Although familial forms of cerebral cavernous malformation are mainly attributed to three CCM genes (KRIT1, CCM2 and PDCD10), no mutation is identified in sporadic cerebral cavernous malformation cases with a unique lesion, indicating additional genes for sporadic cerebral cavernous malformation. To screen the candidate genes, we conducted whole exome sequencing in 31 sporadic cerebral cavernous malformation patients and 32 healthy controls, and identified 5 affected individuals carrying 6 heterozygous deleterious mutations in RNF213 but no RNF213 mutation in healthy individuals. To further confirm RNF213 was associated with cerebral cavernous malformation, we generated rnf213a homozygous knockout zebrafish and found mutation of rnf213a in zebrafish led to a mulberry-like cluster of disordered-flow vascular channels which was reminiscent of human cerebral cavernous malformation. In addition, we revealed kbtbd7 and anxa6 were significantly downregulated due to rnf213a mutation through transcriptomic sequencing and RT-qPCR analysis. Based on the mulberry-like phenotype partly rescued by mRNA of kbtbd7 as well as anxa6, we suggested that rnf213a promoted mulberry-like cluster via downregulation of kbtbd7 and anxa6. Altogether, we firstly demonstrate RNF213is a novel candidate gene for sporadic cerebral cavernous malformation and the mutation of rnf213a is responsible for the mulberry-like cluster in zebrafish.

Moyamoya disease (MMD), most often diagnosed in children and adolescents, is a chronic cerebrovascular disease characterized by progressive stenosis at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. Recently, many investigators show a great interest in MMD with pulmonary arterial hypertension (PAH). Ring finger protein 213 (RNF213) is a major susceptibility gene for MMD and also has strong correlations with PAH. Therefore, this review encapsulates current cases of MMD with PAH and discusses MMD with PAH in the aspects of epidemiology, pathology, possible pathogenesis, clinical manifestations, diagnosis, and treatment.

Purpose: Surgical revascularization is the preferred treatment for most patients with Moyamoya disease (MMD). Nevertheless, a considerable number of eligible patients choose non-surgical management. This study aimed to identify factors influencing treatment decisions, with particular emphasis on asymptomatic MMD patients. Materials and Methods: We conducted a retrospective analysis of MMD patients without surgical contraindications treated at our center between 2010 and 2022. Baseline characteristics were compared using Wilcoxon rank-sum and chi-squared tests. Multivariable logistic regression was used to identify factors associated with treatment selection. Results: Among the 147 included patients, 62.6% underwent surgical treatment. Younger age (OR = 0.88, 95% CI: 0.88–0.94, p < 0.001), married status (OR = 653.3, 95% CI: 41.61–10,264.22, p < 0.001), and absence of hyperlipidemia (OR = 0.16, 95% CI: 0.03–0.85, p < 0.05) were significantly associated with choosing surgery. Asymptomatic patients underwent surgery at a higher rate than symptomatic patients (67.9% vs. 59.6%). Younger age was a significant predictor of surgical preference in both symptomatic and asymptomatic subgroups. Conclusion: Younger age is strongly associated with the choice of surgical treatment in MMD, including in asymptomatic cases.