title: STAT3 mutations in the hyper-IgE syndrome.
abstract: BACKGROUND
  The hyper-IgE syndrome (or Job's syndrome) is a rare disorder of immunity and connective tissue characterized by dermatitis, boils, cyst-forming pneumonias, elevated serum IgE levels, retained primary dentition, and bone abnormalities. Inheritance is autosomal dominant; sporadic cases are also found.
  
  
  METHODS
  We collected longitudinal clinical data on patients with the hyper-IgE syndrome and their families and assayed the levels of cytokines secreted by stimulated leukocytes and the gene expression in resting and stimulated cells. These data implicated the signal transducer and activator of transcription 3 gene (STAT3) as a candidate gene, which we then sequenced.
  
  
  RESULTS
  We found increased levels of proinflammatory gene transcripts in unstimulated peripheral-blood neutrophils and mononuclear cells from patients with the hyper-IgE syndrome, as compared with levels in control cells. In vitro cultures of mononuclear cells from patients that were stimulated with lipopolysaccharide, with or without interferon-gamma, had higher tumor necrosis factor alpha levels than did identically treated cells from unaffected persons (P=0.003). In contrast, the cells from patients with the hyper-IgE syndrome generated lower levels of monocyte chemoattractant protein 1 in response to the presence of interleukin-6 (P=0.03), suggesting a defect in interleukin-6 signaling through its downstream mediators, one of which is STAT3. We identified missense mutations and single-codon in-frame deletions in STAT3 in 50 familial and sporadic cases of the hyper-IgE syndrome. Eighteen discrete mutations, five of which were hot spots, were predicted to directly affect the DNA-binding and SRC homology 2 (SH2) domains.
  
  
  CONCLUSIONS
  Mutations in STAT3 underlie sporadic and dominant forms of the hyper-IgE syndrome, an immunodeficiency syndrome involving increased innate immune response, recurrent infections, and complex somatic features.
authors: National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. smh@nih.gov
authors: Steven M
authors: SM
authors: Holland
authors: Frank R
authors: FR
authors: DeLeo
authors: Houda Z
authors: HZ
authors: Elloumi
authors: Amy P
authors: AP
authors: Hsu
authors: Gulbu
authors: G
authors: Uzel
authors: Nina
authors: N
authors: Brodsky
authors: Alexandra F
authors: AF
authors: Freeman
authors: Andrew
authors: A
authors: Demidowich
authors: Joie
authors: J
authors: Davis
authors: Maria L
authors: ML
authors: Turner
authors: Victoria L
authors: VL
authors: Anderson
authors: Dirk N
authors: DN
authors: Darnell
authors: Pamela A
authors: PA
authors: Welch
authors: Douglas B
authors: DB
authors: Kuhns
authors: David M
authors: DM
authors: Frucht
authors: Harry L
authors: HL
authors: Malech
authors: John I
authors: JI
authors: Gallin
authors: Scott D
authors: SD
authors: Kobayashi
authors: Adeline R
authors: AR
authors: Whitney
authors: Jovanka M
authors: JM
authors: Voyich
authors: James M
authors: JM
authors: Musser
authors: Cristina
authors: C
authors: Woellner
authors: Alejandro A
authors: AA
authors: Schäffer
authors: Jennifer M
authors: JM
authors: Puck
authors: Bodo
authors: B
authors: Grimbacher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016207:Cytokines / Q000097:blood; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D007589:Job Syndrome / Q000235:genetics*; D007962:Leukocytes / Q000276:immunology; D008297:Male; D020125:Mutation, Missense; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D050796:STAT3 Transcription Factor / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human