| Title: | Misdirected yet intact TREX1 exonuclease activity causes human cerebral and systemic small vessel disease |
| Journal: | Brain |
| Published: | 6 Jun 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40476824/ |
| DOI: | https://doi.org/10.1093/brain/awaf085 |
| URL: | https://academic.oup.com/brain/advance-article-pdf/doi/10.1093/brain/awaf085/63445316/awaf085.pdf |
Publication 15046
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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.</p>
13 Keywords
- Cerebral Small Vessel Diseases
- DNA Damage
- Endothelial Cells
- Exodeoxyribonucleases
- Female
- Hereditary Central Nervous System Demyelinating Diseases
- Humans
- Male
- Middle Aged
- Mutation
- Phosphoproteins
- Retinal Diseases
- Vascular Diseases
16 Authors
- Sarah McGlasson
- Katy Reid
- Anna Klingseisen
- Bastien Rioux
- Samuel Chauvin
- Cathrine A Miner
- Joe Holley
- Deborah Forbes
- Bethany Geary
- Jeffrey Kimber
- Katrina Wood
- Candice Roufosse
- Colin Smith
- David Kavanagh
- Jonathan Miner
- David P J Hunt
1 Application
| Application ID | Title |
|---|---|
| 93160 | The role of interferons in the risk of cerebrovascular disease |
Enabling scientific discoveries that improve human health