ArticleBrain : a journal of neurology2025
Misdirected yet intact TREX1 exonuclease activity causes human cerebral and systemic small vessel disease.
Article in Brain : a journal of neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Autoinflammatory syndromes of STING and TREX1 dysfunction.The Journal of clinical investigation · 2026Review
- The enigma of vascular dementia: current state and emerging perspectives.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- First case ofFrontiers in immunology · 2026Article
- Article
- The intersection of TREX1, cGAS, STING and the DNA damage theory of aging.Frontiers in aging · 2025Review
- Exploring targeted therapy in retinal vasculopathy with cerebral leukoencephalopathy: a case report and review of literature.Frontiers in immunology · 2025Review
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Authors and funding
16 authors.
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Abstract
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an incurable microvascular disease caused by C-terminus truncation of the TREX1 exonuclease. There is a pressing need to understand disease mechanisms and identify therapeutic targets. We evaluated TREX1 sequencing data from 469 229 UK Biobank participants together with RVCL-S-related microvascular clinical and imaging outcomes. We show that mono-allelic truncating mutations in TREX1 require intact nuclease activity in order to cause endothelial disease. Differential proteomics identifies loss of interaction with endoplasmic reticulum insertion proteins such as Guided Entry of Tail-Anchored Proteins Factor 3 as a major consequence of pathogenic TREX1 truncation, and this altered trafficking results in the unregulated presence of enzymatically active TREX1 in the nucleus. In endothelial cells with a patient mutation, mislocalized yet enzymatically active TREX1 causes accumulation of a spectrum of DNA damage. These pathological changes can be rescued by inhibiting exonuclease activity. In summary, our data implicate exonuclease-dependent DNA damage in endothelial cells as a key therapeutic target in the pathogenesis of RVCL-S.
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