A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy
A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy
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DOI：
10.1038/s10038-021-00916-y
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发表时间：
2021-03-20
影响因子：
3.5
通讯作者：
Aoki, Yoko
中科院分区：
文献类型：
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作者：
Inoue-Shibui, Aya;Niihori, Tetsuya;Aoki, Yoko
热休克蛋白家族B成员8由HSPB8编码，是伴侣辅助选择性自噬复合物的重要组成部分，该复合物通过降解细胞中受损蛋白来维持肌肉功能。据报道，HSPB8基因突变可导致Charcot-Marie-Tooth型2L、远端遗传性运动神经病变IIa和边缘空泡肌病（RVM）。在这项研究中，我们利用全外显子组测序技术，在一个日本RVM大家族的HSPB8中发现了一个新的杂合移码变异c.525_529del。三个受影响的人有严重的呼吸衰竭，这在以前的研究中没有得到解决。棘旁肌萎缩也是本研究中RVM患者的一个临床特征。移码突变位于最后一个编码外显子，预测突变蛋白含有异亮氨酸-亮氨酸-缬氨酸（ILV）序列，该序列对应于IXI/V（异亮氨酸，X氨基酸，异亮氨酸或缬氨酸）基序。在其他小热休克蛋白中，IXI/V基序对于组装成更大的低聚物是必不可少的，并且预测所有HSPB8移码突变体在c端扩展中共享ILV序列。计算机预测工具显示，ILV序列周围区域的蛋白质溶解度较低，聚集倾向增加。IXI/V基序可能与hspb8相关RVM的发病机制有关。
Heat shock protein family B member 8, encoded by HSPB8, is an essential component of the chaperone-assisted selective autophagy complex, which maintains muscle function by degrading damaged proteins in the cells. Mutations in HSPB8 have been reported to cause Charcot-Marie-Tooth type 2L, distal hereditary motor neuropathy IIa, and rimmed vacuolar myopathies (RVM). In this study, we identified a novel heterozygous frameshift variant c.525_529del in HSPB8 in a large Japanese family with RVM, using whole exome sequencing. Three affected individuals had severe respiratory failure, which has not been addressed by previous studies. Muscle atrophy in the paraspinal muscles was also a clinical feature of the individuals affected with RVM in this study. The frameshift mutation was located in the last coding exon, and the mutated protein was predicted to harbor an isoleucine-leucine-valine (ILV) sequence, which corresponds to the IXI/V (isoleucine, X amino acids, and isoleucine or valine) motif. The IXI/V motif is essential for assembly into larger oligomers in other small heat shock proteins and all frameshift mutants of HSPB8 were predicted to share the ILV sequence in the C-terminal extension. The in silico prediction tools showed low protein solubility and increased aggregation propensity for the region around the ILV sequence. The IXI/V motif might be associated with the pathogenesis of HSPB8-related RVM.