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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Mazur, D.J. & Perrino, F.W. J. Biol. Chem. 274, 19655–19660 (1999).
Chowdhury, D. et al. Mol. Cell 23, 133–142 (2006).
Crow, Y.J. et al. Nat. Genet. 38, 917–920 (2006).
Rice, G. et al. Am. J. Hum. Genet. 80, 811–815 (2007).
Morita, M. et al. Mol. Cell. Biol. 24, 6719–6727 (2004).
Laan, M. & Paabo, S. Nat. Genet. 17, 435–438 (1997).
Boe, S.O. et al. J. Cell Sci. 119, 3284–3295 (2006).
Regad, T. & Chelbi-Alix, M.K. Oncogene 20, 7274–7286 (2001).
de Silva, U. et al. J. Biol. Chem. 282, 10537–10543 (2007).
Mendell, J.T. & Dietz, H.C. Cell 107, 411–414 (2001).
James, J.A., Harley, J.B. & Scofield, R.H. Curr. Opin. Rheumatol. 13, 370–376 (2001).
Stetson, D.B. & Medzhitov, R. Immunity 24, 93–103 (2006).
Napirei, M. et al. Nat. Genet. 25, 177–181 (2000).
Yasutomo, K. et al. Nat. Genet. 28, 313–314 (2001).
Kawane, K. et al. Nature 443, 998–1002 (2006).
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
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
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
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng2091
This article is cited by
-
Deficiency of Trex1 leads to spontaneous development of type 1 diabetes
Nutrition & Metabolism (2024)
-
Disulfiram ameliorates STING/MITA-dependent inflammation and autoimmunity by targeting RNF115
Cellular & Molecular Immunology (2024)
-
Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release
Nature Communications (2024)
-
Genetics of SLE: mechanistic insights from monogenic disease and disease-associated variants
Nature Reviews Nephrology (2023)
-
RBP–RNA interactions in the control of autoimmunity and autoinflammation
Cell Research (2023)