title: Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis.
abstract: BACKGROUND
  Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis.
  
  
  OBJECTIVE
  We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections.
  
  
  METHODS
  PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated.
  
  
  RESULTS
  We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ-induced gene expression, but we found impaired responses to IFN-γ restimulation.
  
  
  CONCLUSIONS
  Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ-mediated inflammation.
authors.affiliation: Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md., USA.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Sampaio
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.forename: Joseph
authors.initials: J
authors.lastname: Pechacek
authors.forename: Hannelore I
authors.initials: HI
authors.lastname: Bax
authors.forename: Dalton L
authors.initials: DL
authors.lastname: Dias
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Paulson
authors.forename: Prabha
authors.initials: P
authors.lastname: Chandrasekaran
authors.forename: Lindsey B
authors.initials: LB
authors.lastname: Rosen
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Carvalho
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Donald C
authors.initials: DC
authors.lastname: Vinh
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Browne
authors.forename: Shrimati
authors.initials: S
authors.lastname: Datta
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kuhns
authors.forename: Debra A
authors.initials: DA
authors.lastname: Long Priel
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Sadat
authors.forename: Michael
authors.initials: M
authors.lastname: Shiloh
authors.forename: Brendan
authors.initials: B
authors.lastname: De Marco
authors.forename: Michael
authors.initials: M
authors.lastname: Alvares
authors.forename: Jason W
authors.initials: JW
authors.lastname: Gillman
authors.forename: Vivek
authors.initials: V
authors.lastname: Ramarathnam
authors.forename: Maite
authors.initials: M
authors.lastname: de la Morena
authors.forename: Liliana
authors.initials: L
authors.lastname: Bezrodnik
authors.forename: Ileana
authors.initials: I
authors.lastname: Moreira
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.forename: Daniel
authors.initials: D
authors.lastname: Johnson
authors.forename: Christine
authors.initials: C
authors.lastname: Spalding
authors.forename: Christa S
authors.initials: CS
authors.lastname: Zerbe
authors.forename: Henry
authors.initials: H
authors.lastname: Wiley
authors.forename: David E
authors.initials: DE
authors.lastname: Greenberg
authors.forename: Susan E
authors.initials: SE
authors.lastname: Hoover
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Rosenzweig
authors.forename: John N
authors.initials: JN
authors.lastname: Galgiani
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
mesh_terms: D000293:Adolescent; D000328:Adult; D002461:Cell Line, Transformed; D002648:Child; D003047:Coccidioidomycosis / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation; D006660:Histoplasmosis / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008297:Male; D009154:Mutation; D010766:Phosphorylation; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: D016207:Cytokines; D050828:Protein Inhibitors of Activated STAT; D050794:STAT1 Transcription Factor
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