A missense mutation in the αB-crystallin chaperone gene causes a desmin-related myopathy
A missense mutation in the αB-crystallin chaperone gene causes a desmin-related myopathy
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DOI：
10.1038/1765
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发表时间：
1998-09-01
期刊：
影响因子：
30.8
通讯作者：
Fardeau, M
中科院分区：
文献类型：
--
作者：
Vicart, P;Caron, A;Fardeau, M
结蛋白相关性肌病（DRM）是一种遗传性神经肌肉疾病，其特征为骨骼肌和心肌肌浆细胞中的结蛋白（一种属于III型中间丝家族的蛋白质）聚集体在成人期发病和延迟蓄积（1，2）。在本文中，我们已经绘制了一个大的法国血统的DRM的基因座在染色体11 q21 -23的一个26厘米的间隔。该区域含有α B-晶状体蛋白基因（α B-晶状体蛋白AB），这是一种编码20 kD蛋白的候选基因，该蛋白在透镜中丰富，也存在于许多非眼组织中，包括心肌和骨骼肌（3，4）。α B-晶状体蛋白是小热休克蛋白（shsp）家族的成员，并具有分子伴侣活性（5）。我们确定了一个R120 G错义突变在ESTAB共分离的疾病表型在这个家庭。用突变体WRIAB cDNA转染的肌细胞系显示细胞内聚集体，其含有结蛋白和α B-晶体蛋白，如在来自DRM患者的肌纤维中观察到的。这些结果是第一个确定分子伴侣缺陷是遗传性人类肌肉疾病的原因。
Desmin-related myopathies (DRM) are inherited neuromuscular disorders characterized by adult onset and delayed accumulation of aggregates of desmin, a protein belonging to the type III intermediate filament Family, in the sarcoplasma of skeletal and cardiac muscles(1,2). In this paper, we have mapped the locus for DRM in a large French pedigree to a 26-cM interval in chromosome 11q21-23. This region contains the alpha B-crystallin gene (CRYAB), a candidate gene encoding a 20-kD protein that is abundant in lens and is also present in a number of non-ocular tissues, including cardiac and skeletal muscle(3,4). alpha B-crystallin is a member of the small heat shock protein (shsp) family and possesses molecular chaperone activity(5). We identified an R120G missense mutation in CRYAB that co-segregates with the disease phenotype in this family. Muscle cell lines transfected with the mutant CRYAB cDNA showed intracellular aggregates that contain both desmin and alpha B-crystallin as observed in muscle fibers from DRM patients. These results are the first to identify a defect in a molecular chaperone as a cause for an inherited human muscle disorder.