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Diseases caused by mutations in ORAI1 and STIM1.
Ann N Y Acad Sci. 2015 Nov; 1356:45-79.AN

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+Show Affiliations

Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York.Department of Pathology, New York University School of Medicine, New York, New York.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Review

Language

eng

PubMed ID

26469693

Citation

Lacruz, Rodrigo S., and Stefan Feske. "Diseases Caused By Mutations in ORAI1 and STIM1." Annals of the New York Academy of Sciences, vol. 1356, 2015, pp. 45-79.
Lacruz RS, Feske S. Diseases caused by mutations in ORAI1 and STIM1. Ann N Y Acad Sci. 2015;1356:45-79.
Lacruz, R. S., & Feske, S. (2015). Diseases caused by mutations in ORAI1 and STIM1. Annals of the New York Academy of Sciences, 1356, 45-79. https://doi.org/10.1111/nyas.12938
Lacruz RS, Feske S. Diseases Caused By Mutations in ORAI1 and STIM1. Ann N Y Acad Sci. 2015;1356:45-79. PubMed PMID: 26469693.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diseases caused by mutations in ORAI1 and STIM1. AU - Lacruz,Rodrigo S, AU - Feske,Stefan, Y1 - 2015/10/15/ PY - 2015/10/16/entrez PY - 2015/10/16/pubmed PY - 2016/3/2/medline KW - CRAC channel KW - Ca2+ KW - ORAI1 KW - SOCE KW - STIM1 KW - Stormorken syndrome KW - York platelet syndrome KW - ameloblast KW - autoimmunity KW - calcium KW - channelopathy KW - disease KW - enamel KW - muscular hypotonia KW - mutation KW - platelets KW - skeletal muscle KW - thrombocytopenia KW - tubular aggregate myopathy SP - 45 EP - 79 JF - Annals of the New York Academy of Sciences JO - Ann. N. Y. Acad. Sci. VL - 1356 N2 - 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. SN - 1749-6632 UR - https://www.unboundmedicine.com/medline/citation/26469693/Diseases_caused_by_mutations_in_ORAI1_and_STIM1_ L2 - https://doi.org/10.1111/nyas.12938 DB - PRIME DP - Unbound Medicine ER -