ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia.
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.
McCarl
Christie-Ann
CA
Department of Pathology, New York University, Langone Medical Center, New York, NY 10016, USA.
Picard
Capucine
C
Khalil
Sara
S
Kawasaki
Takumi
T
Röther
Jens
J
Papolos
Alexander
A
Kutok
Jeffery
J
Hivroz
Claire
C
Ledeist
Francoise
F
Plogmann
Katrin
K
Ehl
Stephan
S
Notheis
Gundula
G
Albert
Michael H
MH
Belohradsky
Bernd H
BH
Kirschner
Janbernd
J
Rao
Anjana
A
Fischer
Alain
A
Feske
Stefan
S
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
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