Subtopic Deep Dive
RNF213 Gene in Moyamoya Disease
Research Guide
What is RNF213 Gene in Moyamoya Disease?
The RNF213 gene, particularly its p.R4810K variant, serves as the primary susceptibility factor for Moyamoya disease, predominantly in East Asian populations through founder effects and vascular developmental impacts.
RNF213 was identified as the key susceptibility gene via GWAS mapping to 17q25.3 in Japanese families (Liu et al., 2011, 697 citations). The p.R4810K polymorphism shows high prevalence in East Asians but rarity elsewhere (Liu et al., 2012, 130 citations; Cecchi et al., 2014, 149 citations). Functional studies reveal its role as an AAA+ ATPase affecting angiogenesis (Kobayashi et al., 2015, 154 citations). Over 20 papers detail its ethnic distribution and mechanisms.
Why It Matters
RNF213 p.R4810K enables genetic risk stratification for Moyamoya disease screening in East Asians, guiding early surgical interventions like revascularization (Kossorotoff et al., 2015, 202 citations). Functional assays show the variant impairs endothelial proliferation and tube formation, informing targeted therapies (Kobayashi et al., 2015, 154 citations). Population studies support founder effect models, aiding personalized medicine in high-prevalence regions (Wu et al., 2012, 136 citations; Koizumi et al., 2015, 128 citations). Recent guidelines incorporate RNF213 testing for adult diagnosis (Gonzalez et al., 2023, 124 citations).
Key Research Challenges
Ethnic Variant Specificity
p.R4810K dominates in East Asians but rare variants vary globally, complicating universal screening (Cecchi et al., 2014, 149 citations). Founder effects limit generalizability beyond Asia (Liu et al., 2012, 130 citations). Standardized multi-ethnic genotyping protocols remain undeveloped.
Functional Mechanism Elucidation
RNF213's AAA+ ATPase alters angiogenesis in vitro but in vivo vascular models are limited (Kobayashi et al., 2015, 154 citations; Morito et al., 2014, 110 citations). Oligomerization dynamics need clearer links to Moyamoya stenosis (Bang et al., 2016, 202 citations).
Clinical Translation Barriers
Genetic testing integration into treatment decisions lacks prospective validation (Gonzalez et al., 2023, 124 citations). Rare variant penetrance requires large cohort studies for risk prediction (Mertens et al., 2021, 122 citations).
Essential Papers
Identification of RNF213 as a Susceptibility Gene for Moyamoya Disease and Its Possible Role in Vascular Development
Wanyang Liu, Daisuke Morito, Seiji Takashima et al. · 2011 · PLoS ONE · 697 citations
<div><h3>Background</h3><p>Moyamoya disease is an idiopathic vascular disorder of intracranial arteries. Its susceptibility locus has been mapped to 17q25.3 in Japanese fami...
Moyamoya disease and syndromes: from genetics to clinical management
Manoëlle Kossorotoff, Elisabeth Tournier‐Lasserve, Dominique Hervé et al. · 2015 · The Application of Clinical Genetics · 202 citations
Moyamoya angiopathy is characterized by a progressive stenosis of the terminal portion of the internal carotid arteries and the development of a network of abnormal collateral vessels. This chronic...
The Pathophysiology of Moyamoya Disease: An Update
Oh Young Bang, Miki Fujimura, Seung‐Ki Kim · 2016 · Journal of Stroke · 202 citations
Moyamoya disease (MMD) is a unique cerebrovascular disease characterized by the progressive stenosis of large intracranial arteries and a hazy network of basal collaterals called moyamoya vessels. ...
Biochemical and Functional Characterization of RNF213 (Mysterin) R4810K, a Susceptibility Mutation of Moyamoya Disease, in Angiogenesis In Vitro and In Vivo
Hatasu Kobayashi, Yoshiko Matsuda, Toshiaki Hitomi et al. · 2015 · Journal of the American Heart Association · 154 citations
Background P.R4810K of RNF 213 (mysterin: rs112735431), which is an AAA + ATP ase, is the susceptibility polymorphism for moyamoya disease ( MMD ) in East Asians. However, the role of RNF 213 R4810...
