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Lookup NU author(s): Dr Katrina Wood, Professor David KavanaghORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): McGlasson S, Reid K, Klingseisen A, Rioux B, Chauvin S, Miner CA, Holley J, Forbes D, Geary B, Kimber J, Wood K, Roufosse C, Smith C, Kavanagh D, Miner J, Hunt DPJ
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2025
Pages: epub ahead of print
Online publication date: 06/06/2025
Acceptance date: 09/06/2025
Date deposited: 27/06/2025
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: https://doi.org/10.1093/brain/awaf085
DOI: 10.1093/brain/awaf085
Data Access Statement: All data will be made publicly available.
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