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

Miyuki Tsumura, Satoshi Okada, Hidemasa Sakai, Shin'ichiro Yasunaga, Motoaki Ohtsubo, Takuji Murata, Hideto Obata, Takahiro Yasumi, Xiao Fei Kong, Avinash Abhyankar, Toshio Heike, Tatsutoshi Nakahata, Ryuta Nishikomori, Saleh Al-Muhsen, Stéphanie Boisson-Dupuis, Jean Laurent Casanova, Mofareh Alzahrani, Mohammed Al Shehri, Geyhad Elghazali, Yoshihiro TakiharaMasao Kobayashi

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1377-1387
Number of pages11
JournalHuman mutation
Issue number9
StatePublished - Sep 2012
Externally publishedYes


  • Dominant-negative effect
  • MSMD
  • Osteomyelitis
  • STAT1

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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