Background/Purpose: An increased expression of type I interferon regulated genes (IFN signature) has been reported in patients (pts) with Systemic Lupus Erythematosus (SLE) and it is involved in the pathogenesis of the disease. Raised level of IFN-α in the cerebral spinal fluid are found in pts with Aicardi-Goutières syndrome (AGS), a rare genetic encephalopathy characterized by calcification of basal ganglia, abnormalities in white matter and chronic cerebrospinal fluid lymphocytosis. One of AGS-causing mutations is located in the Trex1 gene chromosome3. Subsequent studies demonstrated that up to 2% of pts with SLE had pathogenic mutations in Trex1. The enzymatic function of TREX1protein is still not clear, but 3′ Repair exonuclease (Trex1) is the most abundant mammalian 3′->5′ DNA exonuclease with specificity for ssDNA. The loss or reduction of Trex1 activity may result in the accumulation of double-stranded DNA degradation intermediates that could trigger autoimmune activation. A recent study(1) described significant associations between a risk haplotype made by common single nucleotide polymorphisms (SNPs) of Trex1 and closely linked ATRIP gene in European SLE pts with neurologic manifestations, especially seizures

Methods: 51 SLE pts were screened for Trex1 gene. Genomic DNA was extracted by automatic extraction and stored at -20°C. Trex1 gene was amplified and automatically sequenced (Genetic Analyzer 3130xl, Applied Biosystems). Each fragment was sequenced on both strands. Alignments were viewed using Sequencher 4.8. PolyPhen2 pathogenicity prediction software was used to determine possible pathogenic significance of the not previously described mutation. NM_033629.2 (isoform b-short isoform) was used to report novel variation. Clinical and serological data were collected from clinical charts.

Results: A novel heterozygous variant (NP_338599.1 p.Asp130Asn) was identified in one patient affected by SLE. Trex1 missense variation was classified as probably damaging by PolyPhen2 (score 1/1). This change was absent in 150 control samples sequenced. We also reported mutations of SNP rs11797 in 33 pts and the rs3135944 variation in only 1 patient. We searched for clinical or serological differences among pts with the wildtype rs11797 and the pts with the mutations. No significant  associations were found.  We reported a high prevalence of neuroSLE manifestations in pts who had rs11797 mutations: among the 8 pts who had clinical features of neuroSLE, 1 was homozygous for the major allele, 2 had heterozygous mutations for these SNP and 5 had homozygous mutations. The distribution of mutations of rs11797 were similar between pts and controls, but the homozygous mutations of rs11797 was significantly more frequent in the pts with neuroSLE than in the controls (p=0,00013;OR=11,5).

Conclusion: Although we analyzed a small number of SLE patients, we found a probably novel pathogenic variation (1,96% of pts) of TREX1. Homozygous mutations of rs11797 was significant more frequent in SLE patients with neurologic manifestations than in controls.

(1)Namjou B, Kothari P.H, Kelly J.A. et al. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort; Genes Immun. 2011;12(4):270-9

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/typing-trex1-gene-in-patients-with-systemic-lupus-erythematosus/