Novel and recurrent RNF213 variants in Japanese pediatric patients with moyamoya disease.
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ABSTRACT:
SUBMITTER: Akagawa H
PROVIDER: S-EPMC5784207 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Novel and recurrent <i>RNF213</i> variants in Japanese pediatric patients with moyamoya disease.
Akagawa Hiroyuki H Mukawa Maki M Nariai Tadashi T Nomura Shunsuke S Aihara Yasuo Y Onda Hideaki H Yoneyama Taku T Kudo Takumi T Sumita Kazutaka K Maehara Taketoshi T Kawamata Takakazu T Kasuya Hidetoshi H
Human genome variation 20180125
Moyamoya disease is a progressive steno-occlusive condition of the main intracranial arteries that results in the compensatory formation of fragile moyamoya vessels at the base of the brain. <i>RNF213</i> is the most significant susceptibility gene and is often found with the p.Arg4810Lys founder variant in East Asian patients. We identified three putatively deleterious variants of this gene from three pediatric patients: two were novel, and one was a recurrent missense variant previously report ...[more]
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Project description:A founder variant of RNF213, p.R4810K (c.14429G>A, rs112735431), was recently identified as a major genetic risk factor for moyamoya disease (MMD) in Japan. Although the association of p.R4810K was reported to be highly significant and reproducible, the disease susceptibility of other RNF213 variants remains largely unknown. In the present study, we systematically evaluated the coding variants detected in Japanese patients and controls for associations with MMD. To detect variants of RNF213, all coding exons were sequenced in 27 Japanese MMD patients without p.R4810K. We also validated all previously reported variants in our case-control samples and tested for associations in combination with previous Japanese study cohorts, including the 1000 Genomes Project data set, as population-based controls. Forty-six missense variants other than p.R4810K were identified among 370 combined patients and 279 combined controls in Japan. Sixteen of 46 variants were polymorphisms with minor allele frequency >1%, and, after conditioning on the p.R4810K genotype, were not associated with MMD. We conducted a variable threshold test using Combined Annotation-Dependent Depletion on the remaining 30 rare variants (minor allele frequency <1%), and the results showed that the frequency of potentially functional variants was significantly higher in patients than in controls (permutation, minimum P=0.045). Not only p.4810K but also other functional missense variants of RNF213 conferred susceptibility to MMD. Our analysis also revealed that ≈20% of Japanese MMD patients did not harbor susceptibility variants of RNF213, indicating the presence of other susceptibility genes for MMD.
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Project description:RNF213/Mysterin has been identified as a susceptibility gene for moyamoya disease, a cerebrovascular disease characterized by occlusive lesions in the circle of Willis. The p.R4810K (rs112735431) variant is a founder polymorphism that is strongly associated with moyamoya disease in East Asia. Many non-p.R4810K rare variants of RNF213 have been identified in white moyamoya disease patients, although the ethnic mutations have not been investigated in this population. In the present study, we screened for RNF213 variants in 19 Slovakian and Czech moyamoya disease patients. A total of 69 RNF213 coding exons were directly sequenced in 18 probands and one relative who suffered from moyamoya disease in Slovakia and the Czech Republic. We previously reported one proband harboring RNF213 p.D4013N. Results from the present study identified four rare variants other than p.D4013N (p.R4019C, p.E4042K, p.V4146A, and p.W4677L) in four of the patients. P.V4146A was determined to be a novel de novo mutation, and p.R4019C and p.E4042K were identified as double mutations inherited on the same allele. P.W4677L, found in two moyamoya disease patients and an unaffected subject in the same pedigree, was a rare single nucleotide polymorphism. Functional analysis showed that RNF213 p.D4013N, p.R4019C and p.V4146A-transfected human umbilical vein endothelial cells displayed significant lowered migration, and RNF213 p.V4146A significantly reduced tube formation, indicating that these are disease-causing mutations. Results from the present study identified RNF213 rare variants in 22.2% (4/18 probands) of Slovakian and Czech moyamoya disease patients, confirming that RNF213 may also be a major causative gene in a relative large population of white patients.
