title: Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome.
abstract: BACKGROUND
  Hyper-IgE syndrome (HIES) is a rare, autosomal-dominant immunodeficiency characterized by eczema, Staphylococcus aureus skin abscesses, pneumonia with pneumatocele formation, Candida infections, and skeletal/connective tissue abnormalities. Recently it was shown that heterozygous signal transducer and activator of transcription 3 (STAT3) mutations cause autosomal-dominant HIES.
  
  
  OBJECTIVE
  To determine the spectrum and functional consequences of heterozygous STAT3 mutations in a cohort of patients with HIES.
  
  
  METHODS
  We sequenced the STAT3 gene in 38 patients with HIES (National Institutes of Health score >40 points) from 35 families, quantified T(H)17 cells in peripheral blood, and evaluated tyrosine phosphorylation of STAT3.
  
  
  RESULTS
  Most STAT3 mutations in our cohort were in the DNA-binding domain (DBD; 22/35 families) or Src homology 2 (SH2) domain (10/35) and were missense mutations. We identified 2 intronic mutations resulting in exon skipping and in-frame deletions within the DBD. In addition, we identified 2 mutations located in the transactivation domain downstream of the SH2 domain: a 10-amino acid deletion and an amino acid substitution. In 1 patient, we were unable to identify a STAT3 mutation. T(H)17 cells were absent or low in the peripheral blood of all patients who were evaluated (n = 17). IL-6-induced STAT3-phosphorylation was consistently reduced in patients with SH2 domain mutations but comparable to normal controls in patients with mutations in the DBD.
  
  
  CONCLUSIONS
  Heterozygous STAT3 mutations were identified in 34 of 35 unrelated HIES families. Patients had impaired T(H)17 cell development, and those with SH2 domain mutations had reduced STAT3 phosphorylation.
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine and Children's Hospital and Regional Medical Center, Seattle, Wash 98101-1304, USA.
authors.forename: Ellen D
authors.initials: ED
authors.lastname: Renner
authors.forename: Stacey
authors.initials: S
authors.lastname: Rylaarsdam
authors.forename: Stephanie
authors.initials: S
authors.lastname: Anover-Sombke
authors.forename: Anita L
authors.initials: AL
authors.lastname: Rack
authors.forename: Janine
authors.initials: J
authors.lastname: Reichenbach
authors.forename: John C
authors.initials: JC
authors.lastname: Carey
authors.forename: Qili
authors.initials: Q
authors.lastname: Zhu
authors.forename: Annette F
authors.initials: AF
authors.lastname: Jansson
authors.forename: Julia
authors.initials: J
authors.lastname: Barboza
authors.forename: Lena F
authors.initials: LF
authors.lastname: Schimke
authors.forename: Mark F
authors.initials: MF
authors.lastname: Leppert
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Getz
authors.forename: Reinhard A
authors.initials: RA
authors.lastname: Seger
authors.forename: Harry R
authors.initials: HR
authors.lastname: Hill
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D007589:Job Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D050796:STAT3 Transcription Factor