TREX1 gene variant in neuropsychiatric systemic lupus erythematosus

Vries, Boukje de; Steup-Beekman, G.M.; Haan, Joost; Bollen, E.; Luyendijk, J.; Frants, R.R.; Terwindt, Gisela M.; Buchem, Mark A. van; Huizinga, T.W.J.; Maagdenberg, Arn M. J. M. van den; Ferrari, Michel D.

doi:10.1136/ard.2009.114157

Cited by 49 publications

(25 citation statements)

References 8 publications

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“…Several mutations located in the same region, both missense and synonymous, have been reported in SLE, AGS, and familial chilblain lupus. A missense heterozygous variation pArg128His was described in a patient with neuropsychiatric SLE (15). The authors considered this novel mutation as potentially pathogenic because of its location in the ExoII and also due to the fundamental role of arginine in this position that provides single-strand DNA for the enzyme active site, as it disrupts the double strand.…”

Section: N Discussion and Conclusionmentioning

confidence: 99%

Typing TREX1 gene in patients with systemic lupus erythematosus

et al. 2015

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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.

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Section: N Discussion and Conclusionmentioning

confidence: 99%

Typing TREX1 gene in patients with systemic lupus erythematosus

et al. 2015

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“…Chronic activation of DNA and RNA sensing pathways triggered by infection and cell death can contribute to the type I interferonopathy that predisposes individuals to SLE [166]. Mutations in nucleic acid sensors (such as endosomal Toll-like receptors [168], RIG-I [169], and DAI [170]), interferon regulatory factors [171] and DNases [172, 173] can also increase SLE susceptibility. Recently, Ding and colleagues proposed that the cGAS-STING axis could be another pathway potentially exacerbating SLE, via the upregulation of type I interferon production downstream of cytoplasmic DNA sensing cascades [174].…”

Section: Sting Related Autoimmunitymentioning

confidence: 99%

Regulating STING in health and disease

Li¹,

Wilson

Kiss-Tóth³

2017

J Inflamm

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The presence of cytosolic double-stranded DNA molecules can trigger multiple innate immune signalling pathways which converge on the activation of an ER-resident innate immune adaptor named “STimulator of INterferon Genes (STING)”. STING has been found to mediate type I interferon response downstream of cyclic dinucleotides and a number of DNA and RNA inducing signalling pathway. In addition to its physiological function, a rapidly increasing body of literature highlights the role for STING in human disease where variants of the STING proteins, as well as dysregulated STING signalling, have been implicated in a number of inflammatory diseases. This review will summarise the recent structural and functional findings of STING, and discuss how STING research has promoted the development of novel therapeutic approaches and experimental tools to improve treatment of tumour and autoimmune diseases.

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“…The discovery that TREX1 mutations cause Aicardi-Goutières syndrome (AGS) 3 provides an important link between nucleic acid metabolism, autoimmune disease, and innate antiviral response (5). The additional findings of TREX1 mutations in patients diagnosed with familial chilblain lupus, Cree encephalitis, retinal vasculopathy with cerebral leukodystrophy (RVCL), and systemic lupus erythematosus (SLE) genetically link a spectrum of human autoimmune disorders with overlapping related clinical symptoms (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

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confidence: 99%

The TREX1 C-terminal Region Controls Cellular Localization through Ubiquitination

Orebaugh

Fye

Harvey

et al. 2013

Journal of Biological Chemistry

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Background: Mutations in the TREX1 C-terminal region (CTR) cause human autoimmune disease. Results: The CTR directs TREX1 ubiquitination and interaction with ubiquilin 1. Conclusion: TREX1 ubiquitination and co-localization with ubiquilin 1 are differentially affected in autoimmune disease mutants. Significance: Multiple mechanisms of TREX1 dysfunction include altered covalent modification and diminished catalytic function, resulting in a spectrum of autoimmune diseases.

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TREX1 gene variant in neuropsychiatric systemic lupus erythematosus

Cited by 49 publications

References 8 publications

Typing TREX1 gene in patients with systemic lupus erythematosus

Typing TREX1 gene in patients with systemic lupus erythematosus

Regulating STING in health and disease

The TREX1 C-terminal Region Controls Cellular Localization through Ubiquitination

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