The TREX1 Double-stranded DNA Degradation Activity Is Defective in Dominant Mutations Associated with Autoimmune Disease

Mutations in TREX1 have been linked to a spectrum of human autoimmune diseases including Aicardi-Goutieres syndrome (AGS), familial chilblain lupus (FCL), systemic lupus erythematosus, and retinal vasculopathy and cerebral leukodystrophy. A common feature in these conditions is the frequent detection of antibodies to double-stranded DNA (dsDNA). TREX1 participates in a cell death process implicating this major 3' -> 5' exonuclease in genomic DNA degradation to minimize potential immune activation by persistent self DNA. The TREX1 D200N and D18N dominant heterozygous mutations were identified in AGS and FCL, respectively. TREX1 enzymes containing the D200N and D18N mutations were compared using nicked dsDNA and single-stranded DNA (ssDNA) degradation assays. The TREX1(WT/D200N) and TREX1(WT/D18N) heterodimers are completely deficient at degrading dsDNA and degrade ssDNA at an expected similar to 2-fold lower rate than TREX1WT enzyme. Further, the D200N- and D18N-containing TREX1 homo-and heterodimers inhibit the dsDNA degradation activity of TREX1(WT) enzyme, providing a likely explanation for the dominant phenotype of these TREX1 mutant alleles in AGS and FCL. By comparison, the TREX1 R114H homozygous mutation causes AGS and is found as a heterozygous mutation in systemic lupus erythematosus. The TREX1(R114H/R114H) homodimer has dysfunctional dsDNA and ssDNA degradation activities and does not detectibly inhibit the TREX1(WT) enzyme, whereas the TREX1(WT/R114H) heterodimer has a functional dsDNA degradation activity, supporting the recessive genetics of TREX1 R114H in AGS. The dysfunctional dsDNA degradation activities of these disease-related TREX1 mutants could account for persistent dsDNA from dying cells leading to an aberrant immune response in these clinically related disorders.