Mutations in myotilin cause myofibrillar myopathy
Mutations in myotilin cause myofibrillar myopathy
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DOI：
10.1212/01.wnl.0000123576.74801.75
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发表时间：
2004-04-27
期刊：
影响因子：
9.9
通讯作者：
Engel, AG
中科院分区：
文献类型：
--
作者：
Selcen, D;Engel, AG
背景和目的：肌原纤维肌病(MFM)是一种肌原纤维溶解、肌原纤维降解产物积聚和多种蛋白异位表达的病理模式，是一种尚未明确的术语。超微结构研究表明，Z盘是最初病理改变的部位，在少数MFM患者中发现了两种与Z盘相关的蛋白--结蛋白和α-晶体蛋白的突变。作者的目的是确定肌铁蛋白的突变是否是MFM的另一个原因。Myotilin是Z盘的关键成分，也是肢体带状肌营养不良症(LGMD)1A型的疾病蛋白。方法：采用组织化学、免疫细胞化学、超微结构和突变分析等方法。结果：作者在57例MFM患者中的6例中检测到4个错义突变，位于MYOT富含丝氨酸的外显子2，这两个先前发现的LGMD1A突变位于该区域。三个突变是新的，其中一个已经在LGMD1A中被发现。每个患者都有神经病变的证据，至少有三个亲属有相关的心肌病。3例患者远端软弱大于近端软弱。除有微小差别外，形态特征与其他MFM患者相似。结论：1)myotilin基因突变可引起MFM；2)MYOT外显子2是突变的热点；3)周围神经病、心肌病、远端无力大于近端无力是MFM的一部分；4)并不是所有的MFM病例都具有肢体带状表型；5)大多数MFM病例的分子基础尚不清楚。
Background and Objective: The term myofibrillar myopathy (MFM) is a noncommittal term for a pathologic pattern of myofibrillar dissolution associated with accumulation of myofibrillar degradation products and ectopic expression of multiple proteins. Ultrastructural studies implicate the Z-disk as the site of the initial pathologic change, and mutations in two Z-disk-related proteins, desmin and alphaB-crystallin, have been identified in a minority of patients with MFM. The authors' objective was to determine whether mutations in myotilin, a key Z-disk component and the disease protein in limb-girdle muscular dystrophy ( LGMD) 1A, are another cause of MFM. Methods: The authors used histochemical, immunocytochemical, ultrastructural, and mutation analysis. Results: The authors detected four missense mutations in 6 of 57 patients with MFM in the serine-rich exon 2 of MYOT, where the two previously identified LGMD1A mutations are located. Three mutations were novel, and one had been previously identified in LGMD1A. Each patient had evidence for neuropathy, and at least three kinships had associated cardiomyopathy. Distal weakness greater than proximal weakness was present in three patients. Except for minor differences, the morphologic features were similar to those in other patients with MFM. Conclusions: 1) Mutations in myotilin cause MFM; 2) exon 2 of MYOT is a hotspot for mutations; 3) peripheral neuropathy, cardiomyopathy, and distal weakness greater than proximal weakness are part of the spectrum of myotilinopathy; 4) not all cases of myotilinopathy have a limb-girdle phenotype; and 5) the molecular basis of the majority of MFM cases remains to be discovered.