Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T_H17 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_H17 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_H17 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. Conclusion: Heterozygous STAT3 mutations were identified in 34 of 35 unrelated HIES families. Patients had impaired T_H17 cell development, and those with SH2 domain mutations had reduced STAT3 phosphorylation.