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 and Hajime Karasuyama
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Yoshiyuki Minegishi: Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan
Masako Saito: Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan
Shigeru Tsuchiya: Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
Ikuya Tsuge: Fujita Health University, Aichi 470-1192, Japan
Hidetoshi Takada: Kyushu University, Fukuoka 812-8582, Japan
Toshiro Hara: Kyushu University, Fukuoka 812-8582, Japan
Nobuaki Kawamura: Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
Tadashi Ariga: Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
Srdjan Pasic: Pediatric Immunology, Mother and Child Health Institute, Belgrade 110 70, Serbia
Oliver Stojkovic: Laboratory for Forensic Genetics, Institute of Forensic Medicine, University of Belgrade, Belgrade 110 70, Serbia
Ayse Metin: SB Ankara Diskapi Children's Hospital, Ankara 06110, Turkey
Hajime Karasuyama: Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan

Nature, 2007, vol. 448, issue 7157, 1058-1062

Abstract: 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 abnormalities1. 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.

Date: 2007
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DOI: 10.1038/nature06096

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