Molecular pathology of myofibrillar myopathies
Molecular pathology of myofibrillar myopathies
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DOI：
10.1017/s1462399408000793
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发表时间：
2008-09-03
影响因子：
6.2
通讯作者：
Olive, Montse
中科院分区：
文献类型：
--
作者：
Ferrer, Isidre;Olive, Montse
肌原纤维肌病（MFM）是临床和遗传异质性肌肉疾病，其在形态学上通过肌原纤维溶解灶的存在、肌原纤维降解产物的积累和多种蛋白质的异位表达来定义。MFM是骨骼肌（和心肌）的构象蛋白质疾病的范例，其特征在于肌细胞中的细胞内蛋白质积累。近年来，通过鉴定各种基因中的致病突变，对这组疾病的理解有所进展，其中大多数基因编码肌节Z盘的蛋白质，包括结蛋白、α B-晶体蛋白、肌球蛋白、ZASP和细丝蛋白C。本文综述了这些蛋白质缺陷引起的MFM，总结了这些疾病的遗传和临床特征，然后讨论了导致肌纤维变性的分子致病机制的新认识。蛋白质的有缺陷的溶酶体外降解现在被认为是这一过程中的一个重要因素。几个因素-包括突变蛋白质，有缺陷的泛素-蛋白酶体系统，侵略形成，突变的泛素，p62，氧化应激和一些转录因子的异常调节-被认为参与了在肌纤维中发生的事件级联在MFM。
Myofibrillar myopathies (MFMs) are clinically and genetically heterogeneous muscle disorders that are defined morphologically by the presence of foci of myofibril dissolution, accumulation of myofibrillar degradation products, and ectopic expression of multiple proteins. MFMs are the paradigm of conformational protein diseases of the skeletal (and cardiac) muscles characterised by intracellular protein accumulation in muscle cells. Understanding of this group of disorders has advanced in recent years through the identification of causative mutations in various genes, most of which encode proteins of the sarcomeric Z-disc, including desmin, alpha B-crystallin, myotilin, ZASP and filamin C. This review focuses on the MFMs arising from defects in these proteins, summarising genetic and clinical features of the disorders and then discussing emerging understanding of the molecular pathogenic mechanisms leading to muscle fibre degeneration. Defective extralysosomal degradation of proteins is now recognised as an important element in this process. Several factors - including mutant proteins, a defective ubiquitin-proteasome system, aggresome formation, mutant ubiquitin, p62, oxidative stress and abnormal regulation of some transcription factors - are thought to participate in the cascade of events occurring in muscle fibres in MFMs.