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.
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.
Renner
Ellen D
ED
Department of Pediatrics, University of Washington School of Medicine and Children's Hospital and Regional Medical Center, Seattle, Wash 98101-1304, USA.
Rylaarsdam
Stacey
S
Anover-Sombke
Stephanie
S
Rack
Anita L
AL
Reichenbach
Janine
J
Carey
John C
JC
Zhu
Qili
Q
Jansson
Annette F
AF
Barboza
Julia
J
Schimke
Lena F
LF
Leppert
Mark F
MF
Getz
Melissa M
MM
Seger
Reinhard A
RA
Hill
Harry R
HR
Belohradsky
Bernd H
BH
Torgerson
Troy R
TR
Ochs
Hans D
HD
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
D020381:Interleukin-17; D050796:STAT3 Transcription Factor