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

Abstract

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.

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

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.

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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.

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

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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.

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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). https://doi.org/10.1038/ng.3040

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