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Antigen stimulation of immune cells triggers Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels, promoting the immune response to pathogens by activating the transcription factor NFAT. We have previously shown that cells from patients with one form of hereditary severe combined immune deficiency (SCID) syndrome are defective in store-operated Ca2+ entry and CRAC channel function. Here we identify the genetic defect in these patients, using a combination of two unbiased genome-wide approaches: a modified linkage analysis with single-nucleotide polymorphism arrays, and a Drosophila RNA interference screen designed to identify regulators of store-operated Ca2+ entry and NFAT nuclear import. Both approaches converged on a novel protein that we call Orai1, which contains four putative transmembrane segments. The SCID patients are homozygous for a single missense mutation in ORAI1, and expression of wild-type Orai1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (I(CRAC)). We propose that Orai1 is an essential component or regulator of the CRAC channel complex.
Pubmed ID: 16582901 RIS Download
Mesh terms: Animals | Biological Transport | Calcium | Calcium Channels | Carrier State | Chromosomes, Human, Pair 12 | Drosophila Proteins | Drosophila melanogaster | Electric Conductivity | Gene Dosage | Genome, Human | Heterozygote | Humans | Lod Score | Membrane Proteins | Mutation | NFATC Transcription Factors | ORAI1 Protein | Phenotype | Polymorphism, Single Nucleotide | RNA Interference | Severe Combined Immunodeficiency | T-Lymphocytes
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