A genome-wide association study identifies RNF213 as the first Moyamoya disease gene

Abstract

Moyamoya disease (MMD) shows progressive cerebral angiopathy characterized by bilateral internal carotid artery stenosis and abnormal collateral vessels. Although B15% of MMD cases are familial, the MMD gene(s) remain unknown. A genome-wide association study of 785 720 single-nucleotide polymorphisms (SNPs) was performed, comparing 72 Japanese MMD patients with 45 Japanese controls and resulting in a strong association of chromosome 17q25-ter with MMD risk. This result was further confirmed by a locus-specific association study using 335 SNPs in the 17q25-ter region. A single haplotype consisting of seven SNPs at the RNF213 locus was tightly associated with MMD (P¼5.3Â10 À10 ). RNF213 encodes a really interesting new gene finger protein with an AAA ATPase domain and is abundantly expressed in spleen and leukocytes. An RNA in situ hybridization analysis of mouse tissues indicated that mature lymphocytes express higher levels of Rnf213 mRNA than their immature counterparts. Mutational analysis of RNF213 revealed a founder mutation, p.R4859K, in 95% of MMD families, 73% of non-familial MMD cases and 1.4% of controls; this mutation greatly increases the risk of MMD (P¼1.2Â10 À43 , odds ratio¼190.8, 95% confidence interval¼71.7-507.9). Three additional missense mutations were identified in the p.R4859K-negative patients. These results indicate that RNF213 is the first identified susceptibility gene for MMD.

Distribution of Moyamoya Disease Susceptibility Polymorphism p.R4810K in RNF213 in East and Southeast Asian Populations

“…2,7,10) We previously identified a susceptibility locus for familial moyamoya disease on 17q25.3. 11) Significant associations with genes in this region had been reported, 4,8) but rigorous identification had not been determined. The ring finger 213 (RNF213) gene was finally identified as a susceptibility gene for moyamoya disease by the conventional rigorous positional cloning approach, exome analysis, and functional analysis using zebrafish.…”

Current Status of Revascularization Surgery for Moyamoya Disease: Special Consideration for Its ‘Internal Carotid-External Carotid (IC-EC) Conversion’ as the Physiological Reorganization System

“…A more recent genome-wide association study identified the ring finger protein (RNF) 213 gene (RNF213) in the 17q25-ter region as a susceptibility gene for moyamoya disease among East Asian population (Kamada et al 2011), although the exact function of RNF213 is undetermined. We previously reported that a single-nucleotide polymorphism (SNP) of c.14576G>A in RNF213 was detected in 95% of familial moyamoya diseases and 79% of sporadic cases among Japanese patients (Kamada et al 2011). Although the mechanism underlying SNP of RNF213 in moyamoya disease patients is undetermined, recent in vivo experiment using the RNF213-deficient mice may give clue to address this important question.…”

“…Environmental factors as the secondary insults in addition to the genetic abnormality might be important to develop moyamoya disease, because RNF213 polymorphism characteristic to moyamoya disease is also evident in 1.4% of the normal control population (Kamada et al 2011 . Alternatively, RNF213 polymorphism could directly affect autoimmunity and thus contribute to the development of moyamoya disease, because RNF213 is predominantly expressed in white blood cells and spleen (Kamada et al 2011).…”

Review of Past Research and Current Concepts on the Etiology of Moyamoya Disease

“…Thus, Kamada and colleagues from Tohoku University employed a genome-wide association study and identified ring finger protein (RNF) 213 ( * 613768; http://omim.org/entry/613768) as the first moyamoya disease gene. 29) Around the same time, Liu and colleagues from Kyoto University, the University of Tubingen, Palacky University, the Chinese People's Liberation Army General Hospital, and Seoul National University employed genomewide linkage analysis by assuming the inheritance pattern of moyamoya disease as autosomal dominant mode with incomplete penetrance and whole genome-exome analysis. As a result, they provided evidence suggesting the involvement of RNF213 in genetic susceptibility to moyamoya disease.…”

“…From these view points, several studies have been conducted by using a combination of several methods to specify the susceptibility gene for moyamoya disease (Table 6). 29,38,39,43,47) Of these, two independent groups from Japan have identified, very recently, the susceptibility gene for moyamoya disease by employing a combination of several methods, including linkage analysis, case-control association studies, and gene annotation studies. Thus, Kamada and colleagues from Tohoku University employed a genome-wide association study and identified ring finger protein (RNF) 213 ( * 613768; http://omim.org/entry/613768) as the first moyamoya disease gene.…”