title: Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis.
abstract: Chronic 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-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, 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-α/β, IFN-γ, 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.
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, Institut National de la Santé et de la Recherche Médicale U980 and University Paris Descartes, 75015 Paris, France.
authors: Luyan
authors: L
authors: Liu
authors: Satoshi
authors: S
authors: Okada
authors: Xiao-Fei
authors: XF
authors: Kong
authors: Alexandra Y
authors: AY
authors: Kreins
authors: Sophie
authors: S
authors: Cypowyj
authors: Avinash
authors: A
authors: Abhyankar
authors: Julie
authors: J
authors: Toubiana
authors: Yuval
authors: Y
authors: Itan
authors: Magali
authors: M
authors: Audry
authors: Patrick
authors: P
authors: Nitschke
authors: Cécile
authors: C
authors: Masson
authors: Beata
authors: B
authors: Toth
authors: Jérome
authors: J
authors: Flatot
authors: Mélanie
authors: M
authors: Migaud
authors: Maya
authors: M
authors: Chrabieh
authors: Tatiana
authors: T
authors: Kochetkov
authors: Alexandre
authors: A
authors: Bolze
authors: Alessandro
authors: A
authors: Borghesi
authors: Antoine
authors: A
authors: Toulon
authors: Julia
authors: J
authors: Hiller
authors: Stefanie
authors: S
authors: Eyerich
authors: Kilian
authors: K
authors: Eyerich
authors: Vera
authors: V
authors: Gulácsy
authors: Ludmyla
authors: L
authors: Chernyshova
authors: Viktor
authors: V
authors: Chernyshov
authors: Anastasia
authors: A
authors: Bondarenko
authors: Rosa María Cortés
authors: RM
authors: Grimaldo
authors: Lizbeth
authors: L
authors: Blancas-Galicia
authors: Ileana Maria Madrigal
authors: IM
authors: Beas
authors: Joachim
authors: J
authors: Roesler
authors: Klaus
authors: K
authors: Magdorf
authors: Dan
authors: D
authors: Engelhard
authors: Caroline
authors: C
authors: Thumerelle
authors: Pierre-Régis
authors: PR
authors: Burgel
authors: Miriam
authors: M
authors: Hoernes
authors: Barbara
authors: B
authors: Drexel
authors: Reinhard
authors: R
authors: Seger
authors: Theresia
authors: T
authors: Kusuma
authors: Annette F
authors: AF
authors: Jansson
authors: Julie
authors: J
authors: Sawalle-Belohradsky
authors: Bernd
authors: B
authors: Belohradsky
authors: Emmanuelle
authors: E
authors: Jouanguy
authors: Jacinta
authors: J
authors: Bustamante
authors: Mélanie
authors: M
authors: Bué
authors: Nathan
authors: N
authors: Karin
authors: Gizi
authors: G
authors: Wildbaum
authors: Christine
authors: C
authors: Bodemer
authors: Olivier
authors: O
authors: Lortholary
authors: Alain
authors: A
authors: Fischer
authors: Stéphane
authors: S
authors: Blanche
authors: Saleh
authors: S
authors: Al-Muhsen
authors: Janine
authors: J
authors: Reichenbach
authors: Masao
authors: M
authors: Kobayashi
authors: Francisco Espinosa
authors: FE
authors: Rosales
authors: Carlos Torres
authors: CT
authors: Lozano
authors: Sara Sebnem
authors: SS
authors: Kilic
authors: Matias
authors: M
authors: Oleastro
authors: Amos
authors: A
authors: Etzioni
authors: Claudia
authors: C
authors: Traidl-Hoffmann
authors: Ellen D
authors: ED
authors: Renner
authors: Laurent
authors: L
authors: Abel
authors: Capucine
authors: C
authors: Picard
authors: László
authors: L
authors: Maródi
authors: Stéphanie
authors: S
authors: Boisson-Dupuis
authors: Anne
authors: A
authors: Puel
authors: Jean-Laurent
authors: JL
authors: Casanova
mesh_terms: D001483:Base Sequence; D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics* / Q000276:immunology*; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D007372:Interferons; D020381:Interleukin-17 / Q000276:immunology*; D007378:Interleukins / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D010766:Phosphorylation; D053633:Receptor, Interferon alpha-beta / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000276:immunology*; D000095022:Interferon Lambda
chemical_list: D007371:Interferon-gamma; D007372:Interferons; D020381:Interleukin-17; D007378:Interleukins; D053633:Receptor, Interferon alpha-beta; D050794:STAT1 Transcription Factor; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C464565:MYDGF protein, human; C494079:STAT1 protein, human