title: Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome.
abstract: BACKGROUND
  Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers.
  
  
  OBJECTIVE
  We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC.
  
  
  METHODS
  We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations.
  
  
  RESULTS
  We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation.
  
  
  CONCLUSIONS
  Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1684, USA.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Sampaio
authors.forename: Monica G
authors.initials: MG
authors.lastname: Lawrence
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.forename: Mary
authors.initials: M
authors.lastname: Hackett
authors.forename: Morna J
authors.initials: MJ
authors.lastname: Dorsey
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Noel
authors.forename: James W
authors.initials: JW
authors.lastname: Verbsky
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.forename: Erin
authors.initials: E
authors.lastname: Janssen
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Bonilla
authors.forename: Joseph
authors.initials: J
authors.lastname: Pechacek
authors.forename: Prabha
authors.initials: P
authors.lastname: Chandrasekaran
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Browne
authors.forename: Anahita
authors.initials: A
authors.lastname: Agharahimi
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Gharib
authors.forename: Sara C
authors.initials: SC
authors.lastname: Mannurita
authors.forename: Jae Joon
authors.initials: JJ
authors.lastname: Yim
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gambineri
authors.forename: Troy
authors.initials: T
authors.lastname: Torgerson
authors.forename: Dat Q
authors.initials: DQ
authors.lastname: Tran
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000276:immunology; D002461:Cell Line, Transformed; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005799:Genes, Dominant; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D016898:Interferon-alpha / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology; D020381:Interleukin-17 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D007410:Intestinal Diseases / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008297:Male; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D016884:Polyendocrinopathies, Autoimmune / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D015533:Transcriptional Activation; D000097043:Interleukin-22
chemical_list: D001323:Autoantibodies; D004247:DNA; D051858:Forkhead Transcription Factors; D016898:Interferon-alpha; D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D050794:STAT1 Transcription Factor; D000097043:Interleukin-22; C418974:FOXP3 protein, human
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