Institute of Neuropathology, Justus Liebig University Giessen, 35392 Giessen, Germany.
Pediatric Heart Center, Justus Liebig University Giessen, 35392 Giessen, Germany.
Mol Genet Metab. 2018 Mar;123(3):388-399. doi: 10.1016/j.ymgme.2018.01.001. Epub 2018 Jan 6.
Myofibrillary myopathies (MFM) are hereditary myopathies histologically characterized by degeneration of myofibrils and aggregation of proteins in striated muscle. Cardiomyopathy is common in MFM but the pathophysiological mechanisms are not well understood. The BAG3-Pro209Leu mutation is associated with early onset MFM and severe restrictive cardiomyopathy (RCM), often necessitating heart transplantation during childhood. We report on a young male patient with a BAG3-Pro209Leu mutation who underwent heart transplantation at eight years of age. Detailed morphological analyses of the explanted heart tissue showed intracytoplasmic inclusions, aggregation of BAG3 and desmin, disintegration of myofibers and Z-disk alterations. The presence of undegraded autophagosomes, seen by electron microscopy, as well as increased levels of p62, LC3-I and WIPI1, detected by immunohistochemistry and western blot analyses, indicated a dysregulation of autophagy. Parkin and PINK1, proteins involved in mitophagy, were slightly increased whereas mitochondrial OXPHOS activities were not altered. These findings indicate that altered autophagy plays a role in the pathogenesis and rapid progression of RCM in MFM caused by the BAG3-Pro209Leu mutation, which could have implications for future therapeutic strategies.
肌原纤维肌病（MFM）是一种遗传性肌病，组织学上表现为肌原纤维变性和横纹肌中蛋白质聚集。MFM 常伴有心肌病，但病理生理机制尚不清楚。BAG3-Pro209Leu 突变与早发性 MFM 和严重限制性心肌病（RCM）相关，儿童时期常需要心脏移植。我们报告了一例携带 BAG3-Pro209Leu 突变的年轻男性患者，他在 8 岁时接受了心脏移植。对移植心脏组织的详细形态学分析显示胞质内包涵体、BAG3 和结蛋白的聚集、肌纤维解体和 Z 盘改变。电镜下可见未降解的自噬体，免疫组化和 Western blot 分析显示 p62、LC3-I 和 WIPI1 水平升高，表明自噬失调。参与线粒体自噬的 Parkin 和 PINK1 蛋白略有增加，而线粒体 OXPHOS 活性没有改变。这些发现表明，BAG3-Pro209Leu 突变导致的 MFM 中 RCM 的发病机制和快速进展与自噬改变有关，这可能对未来的治疗策略有影响。
