Ferrer Isidre, Olivé Montse
Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat, Spain.
Expert Rev Mol Med. 2008 Sep 3;10:e25. doi: 10.1017/S1462399408000793.
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, alphaB-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.
肌原纤维肌病（MFMs）是临床和遗传异质性的肌肉疾病，其形态学定义为存在肌原纤维溶解灶、肌原纤维降解产物的积累以及多种蛋白质的异位表达。MFMs是骨骼肌（和心肌）构象性蛋白质疾病的范例，其特征是肌肉细胞内蛋白质积累。近年来，通过鉴定各种基因中的致病突变，对这组疾病的认识有了进展，其中大多数基因编码肌节Z盘的蛋白质，包括结蛋白、αB-晶状体蛋白、肌联蛋白、ZASP和细丝蛋白C。本综述重点关注由这些蛋白质缺陷引起的MFMs，总结这些疾病的遗传和临床特征，然后讨论对导致肌纤维变性的分子致病机制的新认识。蛋白质的溶酶体外降解缺陷现在被认为是这一过程中的一个重要因素。包括突变蛋白、缺陷的泛素-蛋白酶体系统、聚集体形成、突变泛素、p62、氧化应激和一些转录因子的异常调节在内的几个因素被认为参与了MFMs中肌纤维发生的一系列事件。
