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 language | English |
|---|---|
| Pages (from-to) | 1058-1062 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 448 |
| Issue number | 7157 |
| DOIs | |
| Publication status | Published - Aug 30 2007 |
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All Science Journal Classification (ASJC) codes
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Cite this
Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. / Minegishi, Yoshiyuki; Saito, Masako; Tsuchiya, Shigeru; Tsuge, Ikuya; Takada, Hidetoshi; Hara, Toshiro; Kawamura, Nobuaki; Ariga, Tadashi; Pasic, Srdjan; Stojkovic, Oliver; Metin, Ayse; Karasuyama, Hajime.
In: Nature, Vol. 448, No. 7157, 30.08.2007, p. 1058-1062.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome
AU - Minegishi, Yoshiyuki
AU - Saito, Masako
AU - Tsuchiya, Shigeru
AU - Tsuge, Ikuya
AU - Takada, Hidetoshi
AU - Hara, Toshiro
AU - Kawamura, Nobuaki
AU - Ariga, Tadashi
AU - Pasic, Srdjan
AU - Stojkovic, Oliver
AU - Metin, Ayse
AU - Karasuyama, Hajime
PY - 2007/8/30
Y1 - 2007/8/30
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=34548317417&partnerID=8YFLogxK
U2 - 10.1038/nature06096
DO - 10.1038/nature06096
M3 - Article
C2 - 17676033
AN - SCOPUS:34548317417
VL - 448
SP - 1058
EP - 1062
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7157
ER -