RNF213 variant in a patient with Legius syndrome associated with moyamoya syndrome.
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ABSTRACT:
SUBMITTER: Romanisio G
PROVIDER: S-EPMC8222830 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Moyamoya disease (MMD) is a progressive steno-occlusive vasculopathy that involves large intracranial arteries accompanied by abnormal collateral vessels. Recently, RNF213 was identified as a susceptibility gene for MMD and p.Arg4810Lys (rs112735431) is the most common variant in East Asian MMD patients. Interestingly, many studies have reported that a certain proportion of the general population in Japan, Korea, and China also has this variant. In this study, we investigated the frequency of this variant and estimated an odds ratio of MMD using two different Korean populations.A total of 1,516 anonymous DNA samples, 799 from an umbilical cord blood bank and 717 from routine health-checked adults, were genotyped using targeted Sanger sequencing.The p.Arg4810Lys variant was detected at genotype frequencies of 2.25% (18/799; 95% confidence interval (CI), 1.43-3.53%) in cord blood samples and 2.65% (19/717; 95% CI, 1.70-4.10%) in adult samples, respectively. This variant showed a strong association with MMD (P?<?0.001), giving an odds ratio of 162.7 (95% CI, 65.5-403.9) and 137.8 (95% CI, 55.8-339.9) based on the cord blood and adults samples, respectively.These results confirm that the RNF213 p.Arg4810Lys variant is not uncommon in the general Korean population and provide reference data for the association of this variant and MMD.
| S-EPMC4654917 | biostudies-literature
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.
| S-EPMC5815368 | biostudies-literature
Project description:BackgroundThe genetic architecture of coronary artery disease has not been fully elucidated, especially in Asian countries. Moyamoya disease is a progressive cerebrovascular disease that is reported to be complicated by coronary artery disease. Because most Japanese patients with moyamoya disease carry the p.R4810K variant of the ring finger 213 gene (RNF213), this may also be a risk factor for coronary artery disease; however, this possibility has never been tested.Methods and resultsWe genotyped the RNF213 p.R4810K variant in 956 coronary artery disease patients and 716 controls and tested the association between p.R4810K and coronary artery disease. We also validated the association in an independent population of 311 coronary artery disease patients and 494 controls. In the replication study, the p.R4810K genotypes were imputed from genome-wide genotyping data based on the 1000 Genomes Project. We used multivariate logistic regression analyses to adjust for well-known risk factors such as dyslipidemia and smoking habits. In the primary study population, the frequency of the minor variant allele was significantly higher in patients with coronary artery disease than in controls (2.04% vs. 0.98%), with an odds ratio of 2.11 (p = 0.017). Under a dominant model, after adjustment for risk factors, the association remained significant, with an odds ratio of 2.90 (95% confidence interval: 1.37-6.61; p = 0.005). In the replication study, the association was significant after adjustment for age and sex (odds ratio = 4.99; 95% confidence interval: 1.16-21.53; p = 0.031), although it did not reach statistical significance when further adjusted for risk factors (odds ratio = 3.82; 95% confidence interval: 0.87-16.77; p = 0.076).ConclusionsThe RNF213 p.R4810K variant appears to be significantly associated with coronary artery disease in the Japanese population.
| S-EPMC5393571 | biostudies-literature
Project description:Variants in RNF213 lead to susceptibility to moyamoya disease, a rare cerebral angiopathy characterized by bilateral stenosis of the internal carotid arteries and development of a compensatory collateral network. We describe a 3-month-old female with seizures, arterial narrowing involving the internal carotid and intracranial arteries and inferior abdominal aorta, and persistently elevated transaminases. Whole exome sequencing demonstrated a novel de novo variant in RNF213, securing a molecular diagnosis and directing appropriate intervention. This report underscores the role of whole exome sequencing in cases for which a complex and atypical presentation may mask diagnosis. Furthermore, the early and severe presentation in our patient, in conjunction with a novel de novo RNF213 variant, suggests that specific variants in RNF213 may lead to a Mendelian form of disease rather than simply conferring susceptibility to multifactorial disease.
| S-EPMC4639746 | biostudies-literature
Project description:The cerebrovascular disorder moyamoya disease (MMD) was first described in 1957 in Japan, and is typically considered to be an Asian-specific disease. However, it is globally recognized as one of the major causes of childhood stroke. Although several monogenic diseases are known to be complicated by Moyamoya angiopathy, the ring finger protein 213 gene (RNF213) was identified as a susceptibility gene for MMD. RNF213 is unusual, because (1) it induces MMD with no other recognizable phenotypes, (2) the RNF213 p.R4810K variant is an Asian founder mutation common to Japanese, Korean and Chinese with carrier rates of 0.5-2% of the general population but a low penetrance, and (3) it encodes a relatively largest proteins with a dual AAA+ ATPase and E3 Ligase activities. In this review, we focus on the genetics and genetic epidemiology of RNF213, the pathology of RNF213 R4810K, and the molecular functions of RNF213, and also address the public health contributions to current unresolved issues of MMD. We also emphasize the importance of a more updated definition for MMD, of qualified cohort studies based on genetic epidemiology and an awareness of the ethical issues associated with genetic testing of carriers.
