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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Dominant-negative STAT1 SH2 domain mutations in unrelated patients with mendelian susceptibility to mycobacterial disease
Human Mutation, Volume 33, No. 9, Year 2012
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Description
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. © 2012 Wiley Periodicals, Inc.
Authors & Co-Authors
Tsumura, Miyuki
Japan, Hiroshima
Hiroshima University Graduate School of Biomedical and Health Sciences
Okada, Satoshi
Japan, Hiroshima
Hiroshima University Graduate School of Biomedical and Health Sciences
United States, New York
Rockefeller University
Sakai, Hidemasa
Japan, Kyoto
Graduate School of Medicine
Yasunaga, Shin'Ichiro
Japan, Higashihiroshima
Hiroshima University
Ohtsubo, Motoaki
Japan, Higashihiroshima
Hiroshima University
Murata, Takuji
Japan, Takatsuki
Osaka Medical and Pharmaceutical University
Obata, Hideto
Japan, Suita
Graduate School of Medicine
Japan, Osaka
Yukoukai General Hospital
Yasumi, Takahiro
Japan, Kyoto
Graduate School of Medicine
Kong, Xiao Fei
United States, New York
Rockefeller University
Abhyankar, Avinash
United States, New York
Rockefeller University
Heike, Toshio
Japan, Kyoto
Graduate School of Medicine
Nakahata, Tatsutoshi
Japan, Kyoto
Center for Ips Cell Research and Application
Nishikomori, Ryuta
Japan, Kyoto
Graduate School of Medicine
Al-Muhsen, Saleh Zaid
Saudi Arabia, Riyadh
College of Medicine
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Boisson-Dupuis, Stéphanie
United States, New York
Rockefeller University
France, Paris
L'institut Des Maladies Génétiques Imagine
Casanova, Jean Laurent
United States, New York
Rockefeller University
France, Paris
L'institut Des Maladies Génétiques Imagine
AlZahrani, Mofareh S.
Saudi Arabia, Riyadh
Faculty of Medicine
Shehri, Mohammed Al
Saudi Arabia, Riyadh
Faculty of Medicine
ElGhazali, Gehad Eltayeb B.
Saudi Arabia, Riyadh
Faculty of Medicine
Takihara, Yoshihiro
Japan, Higashihiroshima
Hiroshima University
Kobayashi, Masao
Japan, Hiroshima
Hiroshima University Graduate School of Biomedical and Health Sciences
Statistics
Citations: 75
Authors: 21
Affiliations: 12
Identifiers
Doi:
10.1002/humu.22113
ISSN:
10597794
e-ISSN:
10981004
Research Areas
Cancer
Genetics And Genomics