Skip to main content

Thank you for visiting nature.com. 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.

Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus

Abstract

TREX1 acts in concert with the SET complex in granzyme A–mediated apoptosis, and mutations in TREX1 cause Aicardi-Goutières syndrome and familial chilblain lupus. Here, we report monoallelic frameshift or missense mutations and one 3′ UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls (P = 4.1 × 10−7). We demonstrate that two mutant TREX1 alleles alter subcellular targeting. Our findings implicate TREX1 in the pathogenesis of SLE.

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.

$32.00

All prices are NET prices.

Figure 1: TREX1 mutations alter subcellular targeting.

References

  1. Mazur, D.J. & Perrino, F.W. J. Biol. Chem. 274, 19655–19660 (1999).

    Article  CAS  Google Scholar 

  2. Chowdhury, D. et al. Mol. Cell 23, 133–142 (2006).

    Article  CAS  Google Scholar 

  3. Crow, Y.J. et al. Nat. Genet. 38, 917–920 (2006).

    Article  CAS  Google Scholar 

  4. Rice, G. et al. Am. J. Hum. Genet. 80, 811–815 (2007).

    Article  CAS  Google Scholar 

  5. Morita, M. et al. Mol. Cell. Biol. 24, 6719–6727 (2004).

    Article  CAS  Google Scholar 

  6. Laan, M. & Paabo, S. Nat. Genet. 17, 435–438 (1997).

    Article  CAS  Google Scholar 

  7. Boe, S.O. et al. J. Cell Sci. 119, 3284–3295 (2006).

    Article  Google Scholar 

  8. Regad, T. & Chelbi-Alix, M.K. Oncogene 20, 7274–7286 (2001).

    Article  CAS  Google Scholar 

  9. de Silva, U. et al. J. Biol. Chem. 282, 10537–10543 (2007).

    Article  CAS  Google Scholar 

  10. Mendell, J.T. & Dietz, H.C. Cell 107, 411–414 (2001).

    Article  CAS  Google Scholar 

  11. James, J.A., Harley, J.B. & Scofield, R.H. Curr. Opin. Rheumatol. 13, 370–376 (2001).

    Article  CAS  Google Scholar 

  12. Stetson, D.B. & Medzhitov, R. Immunity 24, 93–103 (2006).

    Article  CAS  Google Scholar 

  13. Napirei, M. et al. Nat. Genet. 25, 177–181 (2000).

    Article  CAS  Google Scholar 

  14. Yasutomo, K. et al. Nat. Genet. 28, 313–314 (2001).

    Article  CAS  Google Scholar 

  15. Kawane, K. et al. Nature 443, 998–1002 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all subjects for participation in this study. We thank W.L. Gross, E. Gromnica-Ihle, H.-H. Peter, S. Schnarr and M. Linné for clinical assistance. We acknowledge technical assistance of C. Flachmeier, M. Schwarz and A. Müller. We thank M. Weber at the Technische Universität Dresden confocal microscopy core facility. We thank M.T. Pisabarro, K. Köhler, M.C. Cardoso and F.C. Luft for helpful discussions and comments. This work was supported by a Marie Curie Development Host Fellowship from the European Commission to M.A.L.-K., a grant from the German Ministry of Science and Education (BMBF Kompetenznetz Rheuma C2.12) to T.W., US National Institutes of Health (NIH) grant AI45587 to J.L., NIH grant GM069962 to F.W.P. and a grant-in-aid from the National Genome Research Network (NGFN2) of the German Ministry of Science and Education (BMBF) to Y.-A.L. and N.H.

Author information

Authors and Affiliations

Authors

Contributions

M.A.L.-K. developed the project. M.A.L.-K. and N.H. codirected the project. M.G., K.E., L.S., Y.-A.L. and O.H. performed mutation screening. F.W.P., U.d.S., S.L.B., S.H. and T.H. generated bacterial expression constructs, performed biochemical analysis of recombinant TREX1 and generated the structural model of TREX1. L.S. and K.E. generated mammalian expression constructs and performed transfection and immune histochemistry. D.C. and J.L. performed studies on granzyme A–mediated apoptosis. T.J.V., A.W., J.K., S.K., T.W., R.E.S., A.F.D., M.G. and C.P. contributed individuals with SLE or controls. K.R. performed statistical analysis. M.A.L.-K. wrote the paper with J.L. and N.H.

Corresponding authors

Correspondence to Min Ae Lee-Kirsch or Norbert Hübner.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–2, Supplementary Figures 1–3, Supplementary Methods (PDF 200 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lee-Kirsch, M., Gong, M., Chowdhury, D. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 39, 1065–1067 (2007). https://doi.org/10.1038/ng2091

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng2091

This article is cited by

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