1. The CBR Institute for Biomedical Research, and the Departments of
2. Pediatrics and
3. Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
4. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA
5. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA
6. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
7. Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
8. *These authors contributed equally to this work

Correspondence to: Anjana Rao^1,3 Correspondence and requests for materials should be addressed to A.R. (Email: arao@cbr.med.harvard.edu).

Abstract

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.

1. The CBR Institute for Biomedical Research, and the Departments of
2. Pediatrics and
3. Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
4. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA
5. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA
6. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
7. Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
8. *These authors contributed equally to this work

Correspondence to: Anjana Rao^1,3 Correspondence and requests for materials should be addressed to A.R. (Email: arao@cbr.med.harvard.edu).

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