title: Diseases caused by mutations in ORAI1 and STIM1.
abstract: Ca(2+) release-activated Ca(2+) (CRAC) channels mediate a specific form of Ca(2+) influx called store-operated Ca(2+) entry (SOCE) that contributes to the function of many cell types. CRAC channels are composed of 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 sweat gland function and dental enamel formation. The latter defect emphasizes an important role of CRAC channels in tooth development. By contrast, autosomal dominant gain-of-function mutations in ORAI1 and STIM1 result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca(2+) levels that are associated with an overlapping spectrum of diseases, including nonsyndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes. The latter two syndromes are defined, besides myopathy, by thrombocytopenia, thrombopathy, and bleeding diathesis. The fact that myopathy results from both loss- and gain-of-function mutations in ORAI1 and STIM1 highlights the importance of CRAC channels for Ca(2+) 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.
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York.
authors.forename: Rodrigo S
authors.initials: RS
authors.lastname: Lacruz
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York.
authors.forename: Stefan
authors.initials: S
authors.lastname: Feske
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D015220:Calcium Channels / Q000235:genetics / Q000276:immunology*; D053447:Channelopathies / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D009123:Muscle Hypotonia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D000071740:ORAI1 Protein; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1
keywords: CRAC channel; Ca2+; ORAI1; SOCE; STIM1; Stormorken syndrome; York platelet syndrome; ameloblast; autoimmunity; calcium; channelopathy; disease; enamel; muscular hypotonia; mutation; platelets; skeletal muscle; thrombocytopenia; tubular aggregate myopathy