RNF213 and cardiovascular disease: A review of histopathological, genetic perspectives, and potential molecular mechanisms

The ring finger protein 213 (RNF213) gene, identified in 2011 as a susceptibility gene for moyamoya disease (MMD), has since been recognized as a key factor in a broader spectrum of vascular disorders. The p.R4810K mutation in RNF213 is particularly common among Japanese MMD patients, although a smaller percentage of healthy individuals also carry the mutation, indicating that environmental factors, alongside genetic predisposition, likely influence disease onset. RNF213, a large E3 ubiquitin ligase, plays essential roles in vascular homeostasis, immune response, and endoplasmic reticulum stress reaction. Its mutation disrupts normal angiogenesis, contributing to abnormal vascular remodeling in conditions such as pulmonary hypertension and coronary artery disease. This review examines the multifaceted role of RNF213 and its p.R4810K mutation in the pathogenesis of MMD and other vascular conditions, collectively referred to as RNF213-associated vascular diseases. While research has begun to clarify the mutation's effects on angiogenesis and the involved pathways, the roles of RNF213 and its mutation in vascular integrity remain unclear. This comprehensive overview underscores the complex interaction between genetic and environmental factors in RNF213-related vascular diseases and calls for further research to elucidate these mechanisms and develop targeted therapeutic interventions.