title: Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody.
abstract: Heterozygous gain-of-function (GOF) mutations of STAT1 are responsible for chronic mucocutaneous candidiasis disease (CMCD), one of the primary immunodeficiency diseases characterized by susceptibility to mucocutaneous Candida infection. To date, 30 aa changes have been reported: 21 in the coiled-coil domain and 9 in the DNA-binding domain. In this study, we report two novel STAT1 GOF mutations of p.K278E in coiled-coil domain and p.G384D in DNA-binding domain in Japanese CMCD patients. Ectopic expression of these STAT1 mutants in HeLa cells was associated with increased phosphorylation of the mutant and the endogenous wild-type STAT1 due to impaired dephosphorylation, indicating heterodimers of the wild-type and mutant STAT1 cause impaired dephosphorylation, as did homodimers of the mutants. Because IL-17A production was not significantly reduced at least in one of the patients following PMA plus ionomycin stimulation, we further studied Th17-associated cytokines IL-17A, IL-17F, and IL-22 in response to more physiologically relevant stimulations. IL-17A and IL-22 production from PBMCs and CD4(+) cells was significantly reduced in four patients with STAT1 GOF mutations, including the previously reported R274Q in response to anti-CD3 plus anti-CD28 Abs or Candida stimulations. In contrast, IL-17F production was comparable to healthy controls in response to anti-CD3 plus anti-CD28 Abs stimulation. These results indicate impaired production of IL-17A and IL-22 rather than IL-17F was associated with the development of CMCD in these patients. Additionally, only the anti-IL-17F autoantibody was detected in sera from 11 of 17 patients with STAT1 GOF mutations, which may be useful as a marker for this disease.
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; yamadam@med.hokudai.ac.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Human Genetics, National Center for Child Health and Development, Tokyo 157-8535, Japan;
authors.forename: Toshinao
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.affiliation: Department of Human Genetics, National Center for Child Health and Development, Tokyo 157-8535, Japan;
authors.forename: Masafumi
authors.initials: M
authors.lastname: Onodera
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ueki
authors.affiliation: Department of Human Genetics, National Center for Child Health and Development, Tokyo 157-8535, Japan;
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takada
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Takezaki
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; Department of Dentistry for Children and Disabled Persons, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Chida
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kobayashi
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ariga
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D002175:Candida / Q000276:immunology / Q000472:pathogenicity; D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D002675:Child, Preschool; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D000097043:Interleukin-22
chemical_list: D001323:Autoantibodies; D020381:Interleukin-17; D007378:Interleukins; D050794:STAT1 Transcription Factor; D000097043:Interleukin-22; C508717:IL17A protein, human; C440021:IL17F protein, human; C494079:STAT1 protein, human