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Project description:Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by stenosis of the internal carotid arteries with compensatory development of collateral vessels. Although a founder variant of RNF213, p.Arg4810Lys (c.14429G>A, rs112735431), is a major genetic risk factor for MMD in East Asians, the frequency and disease susceptibility of other variants in this gene remain largely unknown. In the present study, we investigated the association of RNF213 variants with MMD in Korean patients and population controls.For all RNF213 variants listed in the Human Gene Mutation Database (HGMD) as disease-causing or likely disease-causing mutations for MMD, genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Genetic data from 264 adult patients with MMD were analyzed and compared with two control populations comprised of 622 and 1,100 Korean individuals, respectively.Among the 30 RNF213 variants that were listed in the HGMD, p.Arg4810Lys was identified in 67.4% (178/264) of patients with MMD and showed a significantly higher allele frequency than in the controls, giving an odds ratio of 63.29 (95% confidence interval, 33.11-120.98) for the 622 controls and 48.55 (95% confidence interval, 31.00-76.03) for the 1100 controls. One additional variant, p.Ala5021Val (c.15062C>T, rs138130613), was identified in 0.8% (2/264) of patients; however, the allele frequencies were not significantly different from those in the controls.These results suggest that, in our cohort of Korean patients, the p.Arg4810Lys is the only variant that is strongly associated with MMD among the 30 RNF213 variants listed in the HGMD.
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Project description:In this report, we present a European family with six individuals affected with Moyamoya disease (MMD). We detected two novel missense variants in the Moyamoya susceptibility gene RNF213, c.12553A>G (p.(Lys4185Glu)) and c.12562G>A (p.(Ala4188Thr)). Cosegregation of the variants with MMD, as well as a previous report of a variant affecting the same amino acid residue in unrelated MMD patients, supports the role of RNF213 in the pathogenesis of MMD.
| S-EPMC6804521 | biostudies-literature
Project description:Although a founder variant of RNF213 4810G>A is a major genetic risk factor for moyamoya disease (MMD) in East Asians, the frequency and disease susceptibility of RNF213 variants remain largely unknown. This study investigated the mutation analysis of RNF213 (4448, 4810, 4863, and 4950) between Korean MMD and healthy controls. We performed a polymerase chain reaction-restriction fragment length polymorphism analysis. To identify the association between RNF213 gene polymorphisms and MMD disease, we performed statistical analyses such as multivariable logistic regression and Fisher's exact test. Genetic data from 117 MMD patients were analyzed and compared with 253 healthy controls. We assessed and compared single nucleotide polymorphisms of RNF213 (4448, 4810, 4863, and 4950) between MMD and control groups. We performed genome-wide association studies to investigate the genetic pathophysiology of MMD. Among the RNF213 variants (4448G>A, 4810G>A, 4863G>A, and 4950G>A), RNF213 4810G>A and 4950G>A variants were more frequent in MMD patients. In a subgroup analysis, the RNF213 4810G>A was more frequent in moyamoya disease, and the comparison with GG+AA genotype was also significantly different in moyamoya patients. These results confirm that RNF213 4810G>A and RNF213 4950G>A were more frequent in MMD patients. We have confirmed that RNF213 4810G>A and 4950G>A are strongly associated with Korean MMD in children and adults as well as for the ischemic and hemorrhagic types.
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Project description:BACKGROUND:The p.R4810K and other rare variants of ring finger protein 213 gene (RNF213) were illustrated as susceptibility variants for moyamoya (MMD) and non-moyamoya intracranial artery stenosis/occlusion disease (ICASO) recently. However, the effect sizes of p.R4810K were in great discrepancy even in studies of the same ethnic population and firm conclusions of other rare variants have been elusive given the small sample sizes and lack of replication. Thus, we performed this study to quantitatively evaluate whether or to what extent the rare variants of RNF213 contribute to MMD and ICASO in different populations. METHODS:A systematic search of PubMed, EMBASE, ISI web of science, CNKI, and WANFANG DATA was conducted up to 5 September 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random- or fixed-effect models based on the between-study heterogeneity. The subgroup analyses were performed by the ethnicity and family history. Sensitivity and publication bias analysis were performed to test the robustness of associations. All the statistical analyses were conduct using STATA 12.0. RESULTS:Twenty studies including 2353 MMD cases and 5488 controls and 11 studies including 1778 ICASO cases and 3140 controls were included in this study. Pooled ORs indicated that RNF213 p.R4810K significantly increased MMD and ICASO risk in East Asians with great effect sizes of discrepancy (dominant model: odds ratios 184.04, 109.77, and 31.53 and 10.07, 28.52, and 5.59 for MMD and ICASO, respectively, in Japan, Korea, and China). It significantly increased familial MMD risk in Japan, Korea, and China with 5 ~ 36 times larger effect sizes than that for sporadic ones in each country (dominant model ORs 1802.44, 512.42, 1109.02 and 134.35, 99.82, and 30.52, respectively, for familial and sporadic cases). The effect sizes of RNF213 p.R4810K to sporadic MMD were 3 ~ 4 times larger in Japan and Korea than those in China. RNF213 p.R4810K also increased the ICASO risk in Japan and Korea with 2 ~ 4 times larger effect sizes than that in China (dominant model ORs 10.71, 28.52, and 5.59, respectively). Another two rare variants- p.E4950D and p.A5021V significantly increased MMD risk in Chinese population (dominant model ORs 9.06 and 5.01, respectively). Various other rare variants in RNF213 were identified in Japanese, Chinese, European, and Hispanic American populations without association evidence available yet. CONCLUSIONS:This meta-analysis shows the critical roles of RNF213 p.R4810K in MMD especially familial MMD and ICASO in Japan, Korea, and China. Except for RNF213 p.R4810K, MMD seems to have more complex determiners in China. Distinct genetic background exists and other environmental or genetic factor(s) may contribute to MMD. Studies focused on delineating the ethnicity-specific factors and pathological role of RNF213 variants in MMD and ICASO are needed.
