RNF213 in moyamoya disease: Genotype–phenotype association and the underlying mechanism

Abstract Moyamoya disease (MMD) is a cerebrovascular disorder characterized by a steno-occlusive internal carotid artery and compensatory vascular network formation. Although the precise pathogenic mechanism remains elusive, genetic association studies have identified RNF213 as the principal susceptibility gene for MMD, with the single nucleotide polymorphism p.R4810K recognized as the founder variant predominantly in the Asian populations. Distinct genotype–phenotype correlations are observable in RNF213 -related MMD. The clinical manifestations linked to p.R4810K bear commonalities within Asian cohort, including familial predisposition, earlier age of onset, ischemic episodes, and involvement of the posterior cerebral artery (PCA). However, despite these shared phenotypic characteristics, there is significant heterogeneity in RNF213 -related MMD presentations. This diversity manifests as variations across ethnic groups, inconsistent clinical symptoms and prognosis, and occurrence of other vasculopathies involving RNF213 . This heterogeneity, in conjunction with the observed low disease penetrance of RNF213 mutations, suggests that the presence of these mutations may not be sufficient to cause MMD, underscoring the potential influence of other genetic or environmental factors. Although the current research might not have fully identified these additional contributors, experimental evidence points toward the involvement of RNF213 in angiogenesis, lipid metabolism, and the immune response. Future research is required to unveil the molecular mechanisms and identify the factors that synergize with RNF213 in the pathogenesis of MMD.