Dominant-negative STAT1 SH2 domain mutations in unrelated patients with mendelian susceptibility to mycobacterial disease

Authors

  • Miyuki Tsumura,

    1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
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    • These two authors contributed equally to this work.

  • Satoshi Okada,

    1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
    2. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York
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    • These two authors contributed equally to this work.

  • Hidemasa Sakai,

    1. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  • Shin'ichiro Yasunaga,

    1. Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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  • Motoaki Ohtsubo,

    1. Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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  • Takuji Murata,

    1. Department of Pediatrics, Osaka Medical College, Osaka, Japan
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  • Hideto Obata,

    1. Department of Orthopedics, Osaka University Graduate School of Medicine, Osaka, Japan
    2. Department of Orthopedic Surgery, Yukoukai General Hospital, Osaka, Japan
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  • Takahiro Yasumi,

    1. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  • Xiao-Fei Kong,

    1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York
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  • Avinash Abhyankar,

    1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York
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  • Toshio Heike,

    1. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  • Tatsutoshi Nakahata,

    1. Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
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  • Ryuta Nishikomori,

    1. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  • Saleh Al-Muhsen,

    1. Prince Naif Center for Immunology Research, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
    2. Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Stéphanie Boisson-Dupuis,

    1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York
    2. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U980 and University Paris Descartes, Necker Medical School, Paris, France
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  • Jean-Laurent Casanova,

    1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York
    2. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U980 and University Paris Descartes, Necker Medical School, Paris, France
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  • Mofareh AlZahrani,

    1. Department of Immunology, Faculty of Medicine, King Fahad Medical City, Riyadh 11525, Saudi Arabia
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  • Mohammed Al Shehri,

    1. Department of Immunology, Faculty of Medicine, King Fahad Medical City, Riyadh 11525, Saudi Arabia
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  • Geyhad ElGhazali,

    1. Department of Immunology, Faculty of Medicine, King Fahad Medical City, Riyadh 11525, Saudi Arabia
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  • Yoshihiro Takihara,

    1. Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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    • These two authors contributed equally to this work and are considered cosenior authors.

  • Masao Kobayashi

    Corresponding author
    1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
    • Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
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    • These two authors contributed equally to this work and are considered cosenior authors.


  • Communicated by Jacques S. Beckmann

Abstract

Patients carrying two loss-of-function (or hypomorphic) alleles of STAT1 are vulnerable to intracellular bacterial and viral diseases. Heterozygosity for loss-of-function dominant-negative mutations in STAT1 is responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD), whereas heterozygosity for gain-of-function loss-of-dephosphorylation mutations causes AD chronic mucocutaneous candidiasis (CMC). The two previously reported types of AD MSMD-causing STAT1 mutations are located in the tail segment domain (p.L706S) or in the DNA-binding domain (p.E320Q and p.Q463H), whereas the AD CMC-causing mutations are located in the coiled-coil domain. We identified two cases with AD-STAT1 deficiency in two unrelated patients from Japan and Saudi Arabia carrying heterozygous missense mutations affecting the SH2 domain (p.K637E and p.K673R). p.K673R is a hypomorphic mutation that impairs STAT1 tyrosine phosphorylation, whereas the p.K637E mutation is null and affects both STAT1 phosphorylation and DNA-binding activity. Both alleles are dominant negative and result in impaired STAT1-mediated cellular responses to interferon (IFN)-γ and IL-27. In contrast, STAT1-mediated cellular responses against IFN-α and IFN-λ1 were preserved at normal levels in patients' cells. We describe here the first dominant mutations in the SH2 domain of STAT1, revealing the importance of this domain for tyrosine phosphorylation and DNA binding, as well as for antimycobacterial immunity. Hum Mutat 33:1377–1387, 2012. © 2012 Wiley Periodicals, Inc.

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