排序方式: 共有39条查询结果,搜索用时 31 毫秒
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Willer T Lee H Lommel M Yoshida-Moriguchi T de Bernabe DB Venzke D Cirak S Schachter H Vajsar J Voit T Muntoni F Loder AS Dobyns WB Winder TL Strahl S Mathews KD Nelson SF Moore SA Campbell KP 《Nature genetics》2012,44(5):575-580
Walker-Warburg syndrome (WWS) is clinically defined as congenital muscular dystrophy that is accompanied by a variety of brain and eye malformations. It represents the most severe clinical phenotype in a spectrum of diseases associated with abnormal post-translational processing of a-dystroglycan that share a defect in laminin-binding glycan synthesis1. Although mutations in six genes have been identified as causes of WWS, only half of all individuals with the disease can currently be diagnosed on this basis2. A cell fusion complementation assay in fibroblasts from undiagnosed individuals with WWS was used to identify five new complementation groups. Further evaluation of one group by linkage analysis and targeted sequencing identified recessive mutations in the ISPD gene (encoding isoprenoid synthase domain containing). The pathogenicity of the identified ISPD mutations was shown by complementation of fibroblasts with wild-type ISPD. Finally, we show that recessive mutations in ISPD abolish the initial step in laminin-binding glycan synthesis by disrupting dystroglycan O-mannosylation. This establishes a new mechanism for WWS pathophysiology. 相似文献
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Mi W Pawlik M Sastre M Jung SS Radvinsky DS Klein AM Sommer J Schmidt SD Nixon RA Mathews PM Levy E 《Nature genetics》2007,39(12):1440-1442
Using transgenic mice expressing human cystatin C (encoded by CST3), we show that cystatin C binds soluble amyloid-beta peptide and inhibits cerebral amyloid deposition in amyloid-beta precursor protein (APP) transgenic mice. Cystatin C expression twice that of the endogenous mouse cystatin C was sufficient to substantially diminish amyloid-beta deposition. Thus, cystatin C has a protective role in Alzheimer's disease pathogenesis, and modulation of cystatin C concentrations may have therapeutic implications for the disease. 相似文献
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Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies 总被引:24,自引:0,他引:24
Michele DE Barresi R Kanagawa M Saito F Cohn RD Satz JS Dollar J Nishino I Kelley RI Somer H Straub V Mathews KD Moore SA Campbell KP 《Nature》2002,418(6896):417-422
Muscle eye brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) are congenital muscular dystrophies with associated, similar brain malformations. The FCMD gene, fukutin, shares some homology with fringe-like glycosyltransferases, and the MEB gene, POMGnT1, seems to be a new glycosyltransferase. Here we show, in both MEB and FCMD patients, that alpha-dystroglycan is expressed at the muscle membrane, but similar hypoglycosylation in the diseases directly abolishes binding activity of dystroglycan for the ligands laminin, neurexin and agrin. We show that this post-translational biochemical and functional disruption of alpha-dystroglycan is recapitulated in the muscle and central nervous system of mutant myodystrophy (myd) mice. We demonstrate that myd mice have abnormal neuronal migration in cerebral cortex, cerebellum and hippocampus, and show disruption of the basal lamina. In addition, myd mice reveal that dystroglycan targets proteins to functional sites in brain through its interactions with extracellular matrix proteins. These results suggest that at least three distinct mammalian genes function within a convergent post-translational processing pathway during the biosynthesis of dystroglycan, and that abnormal dystroglycan-ligand interactions underlie the pathogenic mechanism of muscular dystrophy with brain abnormalities. 相似文献
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M B Mathews 《Nature》1970,228(5272):661-663
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Translation of globin messenger RNA in a heterologous cell-free system 总被引:15,自引:0,他引:15
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Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity 总被引:39,自引:0,他引:39
Yan R Bienkowski MJ Shuck ME Miao H Tory MC Pauley AM Brashier JR Stratman NC Mathews WR Buhl AE Carter DB Tomasselli AG Parodi LA Heinrikson RL Gurney ME 《Nature》1999,402(6761):533-537
Mutations in the gene encoding the amyloid protein precursor (APP) cause autosomal dominant Alzheimer's disease. Cleavage of APP by unidentified proteases, referred to as beta- and gamma-secretases, generates the amyloid beta-peptide, the main component of the amyloid plaques found in Alzheimer's disease patients. The disease-causing mutations flank the protease cleavage sites in APP and facilitate its cleavage. Here we identify a new membrane-bound aspartyl protease (Asp2) with beta-secretase activity. The Asp2 gene is expressed widely in brain and other tissues. Decreasing the expression of Asp2 in cells reduces amyloid beta-peptide production and blocks the accumulation of the carboxy-terminal APP fragment that is created by beta-secretase cleavage. Solubilized Asp2 protein cleaves a synthetic APP peptide substrate at the beta-secretase site, and the rate of cleavage is increased tenfold by a mutation associated with early-onset Alzheimer's disease in Sweden. Thus, Asp2 is a new protein target for drugs that are designed to block the production of amyloid beta-peptide peptide and the consequent formation of amyloid plaque in Alzheimer's disease. 相似文献
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Analysis of human transcriptomes 总被引:47,自引:0,他引:47