Complex phenotypes associated with STIMI mutations in both coiled coil and EF-hand
Complex phenotypes associated with STIMI mutations in both coiled coil and EF-hand
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DOI：
10.1016/j.nmd.2017.05.002
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发表时间：
2017-09-01
影响因子：
2.8
通讯作者：
Barresi, Rita
中科院分区：
文献类型：
--
作者：
Harris, Elizabeth;Burki, Umar;Barresi, Rita
STIM1的显性突变是导致三种等位基因疾病的原因：管状聚集性肌病、Stormorken综合征(一种复杂的表型，包括肌病、脾功能低下、低钙血症和出血素质)，以及一种血小板功能障碍，约克血小板综合征。以前的报告表明，与肾小管聚集性肌病相关的N-末端EF-HAND区域的突变与基因型表型相关，与Stormorken综合征相关的螺旋线圈区域的p.R304W处的一个常见突变与此相关。在这项研究中，通过外显子组测序或STIMI直接测序鉴定了携带STIMI变异的个体，并评估了STIMI等位基因障碍的神经肌肉、血液学和生化证据。通过成纤维细胞钙离子成像和三维建模研究STIMI突变。共发现6例STIM1突变个体，其中包括两个新突变(C.262A>；G(p.S88G)和c.911G>；A(p.R304Q))。在EF-HAND和CC区均有突变的6例患者中，有5/6出现额外的神经肌肉症状，包括血小板减少、血小板功能障碍、低钙血症或脾功能低下。3/6的患者有精神障碍，以前在STIMI病中没有报道。对已发表的STIM1患者(n=49)的回顾证实，大多数患者都存在神经肌肉症状。我们得出结论，与激活STIM1突变相关的表型通常包括神经肌肉外特征，如低钙血症、低/无脾和血小板功能障碍，而与突变区域无关。(C)2017爱思唯尔B.V.保留所有权利。
Dominant mutations in STIM1 are a cause of three allelic conditions: tubular aggregate myopathy, Stormorken syndrome (a complex phenotype including myopathy, hyposplenism, hypocalcaemia and bleeding diathesis), and a platelet dysfunction disorder, York platelet syndrome. Previous reports have suggested a genotype phenotype correlation with mutations in the N -terminal EF-hand domain associated with tubular aggregate myopathy, and a common mutation at p.R304W in a coiled coil domain associated with Stormorken syndrome. In this study individuals with STIMI variants were identified by exome sequencing or STIMI direct sequencing, and assessed for neuromuscular, haematological and biochemical evidence of the allelic disorders of STIMI. STIMI mutations were investigated by fibroblast calcium imaging and 3D modelling. Six individuals with STIM1 mutations, including two novel mutations (c.262A>G (p.S88G) and c.911G>A (p.R304Q)), were identified. Extra neuromuscular symptoms including thrombocytopenia, platelet dysfunction, hypocalcaemia or hyposplenism were present in 5/6 patients with mutations in both the EF-hand and CC domains. 3/6 patients had psychiatric disorders, not previously reported in STIMI disease. Review of published STIM1 patients (n = 49) confirmed that neuromuscular symptoms are present in most patients. We conclude that the phenotype associated with activating STIM1 mutations frequently includes extra -neuromuscular features such as hypocalcaemia, hypo-/asplenia and platelet dysfunction regardless of mutation domain. (C) 2017 Elsevier B.V. All rights reserved.