Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome

Yoshiyuki Minegishi, Masako Saito, Shigeru Tsuchiya, Ikuya Tsuge, Hidetoshi Takada, Toshiro Hara, Nobuaki Kawamura, Tadashi Ariga, Srdjan Pasic, Oliver Stojkovic, Ayse Metin, Hajime Karasuyama

Research output: Contribution to journalArticlepeer-review

699 Citations (Scopus)

Abstract

Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities. Although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported, most cases of HIES are sporadic, and their pathogenesis has remained mysterious for a long time. Here we show that dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES. We found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were found, all of which were located in the STAT3 DNA-binding domain. The patients' peripheral blood cells showed defective responses to cytokines, including interleukin (IL)-6 and IL-10, and the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3. These results highlight the multiple roles played by STAT3 in humans, and underline the critical involvement of multiple cytokine pathways in the pathogenesis of HIES.

Original languageEnglish
Pages (from-to)1058-1062
Number of pages5
JournalNature
Volume448
Issue number7157
DOIs
Publication statusPublished - Aug 30 2007

All Science Journal Classification (ASJC) codes

  • General

Fingerprint Dive into the research topics of 'Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome'. Together they form a unique fingerprint.

Cite this