Dominant mutations in ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca2+ channels
Dominant mutations in ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca2+ channels
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DOI：
10.1093/hmg/ddu477
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发表时间：
2015-02-01
影响因子：
3.5
通讯作者：
Nishino, Ichizo
中科院分区：
文献类型：
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作者：
Endo, Yukari;Noguchi, Satoru;Nishino, Ichizo
钙库操纵的Ca 2+释放激活的Ca 2+（CRAC）通道通过内质网和肌浆网（SR）中腔Ca 2+水平的降低而激活，并构成各种组织中主要的Ca 2+进入途径之一。管状聚集体（TA）是骨骼肌中的异常结构，尽管其形成机制尚未阐明，但与SR紊乱相关的Ca2+稳态改变被认为是主要的促成因素之一。TA肌病是一种遗传性肌肉疾病，其病理特征是存在TA。最近，STIM1基因中的显性突变，编码控制CRAC通道的Ca2+传感器，已被确定为引起管状聚集性肌病（TAM）。在这里，我们确定了杂合错义突变的ORAI1基因，编码CRAC通道本身，在三个家庭的影响，显性遗传TAM与低钙血症。来自受影响个体的骨骼肌肌管和表达突变的ORAI1蛋白的HEK293细胞显示自发的细胞外Ca2+进入细胞，而不减少管腔Ca2+或与STIM 1的关联。我们的研究结果表明，STIM1的独立激活CRAC通道诱导的显性突变在ORAI1引起改变Ca2+稳态，导致TAM与低钙血症。
The store-operated Ca2+ release-activated Ca2+ (CRAC) channel is activated by diminished luminal Ca2+ levels in the endoplasmic reticulum and sarcoplasmic reticulum (SR), and constitutes one of the major Ca2+ entry pathways in various tissues. Tubular aggregates (TAs) are abnormal structures in the skeletal muscle, and although their mechanism of formation has not been clarified, altered Ca2+ homeostasis related to a disordered SR is suggested to be one of the main contributing factors. TA myopathy is a hereditary muscle disorder that is pathologically characterized by the presence of TAs. Recently, dominant mutations in the STIM1 gene, encoding a Ca2+ sensor that controls CRAC channels, have been identified to cause tubular aggregate myopathy (TAM). Here, we identified heterozygous missense mutations in the ORAI1 gene, encoding the CRAC channel itself, in three families affected by dominantly inherited TAM with hypocalcemia. Skeletal myotubes from an affected individual and HEK293 cells expressing mutated ORAI1 proteins displayed spontaneous extracellular Ca2+ entry into cells without diminishment of luminal Ca2+ or the association with STIM1. Our results indicate that STIM1-independent activation of CRAC channels induced by dominant mutations in ORAI1 cause altered Ca2+ homeostasis, resulting in TAM with hypocalcemia.