title: STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis.
abstract: BACKGROUND
  Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to candida infection of skin, nails, and mucous membranes. Patients with recessive CMC and autoimmunity have mutations in the autoimmune regulator AIRE. The cause of autosomal dominant CMC is unknown.
  
  
  METHODS
  We evaluated 14 patients from five families with autosomal dominant CMC. We incubated their peripheral-blood mononuclear cells with different combinations of stimuli to test the integrity of pathways that mediate immunity, which led to the selection of 100 genes that were most likely to contain the genetic defect. We used an array-based sequence-capture assay, followed by next-generation sequencing, to identify mutations.
  
  
  RESULTS
  The mononuclear cells from the affected patients were characterized by poor production of interferon-γ, interleukin-17, and interleukin-22, suggesting that the defect lay within the interleukin-12 receptor and interleukin-23 receptor signaling pathways. We identified heterozygous missense mutations in the DNA sequence encoding the coiled-coil (CC) domain of signal transducer and activator of transcription 1 (STAT1) in the patients. These mutations lead to defective responses in type 1 and type 17 helper T cells (Th1 and Th17). The interferon-γ receptor pathway was intact in these patients.
  
  
  CONCLUSIONS
  Mutations in the CC domain of STAT1 underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses, which may explain the increased susceptibility to fungal infection. (Funded by the Netherlands Organization for Scientific Research and others.).
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Sanne P
authors.initials: SP
authors.lastname: Smeekens
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Peer
authors.initials: P
authors.lastname: Arts
authors.forename: Diana C
authors.initials: DC
authors.lastname: Rosentul
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carmichael
authors.forename: Chantal A A
authors.initials: CA
authors.lastname: Smits-van der Graaf
authors.forename: Bart Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Desa
authors.initials: D
authors.lastname: Lilic
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics* / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D050794:STAT1 Transcription Factor / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D050794:STAT1 Transcription Factor; D000097043:Interleukin-22; C494079:STAT1 protein, human