Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease


Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Activating STAT3 mutations cause early-onset autoimmune disease.
Figure 2

Accession codes


NCBI Reference Sequence


  1. Barrett, J.C. et al. Nat. Genet. 41, 703–707 (2009).

    Article  CAS  Google Scholar 

  2. Barrett, J.C. et al. Nat. Genet. 40, 955–962 (2008).

    Article  CAS  Google Scholar 

  3. Stahl, E.A. et al. Nat. Genet. 42, 508–514 (2010).

    Article  CAS  Google Scholar 

  4. Bennett, C.L. et al. Nat. Genet. 27, 20–21 (2001).

    Article  CAS  Google Scholar 

  5. Finnish-German APECED Consortium. Nat. Genet. 17, 399–403 (1997).

  6. Sharfe, N. et al. Proc. Natl. Acad. Sci. USA 94, 3168–3171 (1997).

    Article  CAS  Google Scholar 

  7. Rubio-Cabezas, O. et al. Diabetes Care 32, 111–116 (2009).

    Article  CAS  Google Scholar 

  8. Koskela, H.L. et al. N. Engl. J. Med. 366, 1905–1913 (2012).

    Article  CAS  Google Scholar 

  9. Yang, X.O. et al. J. Biol. Chem. 282, 9358–9363 (2007).

    Article  CAS  Google Scholar 

  10. Harris, T.J. et al. J. Immunol. 179, 4313–4317 (2007).

    Article  CAS  Google Scholar 

  11. Shao, S. et al. Cell. Immunol. 280, 16–21 (2012).

    Article  CAS  Google Scholar 

  12. Ma, C.S. et al. J. Exp. Med. 205, 1551–1557 (2008).

    Article  CAS  Google Scholar 

  13. Minegishi, Y. et al. Nature 448, 1058–1062 (2007).

    Article  CAS  Google Scholar 

  14. Pilati, C. et al. J. Exp. Med. 208, 1359–1366 (2011).

    Article  CAS  Google Scholar 

  15. Tsoi, L.C. et al. Nat. Genet. 44, 1341–1348 (2012).

    Article  CAS  Google Scholar 

  16. Jakkula, E. et al. Am. J. Hum. Genet. 86, 285–291 (2010).

    Article  CAS  Google Scholar 

  17. Fung, E.Y. et al. Genes Immun. 10, 188–191 (2009).

    Article  CAS  Google Scholar 

  18. Seddighzadeh, M. et al. J. Rheumatol. 39, 1509–1516 (2012).

    Article  CAS  Google Scholar 

  19. Levy, D.E. & Darnell, J.E. Jr. Nat. Rev. Mol. Cell Biol. 3, 651–662 (2002).

    Article  CAS  Google Scholar 

  20. Holland, S.M. et al. N. Engl. J. Med. 357, 1608–1619 (2007).

    Article  CAS  Google Scholar 

  21. Heimall, J. et al. Clin. Immunol. 139, 75–84 (2011).

    Article  CAS  Google Scholar 

  22. Lango Allen, H. et al. Nat. Genet. 44, 20–22 (2012).

    Article  Google Scholar 

  23. Ellard, S. et al. Diabetologia 56, 1958–1963 (2013).

    Article  CAS  Google Scholar 

  24. Russell, M.A. et al. Islets 5, 95–105 (2013).

    Article  Google Scholar 

Download references


We thank J. Chilton, A. Damhuis, R. Raman and B. Yang for technical assistance. This work was supported by the UK National Institute for Health Research (NIHR) Exeter Clinical Research Facility through funding for S.E. and A.T.H. A.T.H. is an NIHR Senior Investigator. S.E. and A.T.H. are supported by Wellcome Trust Senior Investigator awards. Further funding was provided by Diabetes UK and the Finnish Medical Foundation.

