A new horizon of moyamoya disease and associated health risks explored through RNF213

Koizumi, Akio; Kobayashi, Hatasu; Hitomi, Toshiaki; Harada, Kouji H.; Habu, Toshiyuki; Youssefian, Shohab

doi:10.1007/s12199-015-0498-7

Cited by 105 publications

(74 citation statements)

References 122 publications

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“…Although Rnf213-knockout models inflict different angiogenesis alternations under different circumstances, 49,53 we imply that RNF213 is critical in vascularwall remodeling, which can explain the pathogeneses of both MMD and IAs. Additionally, the increased ATP hydro- 56 and Koizumi et al 66 14 variants found in the current study are marked in red, variants reported in Moteki et al 64 are marked in blue, MMD variants reported in Cecchi et al are marked in black, and MMD variants found in other studies are marked in gray. The results show that FC IA-affected individuals harbor more deleterious mutations in the AAAþ domains than other populations do.…”

Section: Aaaþ Atp Domain Variants and The Risk Of Iassupporting

confidence: 56%

“…41 In our IA study, we found several deleterious variants in the AAAþ domains, whereas other studies focused on MMDaffected individuals did not ( Figure 5). 56,66 We can assume that variants in different locations of RNF213 act as risk factors for different cerebrovascular disorders by affecting gene function differently. Whereas Cecchi et al 56 suggested that the C-terminal domain of RNF213 is the main risk region for MMD, we believe that exon 29, which encodes AAAþ domains, might be the risk region for IAs.…”

Section: Aaaþ Atp Domain Variants and The Risk Of Iasmentioning

confidence: 99%

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RNF213 Is Associated with Intracranial Aneurysms in the French-Canadian Population

Zhou

Ambalavanan

Rochefort

et al. 2016

The American Journal of Human Genetics

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Intracranial aneurysms (IAs) are the result of focal weakness in the artery wall and have a complex genetic makeup. To date, genome-wide association and sequencing studies have had limited success in identifying IA risk factors. Distinct populations, such as the French-Canadian (FC) population, have increased IA prevalence. In our study, we used exome sequencing to prioritize risk variants in a discovery cohort of six FC families affected by IA, and the analysis revealed an increased variation burden for ring finger protein 213 (RNF213). We resequenced RNF213 in a larger FC validation cohort, and association tests on further identified variants supported our findings (SKAT-O, p = 0.006). RNF213 belongs to the AAA+ protein family, and two variants (p.Arg2438Cys and p.Ala2826Thr) unique to affected FC individuals were found to have increased ATPase activity, which could lead to increased risk of IA by elevating angiogenic activities. Common SNPs in RNF213 were also extracted from the NeuroX SNP-chip genotype data, comprising 257 FC IA-affected and 1,988 control individuals. We discovered that the non-ancestral allele of rs6565666 was significantly associated with the affected individuals (p = 0.03), and it appeared as though the frequency of the risk allele had changed through genetic drift. Although RNF213 is a risk factor for moyamoya disease in East Asians, we demonstrated that it might also be a risk factor for IA in the FC population. It therefore appears that the function of RNF213 can be differently altered to predispose distinct populations to dissimilar neurovascular conditions, highlighting the importance of a population's background in genetic studies of heterogeneous disease.

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Section: Aaaþ Atp Domain Variants and The Risk Of Iassupporting

confidence: 56%

Section: Aaaþ Atp Domain Variants and The Risk Of Iasmentioning

confidence: 99%

RNF213 Is Associated with Intracranial Aneurysms in the French-Canadian Population

Zhou

Ambalavanan

Rochefort

et al. 2016

The American Journal of Human Genetics

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“…Indeed, although heavily associated with MMA in Japan (OR4200, Po10 -100 in a meta-analysis), 9 the penetrance of MMA in p.(R4810K) carriers is estimated to be 1/150 in the Japanese population. 35 This very low penetrance, on a population basis, contrasts with the incomplete but much higher penetrance observed in a family context. One possible explanation could be that the development of MMA requires, in addition to RNF213 pathogenic variants, at least one additional genetic factor which is most likely shared in families.…”

Section: Discussionmentioning

confidence: 88%

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

Guey¹,

Kraemer²,

Hervé³

et al. 2017

Eur J Hum Genet

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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.

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“…RNF213 is an E3 ubiquitin-protein ligase with two AAA+ ATPase domains, which are characteristic of energy-dependent unfoldases (Koizumi et al 2016). It has been shown that RNF213 is involved in angiogenesis by promoting vessel regression (Scholz et al 2016).…”

Section: Discussionmentioning

confidence: 99%

RNF213variation, a broader role in neurovascular disease in Caucasian and Japanese populations

Lorenzo‐Betancor

Blackburn

Farrugia

et al. 2020

Preprint

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Moyamoya disease (MMD) is a chronic, occlusive cerebrovascular disease that predominantly affects East Asian populations. The major genetic mutation associated with MMD in Asian populations is the p.R4810K substitution in Ring Finger Protein 213 (RNF213). Interestingly, variants in the RNF213 gene have also been implicated in intracranial aneurysms (IA) in French-Canadian population, suggesting that variation in this gene may play a broader role in cerebrovascular phenotypes. In a recent genome-wide association study (GWAS) in a Caucasian population, variants rs6565653 and rs12601526 in the Solute Carrier Family 26 Member 11 (SLC26A11) gene, which is less than 10kb away from RNF213, showed a suggestive association with young onset ischemic stroke. We propose that the signal could be tagging an association with common variation in the RNF213 gene. We analyzed the linkage disequilibrium (LD) pattern in the SLC26A11-RNF213 gene region and we observed a high LD between variants in this region based on D’ values. We show that SLC26A11 rs6565653 variant tags RNF213 rs12944088, a missense variant that is more common among subjects with IA than in healthy individuals. Given the fact that rs6565653 tags several RNF213 variants, it is highly likely that some of these tagged variants modify the risk of suffering stroke. The LD analyses suggest that the SLC26A11 signal from the young onset ischemic stroke GWAS performed in a Caucasian population is also tagging variation at the RNF213 loci, supporting the hypothesis that RNF213 variation may result in a variety of neurovascular disorders including an increased risk and/or worse prognosis following ischemic stroke in Caucasian population.

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A new horizon of moyamoya disease and associated health risks explored through RNF213

Cited by 105 publications

References 122 publications

RNF213 Is Associated with Intracranial Aneurysms in the French-Canadian Population

RNF213 Is Associated with Intracranial Aneurysms in the French-Canadian Population

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

RNF213variation, a broader role in neurovascular disease in Caucasian and Japanese populations

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