2023-05-182023-05-182011-08Liu, L. Y. vd. (2011). "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis". Journal of Experimental Medicine, 208(8), 1635-1648.0022-1007https://doi.org/10.1084/jem.20110958https://rupress.org/jem/article/208/8/1635/41136/Gain-of-function-human-STAT1-mutations-impair-ILhttp://hdl.handle.net/11452/32710Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-gamma. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-alpha/beta, IFN-gamma, IFN-lambda, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-alpha/beta, IFN-gamma, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.eninfo:eu-repo/semantics/openAccessImmunologyResearch & experimental medicineHyper-ige syndromeSequencing-based discoveryCd4(+) t-cellsTh17 cellsInborn-errorsIfn-gammaTh17-associated cytokinesDeficiencyDiseaseIl-27Base sequenceCandidiasis, chronic mucocutaneousElectrophoretic mobility shift assayEnzyme-linked immunosorbent assayFemaleFlow cytometryFluorescent antibody techniqueGerm-line mutationHumansImmunoblottingInterferon-gammaInterleukin-17InterleukinsMaleModels, molecularMolecular sequence dataPedigreePhosphorylationReceptor, interferon alpha-betaSequence alignmentSequence analysis, DNASTAT1 transcription factorT-lymphocytesArticle0002934415000082-s2.0-7996115444716351648208821727188ImmunologyMedicine, research & experimentalJob Syndrome; Mucocutaneous Candidiasis; MutationInterleukin 17Interleukin 17FInterleukin 21Interleukin 22Interleukin 6STAT1 proteinAlleleArticleAutosomal dominant disorderChildChronic diseaseClinical articleFemaleGain of function mutationGeneHeterozygosityHumanImmunityInfantMaleMucocutaneous candidiasisPriority journalStat 1 geneT lymphocyte