Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1.
Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1.
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DOI：
10.1212/nxg.0000000000000050
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Sonoo M
中科院分区：
文献类型：
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作者：
Okuma H;Saito F;Mitsui J;Hara Y;Hatanaka Y;Ikeda M;Shimizu T;Matsumura K;Shimizu J;Tsuji S;Sonoo M
目的明确管状聚集性肌病（TAM）的基因突变，探讨TAM的发病机制。我们描述了一个受常染色体显性TAM影响的家族，并进行了外显子组和桑格测序以确定突变。我们通过表达研究和细胞内Ca 2+测量进一步分析了所鉴定的突变的功能意义。患者男，42岁，四肢及躯干肌无力、萎缩。肌肉活检和显微镜检查发现他的骨骼肌中有管状聚集物。该家族的遗传分析发现了一个新的杂合突变，c.1450_1451insGA（p.Ile484ArgfsX21），在基质相互作用分子1（STIM 1），肌浆网的钙传感器。我们用STIM 1转染培养的细胞，并证明突变的STIM 1在收缩的细胞质中表现出聚集样外观。此外，我们发现，细胞内Ca 2+内流减少的突变体STIM 1。新突变p.Ile484ArgfsX21位于STIM 1的胞质C-末端抑制结构域（CTID）中。然而，所有的突变报告到目前为止，在TAM驻留在管腔N-末端EF手区。CTID突变体转染的细胞中STIM 1的聚集样外观和细胞内Ca 2+内流减少与这些先前的报道形成鲜明对比。总之，这些发现表明，STIM 1的突变通过Ca 2+稳态失调引起TAM。
To identify the gene mutation of tubular aggregate myopathy (TAM) and gain mechanistic insight into the pathogenesis of the disorder. We described a family affected by autosomal dominant TAM and performed exome and Sanger sequencing to identify mutations. We further analyzed the functional significance of the identified mutation by expression studies and intracellular Ca2+ measurements. A 42-year-old man presented with slowly progressive muscle weakness and atrophy in all 4 limbs and the trunk. Muscle biopsy and microscopic examination revealed tubular aggregates in his skeletal muscle. Genetic analysis of this family identified a novel heterozygous mutation, c.1450_1451insGA (p.Ile484ArgfsX21), in stromal interaction molecule 1 (STIM1), a Ca2+ sensor in sarcoplasmic reticulum. We transfected cultured cells with STIM1 and demonstrated that the mutant STIM1 exhibited aggregation-like appearance in shrunk cytoplasm. Furthermore, we revealed that the intracellular Ca2+ influx is decreased by the mutant STIM1. The novel mutation p.Ile484ArgfsX21 is located in the cytoplasmic C-terminal inhibitory domain (CTID) of STIM1. However, all mutations reported so far in TAM reside in the luminal N-terminal EF hand region. The aggregation-like appearance of STIM1 and the decreased intracellular Ca2+ influx in cells transfected with CTID mutant are in sharp contrast to these previous reports. Taken together, these findings indicate that mutations of STIM1 cause TAM through the dysregulation of Ca2+ homeostasis.