排序方式: 共有5条查询结果,搜索用时 0 毫秒
1
1.
Detelina Grozeva Keren Carss Olivera Spasic-Boskovic Michael?J. Parker Hayley Archer Helen?V. Firth Soo-Mi Park Natalie Canham Susan?E. Holder Meredith Wilson Anna Hackett Michael Field James?A.B. Floyd UKK Consortium Matthew Hurles F.?Lucy Raymond 《American journal of human genetics》2014,94(4):618-624
To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations—four nonsense (c.1195A>T [p.Lys399∗], c.1333C>T [p.Arg445∗], c.1866C>G [p.Tyr622∗], and c.3001C>T [p.Arg1001∗]) and three frameshift (c.2177_2178del [p.Thr726Asnfs∗39], c.3771dup [p.Ser1258Glufs∗65], and c.3856del [p.Ser1286Leufs∗84])—were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID. 相似文献
2.
Elizabeth Stevens Keren?J. Carss Sebahattin Cirak A.?Reghan Foley Silvia Torelli Tobias Willer Dimira?E. Tambunan Shu Yau Lina Brodd Caroline?A. Sewry Lucy Feng Goknur Haliloglu Diclehan Orhan William?B. Dobyns Gregory?M. Enns Melanie Manning Amanda Krause Mustafa?A. Salih Christopher?A. Walsh Matthew Hurles Kevin?P. Campbell M.?Chiara Manzini UKK Consortium Derek Stemple Yung-Yao Lin Francesco Muntoni 《American journal of human genetics》2013,92(3):354-365
Mutations in several known or putative glycosyltransferases cause glycosylation defects in α-dystroglycan (α-DG), an integral component of the dystrophin glycoprotein complex. The hypoglycosylation reduces the ability of α-DG to bind laminin and other extracellular matrix ligands and is responsible for the pathogenesis of an inherited subset of muscular dystrophies known as the dystroglycanopathies. By exome and Sanger sequencing we identified two individuals affected by a dystroglycanopathy with mutations in β-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2). B3GALNT2 transfers N-acetyl galactosamine (GalNAc) in a β-1,3 linkage to N-acetyl glucosamine (GlcNAc). A subsequent study of a separate cohort of individuals identified recessive mutations in four additional cases that were all affected by dystroglycanopathy with structural brain involvement. We show that functional dystroglycan glycosylation was reduced in the fibroblasts and muscle (when available) of these individuals via flow cytometry, immunoblotting, and immunocytochemistry. B3GALNT2 localized to the endoplasmic reticulum, and this localization was perturbed by some of the missense mutations identified. Moreover, knockdown of b3galnt2 in zebrafish recapitulated the human congenital muscular dystrophy phenotype with reduced motility, brain abnormalities, and disordered muscle fibers with evidence of damage to both the myosepta and the sarcolemma. Functional dystroglycan glycosylation was also reduced in the b3galnt2 knockdown zebrafish embryos. Together these results demonstrate a role for B3GALNT2 in the glycosylation of α-DG and show that B3GALNT2 mutations can cause dystroglycanopathy with muscle and brain involvement. 相似文献
3.
Aideen?M. McInerney-Leo Miriam Schmidts Claudio?R. Cortés Paul?J. Leo Blanca Gener Andrew?D. Courtney Brooke Gardiner Jessica?A. Harris Yeping Lu Mhairi Marshall UKK?Consortium Peter?J. Scambler Philip?L. Beales Matthew?A. Brown Andreas Zankl Hannah?M. Mitchison Emma?L. Duncan Carol Wicking 《American journal of human genetics》2013,93(3):515-523
4.
Alexandros Onoufriadis Tamara Paff Dinu Antony Amelia Shoemark Dimitra Micha Bertus Kuyt Miriam Schmidts Stavroula Petridi Jeanette?E. Dankert-Roelse Eric?G. Haarman Johannes?M.A. Daniels Richard?D. Emes Robert Wilson Claire Hogg Peter?J. Scambler Eddie?M.K. Chung UKK Gerard Pals Hannah?M. Mitchison 《American journal of human genetics》2013,92(1):88-98
5.
Emily?C. Oates Alexander?M. Rossor Majid Hafezparast Michael Gonzalez Fiorella Speziani Daniel?G. MacArthur Monkol Lek Ellen Cottenie Mariacristina Scoto A.?Reghan Foley Matthew Hurles Henry Houlden Linda Greensmith Michaela Auer-Grumbach Thomas?R. Pieber Tim?M. Strom Rebecca Schule David?N. Herrmann Janet?E. Sowden Gyula Acsadi Manoj?P. Menezes Nigel?F. Clarke Stephan Züchner UKK Francesco Muntoni Kathryn?N. North Mary?M. Reilly 《American journal of human genetics》2013,92(6):965-973
Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein-dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons. 相似文献
1