Author information

Authors and Affiliations



S.E.F., S.E. and A.T.H. designed the study. N.P.M., T.M., T.O., E.H., K.H., T.H.-K., M.K., A.R., A.L. and J.B. recruited subjects to the study. R.C. and E.D.F. performed the exome sequencing and targeted next-generation sequence analysis. H.L.A. performed the bioinformatics analysis. S.E.F. and E.H. performed the Sanger sequencing analysis and the interpretation of the resulting data. S.E.F., T.J.M., E.H., M.S., J.K. and A.T.H. analyzed the clinical data. M.A.R. and N.G.M. designed and performed the functional studies. H.R. and S.M. performed the T cell assays. S.E.F., M.A.R. and A.T.H. prepared the draft manuscript. All authors contributed to discussion of the results and to manuscript preparation.

Corresponding authors

Correspondence to Juha Kere, Noel G Morgan or Andrew T Hattersley.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 STAT3 expression in HEK293 cells

Western blot showing the expression of STAT3 protein in HEK293 cells transfected with STAT3 constructs. HEK293 cells were lysed, and protein extracts were probed with anti-STAT3 antibody. β-actin was used as a loading control. The experiment was repeated twice with similar results.

Supplementary Figure 2 Genotype-phenotype relationship in STAT3 alterations.

The predicted effects of the STAT3 alterations were modeled in PDB structure 1BG1 (mouse STAT3/DNA complex) using SWISS-MODEL and visualized in the Swiss-PdbViewer. (a) Overview of the STAT3 dimer bound to DNA; STAT3 chains are shown in ribbon form, with residues N646 (red) and N647 (green) shown as space-filling residues on the left chain only; DNA strands are shown as blue and turquoise ribbons. (b) As in a, but expanded to show the proximity of residues N646 and N647 to both the DNA-binding and dimerization surfaces. (c) Predicted molecular surfaces of wild-type STAT3 (wt) and mutants N646K, N647D and N647I; surfaces are colored for positive charge (blue; top row), negative charge (red; middle row) and hydrophobicity (brown (most polar) to blue (most hydrophobic); bottom row); structures have been rotated compared to in a and b to show relevant groups more clearly. The N646K alteration reported here results in increased positive charge (circled, N646K column, upper row) at the DNA-binding surface; this is likely to result in higher DNA binding affinity due to electrostatic interaction with the DNA backbone and, hence, increased STAT3 activity. Conversely, the N647D substitution, previously reported as a loss-of-function alteration in HIES, leads to increased negative surface charge in this region (circled, N647D column, middle row) and is likely to inhibit DNA binding and/or dimerization. By comparison, a different substitution at this position, N647I, has been previously reported as an activating alteration in LGLL; it has been postulated that STAT3 mutations in LGLL promote STAT3 dimerization and, hence, biological activity, as a result of increased hydrophobicity at the dimerization surface. This is consistent with protein modeling in silico, which predicts increased hydrophobicity in this region (circled, N646I column, bottom row) compared to wild-type STAT3 or other variants.

Supplementary Figure 3 Increased basal STAT3 activity in vitro.

The intracellular expression of IFN-γ and TNF-α was measured from unstimulated and stimulated (anti-CD3, anti-CD28, anti-CD49d) CD4+ and CD8+ T cells after 6-h incubation using flow cytometry. Samples were available from six healthy controls and two patients (patient 3 (p.K392R) and patient 5 (p.K658N)). In all analyzed cases, the expression of IFN-γ/TNF-α was under 1% in unstimulated cells. The median percentage of stimulated cytokine-producing CD4+ and CD8+ cells was 8.0% and 12%, respectively, among healthy controls (data of one control shown). CD4+ cells from patient 2 showed increased cytokine production when stimulated. IFN, interferon; TCR, T cell receptor; TNF, tumor necrosis factor.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Tables 1–6. (PDF 1455 kb)

Source data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Flanagan, S., Haapaniemi, E., Russell, M. et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet 46, 812–814 (2014).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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