Constitutive Activation of the Calcium Sensor STIM1 Causes Tubular-Aggregate Myopathy
Constitutive Activation of the Calcium Sensor STIM1 Causes Tubular-Aggregate Myopathy
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DOI：
10.1016/j.ajhg.2012.12.007
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发表时间：
2013-02-07
影响因子：
9.8
通讯作者：
Laporte, Jocelyn
中科院分区：
文献类型：
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作者：
Boehm, Johann;Chevessier, Frederic;Laporte, Jocelyn
管状聚集体是随着年龄增长而在肌肉中积累的膜小管的规则阵列。它们在几种肌肉疾病中被发现为次要特征，包括酒精和药物引起的肌病，运动引起的痉挛和遗传性肌无力，但也以缓慢进行性肌无力为特征的纯遗传形式存在。我们确定显性STIM 1突变是肾小管聚集性肌病（TAM）的遗传原因。基质相互作用分子1（Stromal interaction molecule 1，STIM 1）是内质网中主要的Ca 2+感受器，所有突变均发生在高度保守的内质网内Ca 2+结合EF手上。Ca 2+储存通过称为储存操作的Ca 2+进入（SOCE）的过程重新填充。在Ca 2 +-存储耗尽时，野生型STIM 1寡聚化，从而触发细胞外Ca 2+进入。相反，在我们的四个TAM影响的家庭中发现的错义突变诱导组成性STIM 1聚类，表明Ca 2+传感受损。通过监测TAM成肌细胞对SOCE的钙反应，我们发现TAM细胞的基础钙水平显著升高，细胞内钙稳态失调。由于隐性STIM 1功能丧失突变与免疫缺陷相关，因此我们得出结论，STIM 1丧失或组成性激活的组织特异性影响是不同的，并且STIM 1依赖性SOCE的严格调节是正常肌肉结构和功能的基础。
Tubular aggregates are regular arrays of membrane tubules accumulating in muscle with age. They are found as secondary features in several muscle disorders, including alcohol- and drug-induced myopathies, exercise-induced cramps, and inherited myasthenia, but also exist as a pure genetic form characterized by slowly progressive muscle weakness. We identified dominant STIM1 mutations as a genetic cause of tubular-aggregate myopathy (TAM). Stromal interaction molecule 1 (STIM1) is the main Ca2+ sensor in the endoplasmic reticulum, and all mutations were found in the highly conserved intraluminal Ca2+-binding EF hands. Ca2+ stores are refilled through a process called store-operated Ca2+ entry (SOCE). Upon Ca2+-store depletion, wild-type STIM1 oligomerizes and thereby triggers extracellular Ca2+ entry. In contrast, the missense mutations found in our four TAM-affected families induced constitutive STIM1 clustering, indicating that Ca2+ sensing was impaired. By monitoring the calcium response of TAM myoblasts to SOCE, we found a significantly higher basal Ca2+ level in TAM cells and a dysregulation of intracellular Ca2+ homeostasis. Because recessive STIM1 loss-of-function mutations were associated with immunodeficiency, we conclude that the tissue-specific impact of STIM1 loss or constitutive activation is different and that a tight regulation of STIM1-dependent SOCE is fundamental for normal skeletal-muscle structure and function.