Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

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…

• SG
  St. Giles Foundation
• GC
  Georgia Clinical and Translational Science Alliance
• DF
  Deutsche Forschungsgemeinschaft

  Award: RE2799/3-1
• IN
  Institut National de la Santé et de la Recherche Médicale
• AR
  AXA Research Fund
• SE
  Shanghai Educational Development Foundation
• GR
  Gebert Rüf Stiftung
• LM
  Ludwig-Maximilians-Universität München