A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus.
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.
Lee-Kirsch
Min Ae
MA
Klinik für Kinder-und Jugendmedizin, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany. minae.lee-kirsch@uniklinikum-dresden.de
Chowdhury
Dipanjan
D
Harvey
Scott
S
Gong
Maoliang
M
Senenko
Lydia
L
Engel
Kerstin
K
Pfeiffer
Christiane
C
Hollis
Thomas
T
Gahr
Manfred
M
Perrino
Fred W
FW
Lieberman
Judy
J
Hubner
Norbert
N
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
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