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

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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.

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Figure 1: Impaired responses to IL-6 and IL-10 in HIES patients’ cells.
Figure 2: Heterozygous mutations in the DNA-binding domain of STAT3 from eight HIES patients.
Figure 3: Diminished DNA-binding activity of STAT3 in the HIES patients’ cells.
Figure 4: Loss-of-function and dominant-negative effect of the STAT3 mutants in cytokine signals.

Change history

  • 30 August 2007

    The AOP version of this Letter was originally incorrectly set as an Article.


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We appreciate the willingness of the patients and the families to participate in this research study. This work is supported by the Japanese Ministry of Education, Culture, Sports, Science and Technology, and the Japanese Ministry of Health, Labor and Welfare.

Author Contributions Y.M. designed and conducted most of the experiments; M.S. conducted the genetic analysis and the generation of osteoclasts; S.T., I.T., H.T., T.H., N.K., T.A., S.P. and A.M. diagnosed and collected samples; O.S. collected samples; H.K. oversaw the entire project; Y.M. and H.K. wrote the manuscript with comments from all co-authors.

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Correspondence to Yoshiyuki Minegishi.

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Minegishi, Y., Saito, M., Tsuchiya, S. et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448, 1058–1062 (2007).

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