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.

  • Brief Communication
  • Published:

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

Nature Genetics volume 39, pages 1065–1067 (2007)Cite this article

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: TREX1 mutations alter subcellular targeting.

Similar content being viewed by others

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

Author notes

  1. Maolian Gong, Dipanjan Chowdhury, Lydia Senenko, Kerstin Engel and Young-Ae Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Klinik für Kinder- und Jugendmedizin, Technische Universität Dresden, Dresden, 01307, Germany

    Min Ae Lee-Kirsch, Lydia Senenko, Kerstin Engel & Manfred Gahr

  2. Max Delbrück Center for Molecular Medicine (MDC), Berlin-Buch, 13125, Germany

    Maolian Gong, Young-Ae Lee, Oliver Hummel, Klaus Rohde & Norbert Hübner

  3. Department of Pediatrics, CBR Institute for Biomedical Research, Harvard Medical School, Boston, 02125, Massachusetts, USA

    Dipanjan Chowdhury & Judy Lieberman

  4. Charité - Universitätsmedizin Berlin, Pediatric Pneumology and Immunology, Campus Virchow-Klinikum, Berlin, 13353, Germany

    Young-Ae Lee

  5. Department of Biochemistry, Center for Structural Biology, Wake Forest University Health Sciences, Winston-Salem, 27157, North Carolina, USA

    Udesh de Silva, Suzanna L Bailey & Thomas Hollis

  6. Medizinische Hochschule Hannover, Klinische Immunologie, Hannover, 30625, Germany

    Torsten Witte & Reinhold E Schmidt

  7. Imperial College, Faculty of Medicine, Section of Rheumatology and Molecular Genetics, Hammersmith Hospital, London, W12 0NN, UK

    Timothy J Vyse & Andrew Wong

  8. Department of Biosciences and Nutrition, Karolinska Institute, and Clinical Research Centre, Huddinge, 14157, Sweden

    Juha Kere

  9. Klinik für Dermatologie, Technische Universität Dresden, Dresden, 01307, Germany

    Christiane Pfeiffer

  10. Department of Biochemistry, Wake Forest University Health Sciences, Winston-Salem, 27157, North Carolina, USA

    Scott Harvey & Fred W Perrino

  11. Department of Medical Genetics, University of Helsinki, Helsinki, 00014, Finland

    Sari Koskenmies

  12. Department of Dermatology, 00014, Helsinki, Finland

    Sari Koskenmies

  13. BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, G12 8TA, UK

    Anna F Dominiczak

Authors
  1. Min Ae Lee-Kirsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maolian Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dipanjan Chowdhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lydia Senenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kerstin Engel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Young-Ae Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Udesh de Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Suzanna L Bailey
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Torsten Witte
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Timothy J Vyse
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Juha Kere
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christiane Pfeiffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Scott Harvey
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Andrew Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Sari Koskenmies
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Oliver Hummel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Klaus Rohde
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Reinhold E Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Anna F Dominiczak
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Manfred Gahr
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Thomas Hollis
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Fred W Perrino
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Judy Lieberman
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Norbert Hübner
    View author publications

    You can also search for this author in PubMed Google Scholar

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

Advanced 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