A Dominant STIM1 Mutation Causes Stormorken Syndrome
A Dominant STIM1 Mutation Causes Stormorken Syndrome
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DOI：
10.1002/humu.22544
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发表时间：
2014-05-01
期刊：
影响因子：
3.9
通讯作者：
Frengen, Eirik
中科院分区：
文献类型：
--
作者：
Misceo, Doriana;Holmgren, Asbjorn;Frengen, Eirik
斯托莫肯综合征是一种罕见的常染色体显性遗传病，具有轻微的出血倾向、血小板减少、血小板减少、轻度贫血、脾功能不全、管状聚集性肌病、缩小症、头痛和鱼鳞病。STIM1基因外显子7(C.910C>；T；p.Arg304Trp)(NM_003156.3)杂合性错义突变与本病分离，共4个家系的6例Stormorken综合征患者。当STIM1感觉到内质网腔内的钙离子耗竭时，它会发生构象变化，使其能够与位于质膜上的钙释放激活的钙通道ORAI1相互作用并开放。在Stormorken综合征患者中发现的STIM1突变位于卷曲线圈1区域，这可能在保持STIM1无效的过程中发挥作用。与STIM1可能的功能获得突变一致，患者的血小板处于预激活状态，质膜外表面高暴露氨基磷脂。与对照组相比，患者的血小板静息钙水平升高，储存操作的钙离子进入显著减弱，进一步支持STIM1和ORAI1的结构活性。因此，我们的数据与Stormorken综合征患者中STIM1几乎最大的激活是一致的。我们得出结论，C.910C>；T杂合突变导致了定义该综合征的复杂表型。
Stormorken syndrome is a rare autosomal-dominant disease with mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, asplenia, tubular aggregate myopathy, miosis, headache, and ichthyosis. A heterozygous missense mutation in STIM1 exon 7 (c.910C>T; p.Arg304Trp) (NM_003156.3) was found to segregate with the disease in six Stormorken syndrome patients in four families. Upon sensing Ca2+ depletion in the endoplasmic reticulum lumen, STIM1 undergoes a conformational change enabling it to interact with and open ORAI1, a Ca2+ release-activated Ca2+ channel located in the plasma membrane. The STIM1 mutation found in Stormorken syndrome patients is located in the coiled-coil 1 domain, which might play a role in keeping STIM1 inactive. In agreement with a possible gain-of-function mutation in STIM1, blood platelets from patients were in a preactivated state with high exposure of aminophospholipids on the outer surface of the plasma membrane. Resting Ca2+ levels were elevated in platelets from the patients compared with controls, and store-operated Ca2+ entry was markedly attenuated, further supporting constitutive activity of STIM1 and ORAI1. Thus, our data are compatible with a near-maximal activation of STIM1 in Stormorken syndrome patients. We conclude that the heterozygous mutation c.910C>T causes the complex phenotype that defines this syndrome.