A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus

摘要: We recently described a novel autosomal-dominant genodermatosis, termed familial chilblain lupus, and mapped its genetic locus to chromosome 3p21. Familial lupus manifests in early childhood with ulcerating acral skin lesions is associated arthralgias circulating antinuclear antibodies. In this study, we report the identification of heterozygous missense mutation (D18N) TREX1 encoding 3'-5'repair exonuclease 1 affected individuals family lupus. The homodimeric most abundant intracellular DNase mammalian cells. have shown that plays role apoptotic single-stranded DNA damage induced by killer lymphocyte protease granzyme A. D18N affects highly conserved amino acid residue critical for catalytic activity. Recombinant mutant homodimers are enzymatically inactive, while wild type/mutant heterodimers show residual exonucleolytic activity, suggesting loss function. Lymphoblastoid cells carrying significantly less sensitive A-mediated cell death, caspase-independent form apoptosis pathogenesis Our findings also warrant further investigation common forms erythematosus.