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


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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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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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.

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Correspondence to Min Ae Lee-Kirsch or Norbert Hübner.

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The authors declare no competing financial interests.

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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).

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