title: A heterozygous dominant-negative mutation in the coiled-coil domain of STAT1 is the cause of autosomal-dominant Mendelian susceptibility to mycobacterial diseases.
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 SH2domain, 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.
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ueki
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address: yamadam@med.hokudai.ac.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Fuchu, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Ito
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tozawa
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Fuchu, Japan.
authors.forename: Saeko
authors.initials: S
authors.lastname: Morino
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Fuchu, Japan.
authors.forename: Yuho
authors.initials: Y
authors.lastname: Horikoshi
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takada
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shimaa Said Mohamed Ali
authors.initials: SS
authors.lastname: Abdrabou
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Takezaki
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kobayashi
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ariga
mesh_terms: D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009164:Mycobacterium Infections / Q000235:genetics*; D000072417:Protein Domains; D050794:STAT1 Transcription Factor / Q000235:genetics*
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human
keywords: Autosomal-dominant Mendelian susceptibility to mycobacterial diseases (AD-MSMD); Coiled-coil domain; Dominant negative; Multifocal osteomyelitis; STAT1