Rare RNF213 variants in the C-terminal region encompassing the RING-finger domain are associated with moyamoya angiopathy in Caucasians

Abstract

Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-finger and two AAA+ domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-finger domain of RNF213 (P<10). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 × 10). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected.

Genotype-Phenotype Correlation in Long-Term Cohort of Japanese Patients with Moyamoya Disease

“…This may be because this variant is not located within the functional domains (2 AAAATPase domains and a RING domain) in RNF213, of which the function or the role is not completely analyzed yet. Moreover, rare variants other than the p.R4810K variant were also found in Asian and European patients with MMD [4,6,18,19]. Some of those variants appear to be more pathogenic than the p.R4810K founder variant in in-silico prediction tools, such as PolyPhen or C-score of Combined Annotation Dependent Depletion [20][21][22].…”

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease—study protocol and preliminary results

“…Particularly, data on MA in Western countries, hereby mostly in Europe are lacking. Although a similar phenotype between the US and European patients has been described, the rarity of the disease in Europe, the lack of systematic studies, the multi-ethnic origin, and the heterogeneity of the studied cohorts further impair the acquisition of clear information on clinical feature and disease progression in Europeans [12][13][14][15][28][29][30][31][32]. The identification of clinical and imaging predictors is necessary to improve a prognostic evaluation and develop innovative therapeutic approaches.…”

“…Despite preliminary reports excluded an association between this gene and MA in Caucasians [30]. Recently, rare RNF213 variants have been reported also in some European cases, particularly with early onset and familial MA [31]. Additional familial cases of MA associated with facial dimorphisms and achalasia respectively were recently associated mutations in BRCC3 deubiquitinase and GUCY1A3 gene, encoding the major nitric oxide receptor in vascular smooth muscle cells [32,33].…”

Moyamoya Disease-AssociatedRNF213Alleles Encode Dominant Negative Alleles That Globally Impair Ubiquitylation

“…Different RNF213 SNPs are associated with variable penetrance of MMD (Cecchi et al, 2014;Guey et al, 2017;Kamada et al, 2011;Liu et al, 2011;Sugihara et al, 2019). To explore the role of RNF213 E3 ligase activity on MMD, we assessed the E3 ligase activity associated with SNPs of different penetrance (Fig.…”

“…Furthermore, RNF213 H4014N (higher penetrance, red circles) had lower activity compared with RNF213 R4810K (lower penetrance, purple circles). It has been reported that MMD SNPs in the RING domain of RNF213 have higher disease penetrance (Cecchi et al, 2014;Guey et al, 2017). Intriguingly, RNF213 H4014N and RNF213 C4017S affect RING domain residues in RNF213 and have highly impaired E3 ligase activity, compared with RNF213 R4810K .…”