ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy
ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy
复制标题
DOI：
10.1002/humu.23172
复制
发表时间：
2017-04-01
期刊：
影响因子：
3.9
通讯作者：
Laporte, Jocelyn
中科院分区：
文献类型：
--
作者：
Boehm, Johann;Bulla, Monica;Laporte, Jocelyn
钙离子（Ca 2+）是一个重要的生理因子，对细胞内游离Ca 2+水平的精确调节调节多种细胞功能。钙池操纵的钙内流（SOCE）是控制钙稳态的主要机制，由钙传感器STIM 1和钙通道ORAI 1协同作用介导。STIM 1或ORAI 1的显性功能获得性突变导致管状聚集性肌病（TAM）或Stormorken综合征，而隐性功能丧失性突变与免疫缺陷相关。在这里，我们报告了TAM患者中新的ORAI 1突变的鉴定和功能特征。我们评估基础活性和突变的ORAI 1通道的SOCE，我们证明，G98 S和V107 M突变产生组成型渗透性的ORAI 1通道，而T184 M改变通道的渗透性只有在STIM 1的存在下。这些数据表明突变依赖性病理机制和基因型/表型相关性，因为与最严重症状相关的ORAI 1突变诱导最强的功能性细胞效应。我们的患者的非肌肉特征的检查强烈提示TAM和Stormorken综合征是同一疾病的谱。总的来说，我们的研究结果强调了SOCE在骨骼肌生理学中的重要性，并提供了新的见解的病理机制，涉及异常钙稳态和导致肌肉功能障碍。(C)2017年威利期刊公司
Calcium (Ca2+) is a physiological key factor, and the precise modulation of free cytosolic Ca2+ levels regulates multiple cellular functions. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling Ca2+ homeostasis, and is mediated by the concerted activity of the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, whereas recessive loss-of-function mutations are associated with immunodeficiency. Here, we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI1 channels, whereas T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation-dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non-muscle features of our patients strongly suggests that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca2+ homeostasis and leading to muscle dysfunction. (C) 2017 Wiley Periodicals, Inc.