title: A novel gain-of-function STAT1 mutation resulting in basal phosphorylation of STAT1 and increased distal IFN-γ-mediated responses in chronic mucocutaneous candidiasis.
abstract: Gain-of-function STAT1 mutations have recently been associated with autosomal dominant chronic mucocutaneous candidiasis (CMC). The purpose of this study was to characterize the three members of a non-consanguineous family, the father and his two sons, who presented with recurrent oral thrush and ocular candidiasis since early childhood. The three patients had reduced levels of IL-17-producing T cells. This reduction affected specifically IL-17(+)IFN-γ(-) T cells, because the levels of IL-17(+)IFN-γ(+) T cells were similar to controls. We found that PBMC (peripheral blood mononuclear cells) from the patients did not respond to Candida albicans ex vivo. Moreover, after polyclonal activation, patients' PBMC produced lower levels of IL-17 and IL-6 and higher levels of IL-4 than healthy controls. Genetic analyses showed that the three patients were heterozygous for a new mutation in STAT1 (c.894A>C, p.K298N) that affects a highly conserved residue of the coiled-coil domain of STAT1. STAT1 phosphorylation levels were significantly higher in patients' cells than in healthy controls, both in basal conditions and after IFN-γ stimulation, suggesting a permanent activation of STAT1. Cells from the patients also presented increased IFN-γ-mediated responses measured as MIG and IP-10 production. In conclusion, we report a novel gain-of-function mutation in the coiled-coil domain of STAT1, which increases STAT1 phosphorylation and impairs IL-17-mediated immunity. The mutation is responsible for CMC in this family with autosomal dominant inheritance of the disease.
authors.affiliation: Department of Immunology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Martinez-Martinez
authors.affiliation: Department of Immunology, Hospital de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Martinez-Saavedra
authors.affiliation: Molecular Basis of Disease, Institute for Biomedical Research, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Fuentes-Prior
authors.affiliation: Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Barnadas
authors.affiliation: Department of Immunology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain.
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Rubiales
authors.affiliation: Department of Immunology, Hospital de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Noda
authors.affiliation: Department of Pediatrics, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Badell
authors.affiliation: Department of Immunology, Hospital Son Espases, Palma de Mallorca, Spain; Research Institute of Health Sciences (IdISPa), Palma de Mallorca, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodríguez-Gallego
authors.affiliation: Department of Immunology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain. Electronic address: odlcalle@santpau.cat.
authors.forename: Oscar
authors.initials: O
authors.lastname: de la Calle-Martin
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics* / Q000276:immunology; D002648:Child; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology; D008297:Male; D009154:Mutation; D010375:Pedigree; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: C508717:IL17A protein, human; D020381:Interleukin-17; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma
keywords: Chronic mucocutaneous candidiasis; Coiled-coil domain; Gain-of-function mutation; IFN-γ; IL-17-producing T cells; STAT1