Mutations in ZASP define a novel form of muscular dystrophy in humans
Mutations in ZASP define a novel form of muscular dystrophy in humans
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DOI：
10.1002/ana.20376
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发表时间：
2005-02-01
影响因子：
11.2
通讯作者：
Engel, AG
中科院分区：
文献类型：
--
作者：
Selcen, D;Engel, AG
肌原纤维性肌病（MFM）是一种形态学上独特的疾病，其中Z盘的解体，然后是肌原纤维的解体，随后是多种蛋白质的异常积聚。结蛋白、α B-晶体蛋白和肌球蛋白（所有Z盘相关蛋白）的突变在少数情况下导致MFM。ZASP（一种Z带选择性剪接的PDZ基序蛋白）是另一种Z盘相关蛋白，在小鼠中靶向缺失ZASP会导致骨骼肌和心肌病。因此，我们在54例MFM患者中搜索ZASP突变，并在11例患者中检测到3个杂合错义突变。发病年龄44 ~ 73岁。显性遗传在7例患者中明显，3例心脏受累，5例周围神经病变体征。大多数患者有近端和远端的弱点，但在6个，弱点是远大于近端。其中10例携带第6外显子的两个突变（A147 T和A165 V），位于或位于连接ZASP与Z盘的重要基序内; 1例携带第9外显子的错义突变（R268 C）。我们的结论是：（1）ZASP突变导致刻板的MFM病理学;（2）心肌病远端比近端无力更多，神经病在zaspopathy的范围内;（3）ZASP突变定义了人类常染色体显性肌营养不良症的一种新形式。
Myofibrillar myopathy (MFM) is a morphologically distinct disorder in which disintegration of the Z-disk and then of the myofibrils is followed by abnormal accumulation of multiple proteins. Mutations in desmin, alphaB-crystallin, and myotilin, all Z-disk-related proteins, cause MFM in the minority of cases. ZASP (a Z-band alternatively spliced PDZ motif-containing protein) is another Z-disk-associated protein, and targeted deletion of ZASP in mouse causes skeletal and cardiac myopathy. We therefore searched for mutations in ZASP in 54 MFM patients and detected 3 heterozygous missense mutations in 11. Their age at onset was 44 to 73 years. Dominant inheritance was apparent in seven patients, cardiac involvement in three, and signs of peripheral neuropathy in five. Most patients had proximal and distal weakness, but in six, the weakness was greater distally than proximally. Ten carried either of two mutations in exon 6 (A147T and A165V) at or within a motif important in linking ZASP to the Z-disk; one carried a missense mutation in exon 9 (R268C). We conclude that (1) mutations in ZASP cause stereotyped MFM pathology; (2) cardiomyopathy distal more than proximal weakness, and neuropathy are in the spectrum of zaspopathy-, and (3) mutations in ZASP define a novel form of autosomal dominant muscular dystrophy in humans.