A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus
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We recently described a novel autosomal-dominant genodermatosis, termed familial chilblain lupus, and mapped its genetic locus to chromosome 3p21. Familial chilblain lupus manifests in early childhood with ulcerating acral skin lesions and is associated with arthralgias and circulating antinuclear antibodies. In this study, we report the identification of a heterozygous missense mutation (D18N) in TREX1 encoding the 3′-5′repair exonuclease 1 in affected individuals of the family with chilblain lupus. The homodimeric TREX1 is the most abundant intracellular DNase in mammalian cells. We have recently shown that TREX1 plays a role in apoptotic single-stranded DNA damage induced by the killer lymphocyte protease granzyme A. D18N affects a highly conserved amino acid residue critical for catalytic activity. Recombinant mutant TREX1 homodimers are enzymatically inactive, while wild type/mutant heterodimers show residual exonucleolytic activity, suggesting a heterozygous loss of function. Lymphoblastoid cells carrying the D18N mutation are significantly less sensitive to granzyme A-mediated cell death, suggesting a novel role for this caspase-independent form of apoptosis in the pathogenesis of familial chilblain lupus. Our findings also warrant further investigation of TREX1 in common forms of lupus erythematosus.
KeywordsFamilial chilblain lupus Systemic lupus erythematosus TREX1 Genetics Apoptosis Autoimmune disease
We thank the members of the family for their participation in this study. We thank Maja Linné for clinical assistance and Angela Rösen-Wolff and Joachim Rösler for helpful discussions. This work was supported by a Marie Curie Development Host Fellowship from the European Commission to M.L.-K., US grant GM069962 from the NIH to F.W.P., US grant AI45587 from the NIH to J.L., and a grant-in-aid from the National Genome Research Network (NGFN2) of the German Ministry of Science and Education (BMBF) to N.H.
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