Diseases caused by mutations in ORAI1 and STIM1

Rodrigo Lacruz, Stefan Feske

Research output: Contribution to journalArticle

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 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 Ca2+ 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 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.

Original languageEnglish (US)
Pages (from-to)45-79
Number of pages35
JournalAnnals of the New York Academy of Sciences
Volume1356
Issue number1
DOIs
StatePublished - Nov 1 2015

Fingerprint

Mutation
Muscular Diseases
Congenital Structural Myopathies
Channelopathies
Ectodermal Dysplasia
Severe Combined Immunodeficiency
Sweat Glands
Muscle Hypotonia
Disease Susceptibility
Dental Enamel
Autoimmunity
Endoplasmic Reticulum
Thrombocytopenia
Tooth
Skeletal Muscle
Homeostasis
Blood Platelets
Cell Membrane
Ions
Hemorrhage

Keywords

  • Ameloblast
  • Autoimmunity
  • Ca
  • Calcium
  • Channelopathy
  • CRAC channel
  • Disease
  • Enamel
  • Muscular hypotonia
  • Mutation
  • ORAI1
  • Platelets
  • Skeletal muscle
  • SOCE
  • STIM1
  • Stormorken syndrome
  • Thrombocytopenia
  • Tubular aggregate myopathy
  • York platelet syndrome

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

Diseases caused by mutations in ORAI1 and STIM1. / Lacruz, Rodrigo; Feske, Stefan.

In: Annals of the New York Academy of Sciences, Vol. 1356, No. 1, 01.11.2015, p. 45-79.

Research output: Contribution to journalArticle

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