| S-EPMC4771639 | 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
Project description:Background:Gene polymorphism especially Ring Finger Protein 213 (RNF213) p.R4810K is one of the main cause of moyamoya disease (MMD) in Asian populations, especially among Japanese people. However, missense mutation may not explain the reduced frequency of MMD in Chinese patients. We performed a hospital based case-control study in a Chinese population to elucidate the possible underlying reasons. Methods:Five gene polymorphism loci, namely, rs35692831, rs9916351, rs9913636, rs8074015 and rs112735431, were included. A total of 98 patients and 114 healthy controls were enrolled in the study. Genomic DNA was genotyped by Mass Array methods. Results:A significant difference was observed between patients and healthy controls in rs9916351, rs9913636, and rs8074015 loci under three genotypes and allelic models (P<0.01). Logistic regression analysis revealed the significant differences under the dominant, recessive and additional model in rs9916351 [odds ratio (OR) =4.173, 95% confidence interval (CI): 2.290-7.606, P<0.001; OR =3.152, 95% CI: 1.585-6.267, P=0.001; OR =0.199, 95% CI: 1.727-3.764, P<0.001; respectively] and rs8074015 (OR =0.359, 95% CI: 0.206-0.627, P<0.001; OR =0.348, 95% CI: 0.148-0.81, P=0.015; OR =0.208, 95% CI: 0.311-0.703, P<0.001; respectively), even adjusting for age and gender. In addition, the haplotype rs9913636-rs8074015 under "GACG" showed significant association with MMD. Conclusions:Our results had revealed the polymorphism of RNF213 rs9916351 and rs8074015 were significantly associated with MMD especially in Chinese population.
| S-EPMC7396805 | biostudies-literature
Project description:The p.R4810K (rs11273543, c.14429G > A) variant of the RNF213 gene is associated with increased risk of Moyamoya disease (MMD), which is an idiopathic progressive intracranial vascular steno-occlusive disease, in Asian populations. Numerous variant association studies for this MMD variant have been performed in Japan to date. Since another genetic study that utilized approximately 140,000 single nucleotide polymor (SNPs) has indicated that there still are genetic differences among mainland Japanese, there is a possibility that the variant distribution in patients with MMD and normal individuals varies between different Japanese regions. Additionally, the majority of variant association studies have used Sanger sequencing, which is labor-intensive, time-consuming, and costly. In this study, we analyzed the frequency of the variant genotype in patients with MMD and normal individuals in Kyushu using pyrosequencing, which is an accurate, cost-effective, and automated method. We found differences in the genotype frequencies in familial patients from Kyushu and normal populations in Tohoku compared with west Japan, which suggested that there were differences in the frequency of the variant among different regions in Japan.
| S-EPMC5709714 | biostudies-literature
Project description:ObjectivesRNF213 p.R4810K was identified as a susceptibility variant for moyamoya disease in Asia and non-moyamoya intracranial artery stenosis/occlusion disease in Japan and Korea recently. The occurrence of this variant was evaluated in patients with non-moyamoya intracranial artery stenosis/occlusion disease in China.MethodsTwo study populations were used in this study. One was recruited from the Second Hospital of Hebei Medical University from April 2015 to May 2016. The other was the archived DNA samples of intracranial artery stenosis/occlusion patients in XiangYa Hospital collected in 2014. The occurrence of RNF213 p.R4810K was investigated in a total of 715 patients with non-moyamoya intracranial artery stenosis/occlusion disease. The carrier rate of RNF213 p.R4810K in 507 normal individuals was used as control.ResultsSix of 715 patients (0.84%) with non-moyamoya intracranial artery stenosis/occlusion disease and 2 of the 507 normal controls (0.39%) had RNF213 p.R4810K variant. The carrier rate of RNF213 p.R4810K was higher in non-moyamoya intracranial artery stenosis/occlusion group than that in the normal group. However, no statistically significant association was observed (Odds ratio, 2.14; 95% confidence interval, 0.43-10.63; p = 0.56).ConclusionsThe carrier rate of RNF213 p.R4810K in Chinese non-moyamoya intracranial artery stenosis/occlusion disease patients was significantly lower than that in Korea or Japan. Genetic heterogeneity was highly indicated. Further systematic genetic epidemiology studies with emphasis on Chinese-specific genetic variants and environmental risk factors of intracranial artery stenosis/occlusion disease in larger population are needed.
| S-EPMC5664791 | biostudies-literature
Project description:Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome.
| S-EPMC3038325 | biostudies-literature