Chilblain Lupus
In affected members of the large 5-generation German family with chilblain lupus (CHBL1; 610448) described by Lee-Kirsch et al. (2006), Lee-Kirsch et al. (2007) identified heterozygosity for a 52G-A transition in exon 1 of the TREX1 gene, resulting in an asp18-to-asn (D18N) substitution at a highly conserved residue critical for catalytic activity. The mutation was not found in unaffected family members or in 400 control chromosomes. Recombinant mutant TREX1 homodimers were enzymatically inactive, whereas mutant/wildtype heterodimers had approximately 40% of the activity of wildtype dimers, indicating that D18N is a loss-of-function allele that does not exhibit a dominant-negative effect. Compared to control cells, patient-derived lymphoblastoid cells were substantially less sensitive to cell death after treatment with granzyme A (GZMA; 140050) but not granzyme B (GZMB; 123910), indicating that D18N specifically interferes with GZMA-mediated cell death in the caspase-independent form of apoptosis.
Aicardi-Goutieres Syndrome 1
In a 16-year-old girl with relatively mild Aicardi-Goutieres syndrome (AGS1; 225750), who was negative for mutation in other known AGS genes, Haaxma et al. (2010) identified a de novo heterozygous D18N missense mutation in the TREX1 gene. The mutation was not found in either parent or in 200 control chromosomes. The patient also displayed features of mitochondrial disease, with cytochrome oxidase-negative and ragged-red fibers seen on histologic examination of the quadriceps muscle; biochemical measurements showed decreased overall energy production (ATP and CrP) in the presence of normal activities of individual respiratory chain complexes, again compatible with mitochondrial dysfunction. However, heteroduplex analysis of the entire mitochondrial DNA did not show any mutations. This patient also had peripheral neuropathy with prominent axonal loss and disturbances of myelination without strict demyelination.
Fye et al. (2011) stated that asp18 and asp200 are the 2 aspartates that coordinate the divalent metal ion Mg(2+) at the TREX1 active site and contribute to DNA binding and catalysis. They found that homodimers of recombinant human TREX1 containing D200N (606609.0006) or D18N mutations had negligible nuclease activity against ssDNA and dsDNA compared with wildtype. Heterodimers of wildtype TREX1 with D18N or D200N TREX1 mutants had more modestly reduced ssDNA nuclease activity, but profoundly reduced dsDNA nuclease activity, compared with wildtype homodimers. Fye et al. (2011) concluded that the dominant phenotypes of asp18 and asp200 mutations relates predominantly to impaired dsDNA degradation and indicates that TREX1 dsDNA degradation activity is fundamental to the prevention of autoimmunity.
