Misdirected yet intact TREX1 exonuclease activity causes human cerebral and systemic small vessel disease
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.
Authors
- Jonathan J. Miner (ORCID: https://orcid.org/0000-0001-9551-2962)
- Deborah Forbes (ORCID: https://orcid.org/0000-0003-2584-0236)
- Anna Klingseisen
- David Hunt (ORCID: https://orcid.org/0000-0003-4230-0207)
- Samuel D. Chauvin (ORCID: https://orcid.org/0000-0003-0232-751X)
- David Kavanagh (ORCID: https://orcid.org/0000-0003-4718-0072)
- Bastien Rioux (ORCID: https://orcid.org/0000-0002-0292-259X)
- Katrina Wood
- Candice Roufosse (ORCID: https://orcid.org/0000-0002-6490-4290)
- Cathrine A. Miner
- Bethany Geary (ORCID: https://orcid.org/0000-0002-5592-5532)
- Joe A. Holley
- Colin Smith (ORCID: https://orcid.org/0000-0002-4507-5132)
- Sarah McGlasson (ORCID: https://orcid.org/0000-0002-0077-0991)
- J. Kimber
- Kayleigh M. Reid
Institutions
- National Health Service (GB)
- University of Dundee (GB)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
- Crawley Hospital (GB)
- Newcastle upon Tyne Hospital (GB)
- UK Dementia Research Institute (GB)
- Imperial College London (GB)
- University of Pennsylvania (US)
- University of Edinburgh (GB)
Publication Details
- Journal
- Brain
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1093/brain/awaf085
- Citations
- 8
- Primary Topic
- Ocular Diseases and Behçet’s Syndrome
- Type
- article
- Field-Weighted Citation Impact
- 13.66
Funders
- Rheumatology Research Foundation
- University of Pennsylvania
- Wellcome Trust
- Alzheimer's Society
- Alzheimer’s Research UK
- Stiftung für klinische Forschung zur Förderung der oralen Gesundheit
- Alzheimer’s Society
- UK Dementia Research Institute
- National Institutes of Health
- Medical Research Council
- Medical Research Foundation