A heterozygous dominant-negative mutation in the coiled-coil domain of STAT1 is the cause of autosomal-dominant Mendelian susceptibility to mycobacterial diseases

Masahiro Ueki, Masafumi Yamada, Kenta Ito, Yusuke Tozawa, Saeko Morino, Yuho Horikoshi, Hidetoshi Takada, Shimaa Said Mohamed Ali Abdrabou, Shunichiro Takezaki, Ichiro Kobayashi, Tadashi Ariga

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16 Citations (Scopus)

Abstract

Heterozygous dominant-negative mutations of STAT1 are responsible for autosomal-dominant Mendelian susceptibility to mycobacterial diseases (AD-MSMD). So far, only 7 mutations have been previously described and are localized to 3 domains: the DNA-binding domain, the SH2 domain, and the tail segment. In this study, we demonstrated the first coiled-coil domain (CCD) mutation of c.749G > C, p.G250A (G250A) in STAT1 as a genetic cause of AD-MSMD in a patient with mycobacterial multiple osteomyelitis. This de novo heterozygous mutation was shown to have a dominant-negative effect on the gamma-activated sequence (GAS) transcriptional activity following IFN-γ stimulation, which could be attributable to the abolished phosphorylation of STAT1 from the wild-type (WT) allele. The three-dimensional structure of STAT1 revealed the G250 residue was located distant from a cluster of residues affected by gain-of-function mutations responsible for chronic mucocutaneous candidiasis.

Original languageEnglish
Pages (from-to)24-31
Number of pages8
JournalClinical Immunology
Volume174
DOIs
Publication statusPublished - Jan 1 2017

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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