Dataset Information

RNF213-Associated Vascular Disease: A Concept Unifying Various Vasculopathies.

ABSTRACT: The ring finger protein 213 gene (RNF213) encodes a 590 kDa protein that is thought to be involved in angiogenesis. This gene was first recognized as a vasculopathy-susceptibility locus through genome-wide association studies undertaken in a Japanese population, demonstrating that heterozygotes for RNF213 p.Arg4810Lys (c.14429G>A, rs112735431) had a greatly increased risk of moyamoya disease. The association of RNF213 p.Arg4810Lys as a susceptibility variant of moyamoya disease was reproduced in Korean and Chinese individuals and, later, in Caucasians. Variants of the RNF213 gene have been linked to a number of vascular diseases such as moyamoya disease, intracranial major artery stenosis, pulmonary arterial hypertension, and peripheral pulmonary artery stenosis, and have also been associated with co-occurrent diseases and vascular disease in different organs. Based on the findings that we have reported to date, our paper proposes a new concept of “RNF213-associated vascular disease” to unify these conditions with the aim of capturing patients with multiple diseases but with a common genetic background. This concept will be highly desirable for clarifying all of the diseases in the RNF213-associated vascular disease category by means of global epidemiological investigations because of the possibility of such diseases appearing asymptomatically in some patients.

SUBMITTER: Hiraide T

PROVIDER: S-EPMC9032981 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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<i>RNF213</i>-Associated Vascular Disease: A Concept Unifying Various Vasculopathies.

Hiraide Takahiro T Suzuki Hisato H Momoi Mizuki M Shinya Yoshiki Y Fukuda Keiichi K Kosaki Kenjiro K Kataoka Masaharu M

Life (Basel, Switzerland) 20220408 4

The ring finger protein 213 gene (RNF213) encodes a 590 kDa protein that is thought to be involved in angiogenesis. This gene was first recognized as a vasculopathy-susceptibility locus through genome-wide association studies undertaken in a Japanese population, demonstrating that heterozygotes for RNF213 p.Arg4810Lys (c.14429G>A, rs112735431) had a greatly increased risk of moyamoya disease. The association of RNF213 p.Arg4810Lys as a susceptibility variant of moyamoya disease was reproduced in ...[more]

PMID: 35455046

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Project description:Moyamoya disease is an idiopathic vascular disorder of intracranial arteries. Its susceptibility locus has been mapped to 17q25.3 in Japanese families, but the susceptibility gene is unknown.Genome-wide linkage analysis in eight three-generation families with moyamoya disease revealed linkage to 17q25.3 (P<10(-4)). Fine mapping demonstrated a 1.5-Mb disease locus bounded by D17S1806 and rs2280147. We conducted exome analysis of the eight index cases in these families, with results filtered through Ng criteria. There was a variant of p.N321S in PCMTD1 and p.R4810K in RNF213 in the 1.5-Mb locus of the eight index cases. The p.N321S variant in PCMTD1 could not be confirmed by the Sanger method. Sequencing RNF213 in 42 index cases confirmed p.R4810K and revealed it to be the only unregistered variant. Genotyping 39 SNPs around RNF213 revealed a founder haplotype transmitted in 42 families. Sequencing the 260-kb region covering the founder haplotype in one index case did not show any coding variants except p.R4810K. A case-control study demonstrated strong association of p.R4810K with moyamoya disease in East Asian populations (251 cases and 707 controls) with an odds ratio of 111.8 (P?=?10(-119)). Sequencing of RNF213 in East Asian cases revealed additional novel variants: p.D4863N, p.E4950D, p.A5021V, p.D5160E, and p.E5176G. Among Caucasian cases, variants p.N3962D, p.D4013N, p.R4062Q and p.P4608S were identified. RNF213 encodes a 591-kDa cytosolic protein that possesses two functional domains: a Walker motif and a RING finger domain. These exhibit ATPase and ubiquitin ligase activities. Although the mutant alleles (p.R4810K or p.D4013N in the RING domain) did not affect transcription levels or ubiquitination activity, knockdown of RNF213 in zebrafish caused irregular wall formation in trunk arteries and abnormal sprouting vessels.We provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease.

Dataset Information

RNF213-Associated Vascular Disease: A Concept Unifying Various Vasculopathies.

Publications

<i>RNF213</i>-Associated Vascular Disease: A Concept Unifying Various Vasculopathies.

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