA Scheffer IE Smith R Bomar J Sutton E Vandeleur L Shoubridge C Edkins S Turner SJ Stevens C O'Meara S Tofts C Barthorpe S Buck G Cole J Halliday K Jones D Lee R Madison M Mironenko T Varian J West S Widaa S Wray P Teague J Dicks E Butler A Menzies A Jenkinson A Shepherd R Gusella JF Afawi Z Mazarib A Neufeld MY Kivity S Lev D Lerman-Sagie T Korczyn AD Derry CP Sutherland GR Friend K Shaw M Corbett M Kim HG Geschwind DH Thomas P Haan E Ryan S McKee S 《Nature genetics》2008,40(6):776-781
Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation. 相似文献
130.
Laurie NA Donovan SL Shih CS Zhang J Mills N Fuller C Teunisse A Lam S Ramos Y Mohan A Johnson D Wilson M Rodriguez-Galindo C Quarto M Francoz S Mendrysa SM Guy RK Marine JC Jochemsen AG Dyer MA 《Nature》2006,444(7115):61-66
Most human tumours have genetic mutations in their Rb and p53 pathways, but retinoblastoma is thought to be an exception. Studies suggest that retinoblastomas, which initiate with mutations in the gene retinoblastoma 1 (RB1), bypass the p53 pathway because they arise from intrinsically death-resistant cells during retinal development. In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumour progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Our data provide evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, they support the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma. 相似文献