Typing TREX1 gene in patients with systemic lupus erythematosus

Abstract

An impaired expression of interferon-α regulated genes has been reported in patients with either systemic lupus erythematosus (SLE) or Aicardi-Goutières syndrome (AGS), a rare monogenic encephalopathy with onset in infancy. One of mutations causing AGS is located in the TREX1 gene on chromosome 3. Heterozygous mutations in TREX1 were reported in SLE patients. TREX1 is a DNA exonuclease with specificity for ssDNA. An impairment of its activity may result in the accumulation of nucleid acid. A recent study described a significant association between a haplotype including several common single nucleotide polymorphisms (SNPs) of TREX1 and neurological manifestations in European SLE patients. Fifty-one SLE patients were screened for TREX1 gene, and the corresponding data were collected from clinical charts. A novel heterozygous variant (p.Asp130Asn) was identified in one patient and in none of 150 controls. A missense variation was located in one of the three active sites of the gene and was classified as probably damaging. Variations of SNP rs11797 were detected in 33 SLE patients and a variation of rs3135944 in one. A significantly higher rate of the minor allele (T nucleotide) of SNP rs11797 was found in SLE patients with neuropsychiatric manifestations [12/16 (75%) vs 28/86 (32.5%) O=0.002, odds ratio=6.42 95% confidence interval (1.7-26.2)]. Only 1 out of 8 patients (12.5%) with neuropsychiatric SLE carried the wild-type form in homozygosity. Although we analyzed a small number of patients, we found a novel variation of TREX1, which may be pathogenic. The polymorphism of rs11797 was more frequent in SLE patients with neurological manifestations.

TREX1 531C>T Polymorphism is Associated with High Proviral Load Levels in HTLV-1-Infected Persons

“…Because of the small sample size, the association of ANAs with TREX1 531C>T polymorphism genotypes limits the strength of conclusions but allows the suggestion of a possible influence of ANAs with the C wild allele in the development of HAM/TSP, since two of the individuals presented the CC genotype and one the CT genotype. However, these results are not in agreement with the information presenting the same polymorphism in relation to systemic lupus erythematosus in which the T allele was associated with the disease [15]. In the present study, the presence of ANAs may not be directly related to the wild genotype, probably due to the small sample size of HTLV-1-infected individuals.…”

“…The role of TREX1 531C>T polymorphism in the development of autoimmune diseases is not yet well understood. Although it is not associated with some autoimmune diseases [14], a higher prevalence of this variation was observed in patients with systemic lupus erythematosus and Sjögren's syndrome [15,16].…”

“…Among the polymorphisms studied, rs11797 (TREX1 531C/T) has been investigated in the development of autoimmune diseases [12,[14][15][16]. However, to date, there is no information on the association of the polymorphism with HTLV-1 infection.…”

The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects

“…TREX1 mutations cause impaired degradation of intracellular cytosolic DNA. The risk allele is associated with neurologic complications (seizures), particularly in patients of European descent, 43,142,144,146,147 and a TREX1 single nucleotide polymorphism shows a strong association with anti-nuclear ribonucleoprotein autoantibodies. 144 Trex1 knockout mice produce high levels of IFN-a and a lethal inflammatory myositis with anti-nuclear antibodies.…”

Neuropsychiatric Systemic Lupus Erythematosus Involvement: Towards a Tailored Approach to Our Patients?

“…The discovery of the TREX1 gene (IFN regulator gene), responsible for Aicardi–Goutières syndrome, led to the recognition of association between several polymorphisms in heterozygotes with high NPSLE risk. 44 The TRPC6 gene, involved in the regulation of N-methyl-D-aspartate receptor, seems to be protective of NPSLE manifestations. 45 …”