Misdirected yet intact TREX1 exonuclease activity causes human cerebral and systemic small vessel disease

TY - JOUR

T1 - Misdirected yet intact TREX1 exonuclease activity causes human cerebral and systemic small vessel disease

AU - McGlasson, Sarah

AU - Reid, Katy

AU - Klingseisen, Anna

AU - Rioux, Bastien

AU - Chauvin, Samuel

AU - Miner, Cathrine A.

AU - Holley, Joe

AU - Forbes, Deborah

AU - Geary, Bethany

AU - Kimber, Jeffrey

AU - Wood, Katrina

AU - Roufosse, Candice

AU - Smith, Colin

AU - Kavanagh, David

AU - Miner, Jonathan

AU - Hunt, David P.J.

N1 - Publisher Copyright: © The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2025/8/1

Y1 - 2025/8/1

N2 - 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.

AB - 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.

KW - cell cycle

KW - DNA damage

KW - endothelial

KW - exonuclease

KW - vascular dementia

UR - https://www.scopus.com/pages/publications/105012409182

U2 - 10.1093/brain/awaf085

DO - 10.1093/brain/awaf085

M3 - Article

C2 - 40476824

AN - SCOPUS:105012409182

SN - 0006-8950

VL - 148

SP - 2981

EP - 2994

JO - Brain

JF - Brain

IS - 8

ER -