A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function

Antigen stimulation of immune cells triggers Ca(2+) entry through Ca(2+) release-activated Ca(2+) ( 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) influx and the CRAC current ( I CRAC). We propose that Orai1 is an essential component or regulator of the CRAC channel complex.