Vascular cognitive impairment is highly prevalent, yet its biological basis has not been well studied. The goal of this proposal is to elucidate the molecular and cellular pathological processes underlying retinal vasculopathy with cerebral leukodystrophy (RVCL;OMIM 192315), an autosomal dominant stroke syndrome of adult onset due to a systemic microvasculopathy that is clinically, pathologically, and genetically distinct from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL;OMIM125310). A collaborative effort led to the recent discovery of heterozygous carboxyl-terminal frameshift mutations in TREX1, a 3'-5'DNA exonuclease. These mutant proteins retain exonuclease activity but lose the usual perinuclear subcellular localization of TREX1. The loss of TREX1 function was recently shown to trigger autoimmunity in devastating Aicardi-Gutieres syndrome and systemic lupus erythematosus. A role for TREX1 in the maintenance of systemic vascular integrity and endothelial function has not been previously recognized. Why capillary endothelial cells are especially vulnerable to mutations in this ubiquitously expressed protein is not known. Understanding how TREX1 mutations lead to systemic vasculopathy will provide new strategies for therapeutic intervention and may provide insight to possibly shared mechanisms in inherited, oxidative, and irradiation endothelial damage.

Public Health Relevance

We recently identified the genetic cause of RVCL (retinal vasculopathy with cerebral leukodystrophy), which, like CADASIL, is a familial stroke syndrome that damages white matter in the brain and causes progressive cognitive decline. Studying the molecular mechanisms underlying this newly defined familial stroke syndrome will identify new targets for treatment and help us understand cellular processes that are important in maintaining normal vascular function in health and disease. We also propose to look for new patients and prospectively study all available surviving patients in the U.S. to identify important markers for disease to improve diagnosis and inform future therapeutic trials.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Corriveau, Roderick A
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Kothari, Parul H; Kolar, Grant R; Jen, Joanna C et al. (2018) TREX1 is expressed by microglia in normal human brain and increases in regions affected by ischemia. Brain Pathol 28:806-821
Namjou, B; Kothari, P H; Kelly, J A et al. (2011) Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun 12:270-9
Mateen, F J; Krecke, K; Younge, B R et al. (2010) Evolution of a tumor-like lesion in cerebroretinal vasculopathy and TREX1 mutation. Neurology 75:1211-3