Diseases caused by mutations in ORAI1 and STIM1

Abstract

Ca2+ release-activated Ca2+ (CRAC) channels mediate a specific form of Ca2+ influx called store-operated Ca2+ entry (SOCE) that contributes to the function of many cell types. CRAC channels are formed by ORAI1 proteins located in the plasma membrane, which form its ion-conducting pore. ORAI1 channels are activated by stromal interaction molecule (STIM) 1 and STIM2 located in the endoplasmic reticulum. Loss- and gain-of-function gene mutations in ORAI1 and STIM1 in human patients cause distinct disease syndromes. CRAC channelopathy is caused by loss-of-function mutations in ORAI1 and STIM1 that abolish CRAC channel function and SOCE; it is characterized by severe combined immunodeficiency (SCID)-like disease, autoimmunity, muscular hypotonia, and ectodermal dysplasia, with defects in dental enamel. The latter defect emphasizes an important role of CRAC channels in tooth development. By contrast, autosomal dominant gain-of-function mutations in these genes result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca2+ levels that are associated with an overlapping spectrum of diseases, including non-syndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes, two syndromes defined, besides myopathy, by thrombocytopenia, thrombopathy, and bleeding diathesis. The fact that myopathy results from loss- and gain-of-function mutations in ORAI1 and STIM1 highlights the importance of CRAC channels for Ca2+ homeostasis in skeletal muscle function. The cellular dysfunction and clinical disease spectrum observed in mutant patients provide important information about the molecular regulation of ORAI1 and STIM1 proteins and the role of CRAC channels in human physiology.

Inherited platelet disorders: toward DNA-based diagnosis

“…Both Orai1 and Stim1 are involved in calcium homeostasis, and IPD-causing variants consequently affect platelet signaling, but further research is required into their role in platelet formation. [50][51][52] Novel missense variants were recently identified in SLFN14 in 4 unrelated pedigrees with moderate thrombocytopenia and platelet secretion defects. Although the mechanism is not clear, a defect in platelet formation was observed.…”

Displasia ectodérmica: Un reporte de caso

“…De esta manera, se podría concluir que la displasia ectodérmica que posiblemente presentaba el menor incluía alteraciones del ectodermo expresadas en su cabello fi no y escaso (tricodisplasia) como también lo reporta el trabajo de Rakowska y colaboradores (18) y en la calidad del esmalte dental observado por Lacruz y Feske en 2015 (19).…”

Modulatory Effect of Periostracum Cicadae and Betulae Cortex Extracts on the Activation of Atopic Dermatitis-Related Ion Channels Orai1 and Trpv3

“…TRPV3 is highly expressed in keratinocytes, and TRPV3 activation can mediate their terminal differentiation to form the skin barrier. ORAI1 is a major mechanism for intracellular Ca 2+ increase in non-excitable cells, T lymphocytes, and mast cells, which initiate the hyperimmune response (Lacruz and Feske, 2015). Therefore, agents that regulate these ion channels have been considered recently as novel therapeutics for alleviating AD (Di Capite et al, 2011).…”