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Project description:Segmental infantile hemangiomas (IH) can be associated with congenital anomalies in a regional distribution. PHACE refers to large cervicofacial segmental IH in association with congenital anomalies of the aortic arch and medium-sized arteries of the head and neck, as well as structural anomalies of the posterior fossa and eye. A subset of PHACE patients have arterial anomalies that progress to moyamoya vasculopathy (MMV). MMV is defined as stenosis of the supraclinoid segment of the internal carotid arteries and/or their major branches, with subsequent development of a compensatory collateral vessel network. We describe a patient with MMV and segmental IH on the back and lower body who meets diagnostic criteria for PHACE based on a posterior segment eye anomaly and cerebral arterial anomalies. Whole exome sequencing demonstrated two inherited heterozygous variants in RNF213. Variants in RNF213 are associated with increased susceptibility to MMV. Our findings suggest that RNF213 variants may play a role in the development of MMV in patients with hemangioma syndromes associated with congenital cerebral arterial anomalies.
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Project description:ObjectiveTo test the hypothesis that de novo genetic variants are responsible for moyamoya disease (MMD) in children with unaffected relatives, we performed exome sequencing of 28 affected children and their unaffected parents.MethodsExome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents.ResultsWe identified 3 novel rare de novo RNF213 variants, 1 in the RING domain and 2 in a highly conserved region distal to the RING domain (4,114-4,120). These de novo cases of MMD present at a young age with aggressive MMD and uniquely have additional occlusive vascular lesions, including renal artery stenosis. Two previously reported cases had de novo variants in the same limited region and presented young with aggressive MMD, and 1 case had narrowing of the inferior abdominal aorta.ConclusionsThese results indicate a novel syndrome associated with RNF213 rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.
| S-EPMC8055312 | biostudies-literature
Project description:RNF213 p.R4810K is a founder polymorphism that confers genetic susceptibility to moyamoya disease in East Asia. Only a few studies have investigated the symptoms and disease histories of RNF213 p.R4810K carriers in Japan. This study investigated the frequency of RNF213 p.R4810K in the general Japanese population and the health characteristics of the carriers.Through a health-promotion campaign in the city of Uji, Japan, 519 subjects (120 males and 399 females) of the general Japanese population were genotyped for RNF213 p.R4810K and interviewed to determine health characteristics.Nine RNF213 p.R4810K heterozygous carriers (GA genotype) and no RNF213 p.R4810K homozygous carriers (AA genotype) were found among the 519 individuals. The estimates of the genotypes and allele frequencies for RNF213 p.R4810K were 1.73 and 0.87 %, respectively. There were no obvious differences in age, gender ratio, body mass index, hypertension, dyslipidemia, diabetes, kidney disease, liver disease, heart disease, or drinking or smoking habits between carriers and non-carriers. Interestingly, one patient with moyamoya disease was found among the nine RNF213 p.R4810K carriers.This study showed the genotypes and allele frequencies of RNF213 p.R4810K in the general Japanese population to be similar to results of previous reports.
| S-EPMC5305994 | biostudies-literature
Project description:Ring-finger protein 213 (RNF213) encodes a protein of unknown function believed to play a role in cellular metabolism and angiogenesis. Gene variants are associated with susceptibility to moyamoya disease. Here, we describe two children with moyamoya disease who also demonstrated kidney disease, elevated aminotransferases, and recurrent skin lesions found by exome sequencing to have de novo missense variants in RNF213. These cases highlight the ability of RNF213 to cause Mendelian moyamoya disease in addition to acting as a genetic susceptibility locus. The cases also suggest a new, multi-organ RNF213-spectrum disease characterized by liver, skin, and kidney pathology in addition to severe moyamoya disease caused by heterozygous, de novo C-terminal RNF213 missense variants.
| S-EPMC8360119 | biostudies-literature