title: Dominant-negative STAT1 SH2 domain mutations in unrelated patients with Mendelian susceptibility to mycobacterial disease.
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.
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tsumura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Sakai
authors.forename: Shin'ichiro
authors.initials: S
authors.lastname: Yasunaga
authors.forename: Motoaki
authors.initials: M
authors.lastname: Ohtsubo
authors.forename: Takuji
authors.initials: T
authors.lastname: Murata
authors.forename: Hideto
authors.initials: H
authors.lastname: Obata
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yasumi
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Kong
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
authors.forename: Ryuta
authors.initials: R
authors.lastname: Nishikomori
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Muhsen
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Mofareh
authors.initials: M
authors.lastname: Alzahrani
authors.forename: Mohammed Al
authors.initials: MA
authors.lastname: Shehri
authors.forename: Geyhad
authors.initials: G
authors.lastname: Elghazali
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takihara
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D021581:Active Transport, Cell Nucleus; D000483:Alleles; D001500:BCG Vaccine / Q000009:adverse effects; D002648:Child; D016207:Cytokines / Q000032:analysis; D004252:DNA Mutational Analysis; D004198:Disease Susceptibility / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007223:Infant; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D019656:Loss of Heterozygosity; D008297:Male; D020125:Mutation, Missense; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000302:isolation & purification* / Q000472:pathogenicity; D010766:Phosphorylation; D055503:Protein Multimerization; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D001500:BCG Vaccine; D016207:Cytokines; D016898:Interferon-alpha; D007378:Interleukins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014443:Tyrosine; D007371:Interferon-gamma