Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly Progressive Centronuclear Myopathy
Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly Progressive Centronuclear Myopathy
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DOI：
10.1371/journal.pgen.1003430
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发表时间：
2013-06-01
期刊：
影响因子：
4.5
通讯作者：
Laporte, Jocelyn
中科院分区：
文献类型：
--
作者：
Boehm, Johann;Vasli, Nasim;Laporte, Jocelyn
由BIN1编码的Amphiphysin 2是不同细胞类型中膜感知和重构的关键因子。普遍表达外显子的纯合子BIN1突变与常染色体隐性核心性肌病（CNM）有关，CNM是一种轻度进行性肌肉疾病，在活检中典型表现为异常的核集中。此外，在肌强直性营养不良（DM）中，BIN1剪接的错误调控是导致肌肉缺陷的部分原因。然而，两栖素2的肌肉特异性功能及其在这两种肌肉疾病中的致病性尚不清楚。在这项研究中，我们发现并描述了一个近亲家族中影响肌肉特异性BIN1外显子11剪接的第一个突变，该家族患有快速进展和最终致命的中核性肌病。与此同时，我们发现了与犬遗传性肌病（IMGD）的遗传原因相同的BIN1外显子11受体剪接位点的突变。来自患者肌肉的RNA分析显示，外显子11完全跳过，没有外显子11的BIN1结构不能促进分化肌管的膜管化。对比免疫荧光和超微结构分析显示了常见的结构缺陷，强调了两骨素2在骨骼肌三联肌膜重塑和维持中的重要性。我们的数据表明，两栖素2的肌肉特异性功能的改变是核中心性肌病、肌强直性营养不良和IMGD的共同病理机制。IMGD犬是人类bin1相关CNM的第一个忠实模型，代表了一种可用于潜在疗法临床前试验的哺乳动物模型。
Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies.