Novel and recurrent RNF213 variants in Japanese pediatric patients with moyamoya disease

Akagawa, Hiroyuki; Mukawa, Maki; Nariai, Tadashi; Nomura, Shunsuke; Aihara, Yasuo; Onda, Hideaki; Yoneyama, Taku; Kudo, Takumi; Sumita, Kazutaka; Maehara, Taketoshi; Kawamata, Takakazu; Kasuya, Hidetoshi

doi:10.1038/hgv.2017.60

Cited by 14 publications

(23 citation statements)

References 20 publications

(24 reference statements)

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“…The PubMed database was searched for English publications reporting RNF213 variants detected in MMD patients up to December 2018. We selected studies which performed comprehensive retrieval of RNF213 variants in MMD patients, and found 14 matched studies that reported RNF213 variants detected in MMD patients 18,19,[26][27][28][29][30][31][32][36][37][38][39][40] . One study investigated only exons 41-68 considered to be the genomic hypervariable region of RNF213 31 , whereas the other studies comprehensively investigated the entire RNF213 gene.…”

Section: Review Of Previously Reported Rnf213 Variants Detected In MMmentioning

confidence: 99%

Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis

Hongo

Miyawaki

Imai

et al. 2020

Sci Rep

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intracranial artery stenosis (icAS) is the most common cause of ischemic stroke worldwide. RNF213 single nucleotide variant c.14429G > A (p.Arg4810Lys, rs112735431) was recently reported to be associated with icAS in east Asians. However, the disease susceptibility of other RNF213 variants has not been clarified. This study comprehensively investigated ICAS-associated RNF213 variants in a pool of 168 Japanese ICAS patients and 1,194 control subjects. We found 138 nonsynonymous germline variants by target resequencing of all coding exons in RNF213. Association study between icAS patients and control subjects revealed that only p.Arg4810Lys had significant association with ICAS (P = 1.5 × 10-28 , odds ratio = 29.3, 95% confidence interval 15.31-56.2 [dominant model]). Fourteen of 138 variants were rare variants detected in ICAS patients not harboring p.Arg4810Lys variant. Two of these rare variants (p.Cys118Arg and p.Leu2356Phe) consistent with variants previously reported in moyamoya disease patients characterized by stenosis of intracranial artery and association with RNF213, and three rare variants (p.Ser193Gly, p.Val1817Leu, and p.Asp3329Tyr) were found neither in control subjects and Single Nucleotide Polymorphism Database. The present findings may improve our understanding of the genetic background of intracranial artery stenosis. Intracranial artery stenosis (ICAS) is the most common cause of ischemic stroke worldwide 1-9 and can result in serious lifelong disabilities 4. ICAS is also associated with a high risk of recurrent stroke 3,6-8. The risks of recurrent stroke or death within 1 year and 2 years are 17.5% and 19.5%, respectively, in ICAS patients despite optimum medical management 10. In addition, ICAS is associated with depression, cognitive deficits, and dementia, and is now increasingly the focus of research. ICAS is considered to be a major cause of stroke accounting for 30-50% of cases of ischemic stroke in the Asian, African-American, and Hispanic populations, but only about 10% in Caucasians, who are more likely to have extracranial atherosclerotic disease 1-6,8,11-14. Such racial differences in the prevalence of ICAS have long been a subject of investigations 15. Various explanations for the difference in the prevalence of ICAS include genetic susceptibility of the intracranial vessels to atherosclerosis, as well as differences in lifestyle and risk factor profiles such as advanced age, hypertension, diabetes, dyslipidemia, cigarette smoking, and metabolic syndrome 4,11 .

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Section: Review Of Previously Reported Rnf213 Variants Detected In MMmentioning

confidence: 99%

Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis

Hongo

Miyawaki

Imai

et al. 2020

Sci Rep

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show abstract

“…Without understanding the pathogenetic mechanisms, our data from case-control design could not access the causal relationship between RNF213 variants and ICASO. Furthermore, ICASO and MMD, both RNF213-related disorders, are progressive cerebrovascular diseases [35,44]. Because our study lacked follow-up data, we did not provide information about the progression of ICASO or the prognostic value of RNF213 variants.…”

Section: Discussionmentioning

confidence: 99%

Distribution of Intracranial Major Artery Stenosis/Occlusion According to RNF213 Polymorphisms

Kim

Park

Woo

et al. 2020

IJMS

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Intracranial major artery stenosis/occlusion (ICASO) is the major cause of ischemic stroke. Recent studies have suggested that variants of RNF213, a susceptibility gene for moyamoya disease (MMD), are also related to non-MMD ICASO. Regarding the predominant involvement of steno-occlusion on anterior circulation in MMD, we hypothesized that the ICASO distribution pattern (anterior/posterior) in non-MMD may differ according to RNF213 variants. This study analyzed 1024 consecutive Korean subjects without MMD who underwent computed tomography angiography (CTA) or magnetic resonance angiography (MRA). We evaluated four single nucleotide polymorphisms (SNPs) in the exon region of RNF213: 4448G > A (rs148731719), 4810G > A (rs112735431), 4863G > A (rs760732823), and 4950G > A (rs371441113). Associations between RNF213 variants and anterior/posterior ICASO were examined using multivariate logistic regression analysis. Anterior ICASO was present in 23.0% of study subjects, and posterior ICASO was present in 8.2%. The GA genotype of RNF213 4810G > A (adjusted odds ratio (AOR) [95% confidence interval (CI)], 2.39 [1.14–4.87] compared to GG; p = 0.018) and GA genotype of RNF213 4950G > A (AOR [95% CI], 1.71 [1.11–2.63] compared to GG; p = 0.015) were more frequent in subjects with anterior ICASO. The genotype frequency of RNF213 4863G > A differed significantly according to the presence of posterior ICASO. Further investigations of the functional and biological roles of RNF213 will improve our understanding of the pathomechanisms of ICASO and cerebrovascular disease.

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“…Moyamoya disease (MMD) is a peculiar disease, characterized by progressive steno-occlusion of the distal ends of bilateral internal carotid arteries (ICAs) and their proal vascular network at the base of the brain (moyamoya vessels) is formed as a result of progressive ischemic changes in the brain [1], [2], [3]. The high incidence of MMD in Japanese population and high proportion of familial cases suggest the involvement of a genetic factor, particularly polymorphism in RNF213 gene [4], [5], [6].…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Profile of Distal Middle Cerebral Artery from Moyamoya Disease Patients Reveals a Potential Unique Pathway

Hermanto¹,

Doi²,

Faried³

et al. 2020

Open Access Maced J Med Sci

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BACKGROUND: Moyamoya disease (MMD) is a peculiar disease, characterized by progressive steno-occlusion of the distal ends of bilateral internal carotid arteries and their proximal branches. Numerous studies of MMD investigated as a singular pathway, thus overlooked the complexity of MMD pathobiology. AIM: In this study, we sought to investigate the gene expression in the involved arteries to reveal the novel mechanism of MMD. MATERIALS AND METHODS: Eight middle cerebral artery (MCA) specimens were obtained from six patients underwent surgical procedure superficial temporal artery to MCA (STA-MCA bypass) for MMD and two control patients. We performed RNA extraction and microarray analysis with Agilent Whole Human Genome DNA microarray 4x44K ver.2.0 (Agilent Tech., Inc., Wilmington, DE, USA). RESULTS: From 42,405 gene probes assayed, 921 gene probes were differentially regulated in MCA of patients with MMD. Subsequent pathway analysis with PANTHER database revealed that angiogenesis, inflammation, integrin, platelet-derived growth factor (PDGF), and WNT pathways were distinctly regulated in MMD. Among genes in aforementioned pathways, SOS1 and AKT2 were the mostly distinctly regulated genes and closely associated with RAS pathway. CONCLUSION: The gene expression in MCA of patients with MMD was distinctly regulated in comparison with control MCA; presumably be useful for elucidating MMD pathobiology.

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Novel and recurrent RNF213 variants in Japanese pediatric patients with moyamoya disease

Cited by 14 publications

References 20 publications

Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis

Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis

Distribution of Intracranial Major Artery Stenosis/Occlusion According to RNF213 Polymorphisms

Transcriptomic Profile of Distal Middle Cerebral Artery from Moyamoya Disease Patients Reveals a Potential Unique Pathway

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