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

Author

Listed:
  • Stefan Feske

    (The CBR Institute for Biomedical Research
    Harvard Medical School)

  • Yousang Gwack

    (The CBR Institute for Biomedical Research
    Harvard Medical School)

  • Murali Prakriya

    (Northwestern University, Feinberg School of Medicine)

  • Sonal Srikanth

    (The CBR Institute for Biomedical Research
    Harvard Medical School)

  • Sven-Holger Puppel

    (The CBR Institute for Biomedical Research)

  • Bogdan Tanasa

    (The CBR Institute for Biomedical Research)

  • Patrick G. Hogan

    (The CBR Institute for Biomedical Research)

  • Richard S. Lewis

    (Stanford University School of Medicine)

  • Mark Daly

    (Center for Human Genetic Research, Massachusetts General Hospital
    Broad Institute of Harvard University and Massachusetts Institute of Technology)

  • Anjana Rao

    (The CBR Institute for Biomedical Research
    Harvard Medical School)

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 (ICRAC). We propose that Orai1 is an essential component or regulator of the CRAC channel complex.

Suggested Citation

  • Stefan Feske & Yousang Gwack & Murali Prakriya & Sonal Srikanth & Sven-Holger Puppel & Bogdan Tanasa & Patrick G. Hogan & Richard S. Lewis & Mark Daly & Anjana Rao, 2006. "A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function," Nature, Nature, vol. 441(7090), pages 179-185, May.
    • Handle: RePEc:nat:nature:v:441:y:2006:i:7090:d:10.1038_nature04702
    DOI: 10.1038/nature04702
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    Cited by:

    1. Lena Maltan & Sarah Weiß & Hadil Najjar & Melanie Leopold & Sonja Lindinger & Carmen Höglinger & Lorenz Höbarth & Matthias Sallinger & Herwig Grabmayr & Sascha Berlansky & Denis Krivic & Valentina Hop, 2023. "Photocrosslinking-induced CRAC channel-like Orai1 activation independent of STIM1," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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