title: A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus.
abstract: 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.
authors: Klinik für Kinder-und Jugendmedizin, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany. minae.lee-kirsch@uniklinikum-dresden.de
authors: Min Ae
authors: MA
authors: Lee-Kirsch
authors: Dipanjan
authors: D
authors: Chowdhury
authors: Scott
authors: S
authors: Harvey
authors: Maoliang
authors: M
authors: Gong
authors: Lydia
authors: L
authors: Senenko
authors: Kerstin
authors: K
authors: Engel
authors: Christiane
authors: C
authors: Pfeiffer
authors: Thomas
authors: T
authors: Hollis
authors: Manfred
authors: M
authors: Gahr
authors: Fred W
authors: FW
authors: Perrino
authors: Judy
authors: J
authors: Lieberman
authors: Norbert
authors: N
authors: Hubner
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004252:DNA Mutational Analysis; D019281:Dimerization; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D053804:Granzymes / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D054353:Perforin; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012307:Risk Factors
chemical_list: D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D052899:Pore Forming Cytotoxic Proteins; D011994:Recombinant Proteins; D054353:Perforin; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1; D053804:Granzymes