Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function

• Published in: Stroke (1970) Vol. 53; no. 4; pp. 1263 - 1275
• Main Authors: Roy, Vincent, Ross, Jay P., Pépin, Rémy, Cortez Ghio, Sergio, Brodeur, Alyssa, Touzel Deschênes, Lydia, Le-Bel, Gaëtan, Phillips, Daniel E., Milot, Geneviève, Dion, Patrick A., Guérin, Sylvain, Germain, Lucie, Berthod, François, Auger, François A., Rouleau, Guy A., Dupré, Nicolas, Gros-Louis, François
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 01-04-2022
• Subjects: Adenosine Triphosphatases - genetics; Endothelial Cells - metabolism; Endothelium; Genetic Predisposition to Disease; Humans; Moyamoya Disease - pathology; Transcription Factors; Ubiquitin-Protein Ligases - genetics; genomics; risk factor; endothelial cell; leukocyte; permeability
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.120.032691

Variants in the ring finger protein 213 (
) gene are known to be associated with increased predisposition to cerebrovascular diseases development. Genomic studies have identified
as a major risk factor of Moyamoya disease in East Asian descendants. However, little is known about the RNF213 (ring finger protein 213) biological functions or its associated pathogenic mechanisms underlying Moyamoya disease.
To investigate RNF213 loss-of-function effect in endothelial cell, stable RNF213-deficient human cerebral endothelial cells were generated using the CRISPR-Cas9 genome editing technology.
In vitro assays, using RNF213 knockout brain endothelial cells, showed clear morphological changes and increased blood-brain barrier permeability. Downregulation and delocalization of essential interendothelial junction proteins involved in the blood-brain barrier maintenance, such as PECAM-1 (platelet endothelial cell adhesion molecule-1), was also observed. Brain endothelial RNF213-deficient cells also showed an abnormal potential to transmigration of leukocytes and secreted high amounts of proinflammatory cytokines.
Taken together, these results indicate that RNF213 could be a key regulator of cerebral endothelium integrity, whose disruption could be an early pathological mechanism leading to Moyamoya disease. This study also further reinforces the importance of blood-brain barrier integrity in the development of Moyamoya disease and other RNF213-associated diseases.