/ Loss-of-Function and Gain-of-Function Mutations Inversely Impact on SOCE and Calcium Homeostasis and Cause Multi-Systemic Mirror Diseases.

Abstract

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.