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

This article has been updated

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Grimbacher, B., Holland, S. M. & Puck, J. M. Hyper-IgE syndromes. Immunol. Rev. 203, 244–250 (2005)

    CAS  Article  Google Scholar 

  2. 2

    Gould, H. J. et al. The biology of IGE and the basis of allergic disease. Annu. Rev. Immunol. 21, 579–628 (2003)

    CAS  Article  Google Scholar 

  3. 3

    Grimbacher, B., Belohradsky, B. H. & Holland, S. M. Immunoglobulin E in primary immunodeficiency diseases. Allergy 57, 995–1007 (2002)

    CAS  Article  Google Scholar 

  4. 4

    Davis, S. D., Schaller, J. & Wedgwood, R. J. Job's Syndrome. Recurrent, “cold”, staphylococcal abscesses. Lancet 1, 1013–1015 (1966)

    CAS  Article  Google Scholar 

  5. 5

    Buckley, R. H., Wray, B. B. & Belmaker, E. Z. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics 49, 59–70 (1972)

    CAS  PubMed  Google Scholar 

  6. 6

    Grimbacher, B. et al. Hyper-IgE syndrome with recurrent infections—an autosomal dominant multisystem disorder. N. Engl. J. Med. 340, 692–702 (1999)

    CAS  Article  Google Scholar 

  7. 7

    Renner, E. D. et al. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J. Pediatr. 144, 93–99 (2004)

    CAS  Article  Google Scholar 

  8. 8

    Minegishi, Y. et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25, 745–755 (2006)

    CAS  Article  Google Scholar 

  9. 9

    Schindler, C. & Darnell, J. E. Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu. Rev. Biochem. 64, 621–651 (1995)

    CAS  Article  Google Scholar 

  10. 10

    Ihle, J. N. Cytokine receptor signalling. Nature 377, 591–594 (1995)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Levy, D. E. & Darnell, J. E. STATs: transcriptional control and biological impact. Nature Rev. Mol. Cell Biol. 3, 651–662 (2002)

    CAS  Article  Google Scholar 

  12. 12

    Kisseleva, T., Bhattacharya, S., Braunstein, J. & Schindler, C. W. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285, 1–24 (2002)

    CAS  Article  Google Scholar 

  13. 13

    Grimbacher, B. et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am. J. Hum. Genet. 65, 735–744 (1999)

    CAS  Article  Google Scholar 

  14. 14

    Horvath, C. M., Wen, Z. & Darnell, J. E. A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. Genes Dev. 9, 984–994 (1995)

    CAS  Article  Google Scholar 

  15. 15

    Chapgier, A. et al. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease. PLoS Genet. 2, e131 (2006)

    Article  Google Scholar 

  16. 16

    Takeda, K. et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl Acad. Sci. USA 94, 3801–3804 (1997)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Darnell, J. E. STATs and gene regulation. Science 277, 1630–1635 (1997)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Levy, D. E. & Lee, C. K. What does Stat3 do? J. Clin. Invest. 109, 1143–1148 (2002)

    CAS  Article  Google Scholar 

  19. 19

    O'Brien, C. A., Gubrij, I., Lin, S. C., Saylors, R. L. & Manolagas, S. C. STAT3 activation in stromal/osteoblastic cells is required for induction of the receptor activator of NF-κB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D3 or parathyroid hormone. J. Biol. Chem. 274, 19301–19308 (1999)

    CAS  Article  Google Scholar 

  20. 20

    Itoh, S. et al. A critical role for interleukin-6 family-mediated Stat3 activation in osteoblast differentiation and bone formation. Bone 39, 505–512 (2006)

    CAS  Article  Google Scholar 

  21. 21

    Akira, S. et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77, 63–71 (1994)

    CAS  Article  Google Scholar 

  22. 22

    Zhong, Z., Wen, Z. & Darnell, J. E. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264, 95–98 (1994)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Li, W., Liang, X., Kellendonk, C., Poli, V. & Taub, R. STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration. J. Biol. Chem. 277, 28411–28417 (2002)

    CAS  Article  Google Scholar 

  24. 24

    Robinson, D. S., Larche, M. & Durham, S. R. Tregs and allergic disease. J. Clin. Invest. 114, 1389–1397 (2004)

    CAS  Article  Google Scholar 

  25. 25

    Yang, X. O. et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 282, 9358–9363 (2007)

    CAS  Article  Google Scholar 

  26. 26

    Happel, K. I. et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J. Exp. Med. 202, 761–769 (2005)

    CAS  Article  Google Scholar 

  27. 27

    Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004)

    CAS  Article  Google Scholar 

  28. 28

    Minegishi, Y. & Conley, M. E. Negative selection at the pre-BCR checkpoint elicited by human μ heavy chains with unusual CDR3 regions. Immunity 14, 631–641 (2001)

    CAS  Article  Google Scholar 

  29. 29

    Minegishi, Y. et al. Mutations in Igα (CD79a) result in a complete block in B-cell development. J. Clin. Invest. 104, 1115–1121 (1999)

    CAS  Article  Google Scholar 

  30. 30

    Minegishi, Y. et al. An essential role for BLNK in human B cell development. Science 286, 1954–1957 (1999)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yoshiyuki Minegishi.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figure S1 with Legend and Supplementary Table S1. (PDF 326 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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). https://doi.org/10.1038/nature06096

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing