Silva-Rojas Roberto, Laporte Jocelyn, Böhm Johann
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France.
Front Physiol. 2020 Nov 4;11:604941. doi: 10.3389/fphys.2020.604941. eCollection 2020.
Store-operated Ca entry (SOCE) is a ubiquitous and essential mechanism regulating Ca homeostasis in all tissues, and controls a wide range of cellular functions including keratinocyte differentiation, osteoblastogenesis and osteoclastogenesis, T cell proliferation, platelet activation, and muscle contraction. The main SOCE actors are STIM1 and ORAI1. Depletion of the reticular Ca stores induces oligomerization of the luminal Ca sensor STIM1, and the oligomers activate the plasma membrane Ca channel ORAI1 to trigger extracellular Ca entry. Mutations in and result in abnormal SOCE and lead to multi-systemic disorders. Recessive loss-of-function mutations are associated with CRAC (Ca release-activated Ca) channelopathy, involving immunodeficiency and autoimmunity, muscular hypotonia, ectodermal dysplasia, and mydriasis. In contrast, dominant and gain-of-function mutations give rise to tubular aggregate myopathy and Stormorken syndrome (TAM/STRMK), forming a clinical spectrum encompassing muscle weakness, thrombocytopenia, ichthyosis, hyposplenism, short stature, and miosis. Functional studies on patient-derived cells revealed that CRAC channelopathy mutations impair SOCE and extracellular Ca influx, while TAM/STRMK mutations induce excessive Ca entry through SOCE over-activation. In accordance with the opposite pathomechanisms underlying both disorders, CRAC channelopathy and TAM/STRMK patients show mirror phenotypes at the clinical and molecular levels, and the respective animal models recapitulate the skin, bones, immune system, platelet, and muscle anomalies. Here we review and compare the clinical presentations of CRAC channelopathy and TAM/STRMK patients and the histological and molecular findings obtained on human samples and murine models to highlight the mirror phenotypes in different tissues, and to point out potentially undiagnosed anomalies in patients, which may be relevant for disease management and prospective therapeutic approaches.
钙库操纵性钙内流（SOCE）是一种普遍存在且至关重要的机制，可调节所有组织中的钙稳态，并控制多种细胞功能，包括角质形成细胞分化、成骨细胞生成和破骨细胞生成、T细胞增殖、血小板活化以及肌肉收缩。SOCE的主要作用因子是基质相互作用分子1（STIM1）和钙释放激活钙通道蛋白1（ORAI1）。内质网钙库耗竭会诱导内质网腔钙传感器STIM1寡聚化，而这些寡聚体激活质膜钙通道ORAI1以触发细胞外钙内流。STIM1和ORAI1的突变会导致异常的SOCE，并引发多系统疾病。隐性功能丧失突变与钙释放激活钙（CRAC）通道病相关，涉及免疫缺陷和自身免疫、肌张力减退、外胚层发育不良以及瞳孔散大。相比之下，显性STIM1和ORAI1功能获得性突变会导致管状聚集性肌病和斯托莫尔肯综合征（TAM/STRMK），形成一个临床谱，包括肌无力、血小板减少、鱼鳞病、脾功能减退、身材矮小和瞳孔缩小。对患者来源细胞的功能研究表明，CRAC通道病突变会损害SOCE和细胞外钙内流，而TAM/STRMK突变则通过SOCE过度激活诱导过量钙内流。鉴于这两种疾病潜在的相反发病机制，CRAC通道病和TAM/STRMK患者在临床和分子水平上表现出镜像表型，相应的动物模型再现了皮肤、骨骼、免疫系统、血小板和肌肉异常。在此，我们回顾并比较CRAC通道病和TAM/STRMK患者的临床表现，以及在人类样本和小鼠模型上获得的组织学和分子学发现，以突出不同组织中的镜像表型，并指出患者中可能未被诊断的异常，这可能与疾病管理和前瞻性治疗方法相关。
