Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function

Abstract

Background: Variants in the ring finger protein 213 ( RNF213 ) gene are known to be associated with increased predisposition to cerebrovascular diseases development. Genomic studies have identified RNF213 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. Methods: 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. Results: 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. Conclusions: 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.

Moyamoya disease emerging as an immune-related angiopathy

“…When RNF213 was depleted from human cerebral ECs, the authors reported morphological changes associated with increased blood-brain barrier permeability and abnormally high secretion of proinflammatory cytokines. These results suggest that bloodbrain barrier disruption may play a role in MMA and that endothelial dysfunction is the initiating event leading to MMD pathogenesis, as it is in numerous other cerebrovascular diseases [70].…”

“…Together, these studies draw a picture of RNF213 as a multifunctional protein involved in several key cellular processes, including LD stability [57], lipotoxicity [66], WNT [67] and NF-κB signaling, and inflammation [70] (Figure 3). These functions are likely to be related, especially in light of the recently discovered function of RNF213 as a key antimicrobial host protein [56,58].…”

A Noonan‐like pediatric patient with a de novo CBL pathogenic variant and an RNF213 polymorphism p.R4810K presenting with cardiopulmonary arrest due to left main coronary artery ostial atresia

“…Furthermore, RNF213 knockout is known to cause inflammatory cytokine secretion in brain endothelium, which is implicated in increased blood–brain barrier permeability, and also inhibits HUVEC angiogenesis, causing delayed cell migration and renewed macrophage migration (Roy et al, 2022; Zhang et al, 2022). In contrast, it was reported that CBL knockdown significantly increased retinal neovascular zones, while CBL overexpression suppressed neovascularization in the retinal tissue of oxygen‐induced retinopathy (Chen et al, 2020).…”

The Progression of Pathophysiology of Moyamoya Disease

“…56 As for vascular permeability, RNF213 could be a key regulator of cerebral endothelium integrity, whose disruption could be an early pathological mechanism leading to MMD. 59 Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2)…”