SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles
SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles
复制标题
DOI：
10.1212/wnl.0000000000001864
复制
发表时间：
2015-08-25
期刊：
影响因子：
9.9
通讯作者：
Weihl, Conrad C.
中科院分区：
文献类型：
--
作者：
Bucelli, Robert C.;Arhzaouy, Khalid;Weihl, Conrad C.
目的：确定一种新型远端肌病的遗传病因并表征其临床病理特征。方法：我们对一个常染色体显性远端肌病家系进行了全外显子组测序，并对 1 例散发性远端肌病患者进行了靶向外显子组测序，两者均具有边缘空泡病理。我们还使用免疫组织化学、蛋白质印迹分析和表达研究评估了已识别突变的致病性。结果：测序在 1 个家族的受影响成员和一名不相关的散发性远端肌病患者的 SQSTM1 中鉴定出可能致病性的 c.1165+1 G>A 剪接供体变异。受影响的患者有迟发性远端下肢无力，肌电图显示肌病特征，肌肉病理学显示带有 TAR DNA 结合蛋白 43 和 SQSTM1 包涵体的边缘空泡。 c.1165+1 G>A SQSTM1 变体导致 2 种选择性剪接的 SQSTM1 蛋白的表达：一种缺乏 C 端 PEST2 结构域，另一种缺乏 C 端泛素相关 (UBA) 结构域，两者都具有不同的细胞和骨骼肌定位模式。结论：SQSTM1 是一种自噬接头，可将聚集的泛素化蛋白运送到自噬体通过其 C 端 UBA 结构域进行降解。与 VCP 突变类似，SQSTM1 显性遗传突变现在与边缘空泡肌病、佩吉特骨病、肌萎缩侧索硬化症和额颞叶痴呆相关。我们的数据进一步表明不同表型之间存在致病联系。
Objective:To identify the genetic etiology and characterize the clinicopathologic features of a novel distal myopathy.Methods:We performed whole-exome sequencing on a family with an autosomal dominant distal myopathy and targeted exome sequencing in 1 patient with sporadic distal myopathy, both with rimmed vacuolar pathology. We also evaluated the pathogenicity of identified mutations using immunohistochemistry, Western blot analysis, and expression studies.Results:Sequencing identified a likely pathogenic c.1165+1 G>A splice donor variant in SQSTM1 in the affected members of 1 family and in an unrelated patient with sporadic distal myopathy. Affected patients had late-onset distal lower extremity weakness, myopathic features on EMG, and muscle pathology demonstrating rimmed vacuoles with both TAR DNA-binding protein 43 and SQSTM1 inclusions. The c.1165+1 G>A SQSTM1 variant results in the expression of 2 alternatively spliced SQSTM1 proteins: 1 lacking the C-terminal PEST2 domain and another lacking the C-terminal ubiquitin-associated (UBA) domain, both of which have distinct patterns of cellular and skeletal muscle localization.Conclusions:SQSTM1 is an autophagic adaptor that shuttles aggregated and ubiquitinated proteins to the autophagosome for degradation via its C-terminal UBA domain. Similar to mutations in VCP, dominantly inherited mutations in SQSTM1 are now associated with rimmed vacuolar myopathy, Paget disease of bone, amyotrophic lateral sclerosis, and frontotemporal dementia. Our data further suggest a pathogenic connection between the disparate phenotypes.