title: ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia.
abstract: BACKGROUND
  Defects in the development or activation of T cells result in immunodeficiency associated with severe infections early in life. T-cell activation requires Ca2+ influx through Ca2+-release activated Ca2+ (CRAC) channels encoded by the gene ORAI1.
  
  
  OBJECTIVE
  Investigation of the genetic causes and the clinical phenotype of immunodeficiency in patients with impaired Ca2+ influx and CRAC channel function.
  
  
  METHODS
  DNA sequence analysis for mutations in the genes ORAI1, ORAI2, ORAI3, and stromal interaction molecule (STIM) 1 and 2, as well as mRNA and protein expression analysis of ORAI1 in immunodeficient patients. Immunohistochemical analysis of ORAI1 tissue distribution in healthy human donors.
  
  
  RESULTS
  We identified mutations in ORAI1 in patients from 2 unrelated families. One patient is homozygous for a frameshift nonsense mutation in ORAI1 (ORAI1-A88SfsX25), and a second patient is compound heterozygous for 2 missense mutations in ORAI1 (ORAI1-A103E/L194P). All 3 mutations abolish ORAI1 expression and impair Ca2+ influx and CRAC channel function. The clinical syndrome associated with ORAI1 deficiency is characterized by immunodeficiency with a defect in the function but not in the development of lymphocytes, congenital myopathy, and anhydrotic ectodermal dysplasia with a defect in dental enamel calcification. In contrast with the limited clinical phenotype, we found ORAI1 protein expression in a wide variety of cell types and organs.
  
  
  CONCLUSIONS
  Ca2+ influx through ORAI1 is crucial for lymphocyte function in vivo. Despite almost ubiquitous ORAI1 expression, the channel has a nonredundant role in only a few cell types judging from the limited clinical phenotype in ORAI1-deficient patients.
authors.affiliation: Department of Pathology, New York University, Langone Medical Center, New York, NY 10016, USA.
authors.forename: Christie-Ann
authors.initials: CA
authors.lastname: McCarl
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Sara
authors.initials: S
authors.lastname: Khalil
authors.forename: Takumi
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Jens
authors.initials: J
authors.lastname: Röther
authors.forename: Alexander
authors.initials: A
authors.lastname: Papolos
authors.forename: Jeffery
authors.initials: J
authors.lastname: Kutok
authors.forename: Claire
authors.initials: C
authors.lastname: Hivroz
authors.forename: Francoise
authors.initials: F
authors.lastname: Ledeist
authors.forename: Katrin
authors.initials: K
authors.lastname: Plogmann
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.forename: Gundula
authors.initials: G
authors.lastname: Notheis
authors.forename: Michael H
authors.initials: MH
authors.lastname: Albert
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.forename: Janbernd
authors.initials: J
authors.lastname: Kirschner
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Stefan
authors.initials: S
authors.lastname: Feske
mesh_terms: D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016368:Frameshift Mutation; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000071740:ORAI1 Protein; D000071741:ORAI2 Protein; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D014162:Transfection
chemical_list: D015220:Calcium Channels; D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D000071741:ORAI2 Protein; C514506:ORAI2 protein, human; C522867:Orai3 protein, human; C103530:STIM1 protein, human; C513279:STIM2 protein, human; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D002118:Calcium