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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.

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Figure 1: TREX1 mutations alter subcellular targeting.

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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.

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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
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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.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

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

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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

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