<i>RNF213</i> Rare Variants in an Ethnically Diverse Population With Moyamoya Disease
Alana C. Cecchi, Dongchuan Guo, Zhao Ren et al. · 2014 · Stroke · 149 citations
Background and Purpose— Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease resulting from occlusion of the distal internal carotid arteries. A variant in the Ring F...
Molecular Analysis of RNF213 Gene for Moyamoya Disease in the Chinese Han Population
Zhiyuan Wu, Hanqiang Jiang, Lei Zhang et al. · 2012 · PLoS ONE · 136 citations
<div><h3>Background</h3><p>Moyamoya disease (MMD) is an uncommon cerebrovascular disorder characterized by progressive occlusion of the internal carotid artery causing cereb...
Distribution of Moyamoya Disease Susceptibility Polymorphism p.R4810K in RNF213 in East and Southeast Asian Populations
Wanyang Liu, Toshiaki Hitomi, Hatasu Kobayashi et al. · 2012 · Neurologia medico-chirurgica · 130 citations
Moyamoya disease is an idiopathic vascular disorder of the intracranial arteries. Ring finger 213 (RNF213) was previously identified as the strongest susceptibility gene for moyamoya disease in Eas...
Reading Guide
Foundational Papers
Start with Liu et al. (2011, 697 citations) for gene discovery via GWAS in Japanese cohorts; follow with Cecchi et al. (2014, 149 citations) for ethnic diversity and Wu et al. (2012, 136 citations) for Chinese validation to grasp susceptibility patterns.
Recent Advances
Study Kobayashi et al. (2015, 154 citations) for functional angiogenesis assays; Mertens et al. (2021, 122 citations) for genetic basis synthesis; Gonzalez et al. (2023, 124 citations) for clinical management integration.
Core Methods
Core techniques include GWAS linkage analysis (Liu et al., 2011), targeted sequencing for p.R4810K (Wu et al., 2012), in vitro HUVEC proliferation/tube formation assays (Kobayashi et al., 2015), and zebra fish vascular imaging.
How PapersFlow Helps You Research RNF213 Gene in Moyamoya Disease
Discover & Search
Research Agent uses searchPapers and exaSearch to retrieve all 250M+ papers on RNF213 p.R4810K, surfacing Liu et al. (2011, 697 citations) as top hit; citationGraph maps 20+ descendants like Kobayashi et al. (2015); findSimilarPapers expands to ethnic cohorts.
Analyze & Verify
Analysis Agent applies readPaperContent to parse Liu et al. (2011) GWAS methods, verifyResponse with CoVe cross-checks variant frequencies against Cecchi et al. (2014), and runPythonAnalysis computes allele frequency stats from supplementary tables using pandas; GRADE grading scores evidence as high for East Asian susceptibility.
Synthesize & Write
Synthesis Agent detects gaps in non-Asian rare variants via contradiction flagging across Cecchi et al. (2014) and Wu et al. (2012); Writing Agent uses latexEditText for manuscript sections, latexSyncCitations to link 10+ RNF213 papers, latexCompile for PDF output, and exportMermaid for variant prevalence flowcharts.
Use Cases
"Compute p.R4810K allele frequencies from Liu 2011 and Wu 2012 cohorts"
Research Agent → searchPapers → Analysis Agent → readPaperContent + runPythonAnalysis (pandas aggregation of Japanese/Chinese data) → CSV table of odds ratios and p-values.
"Draft LaTeX review on RNF213 functional studies with citations"
Synthesis Agent → gap detection → Writing Agent → latexEditText (intro/methods) → latexSyncCitations (10 papers) → latexCompile → formatted PDF with RNF213 angiogenesis diagram.
"Find GitHub repos analyzing RNF213 GWAS data"
Research Agent → paperExtractUrls (from Liu 2011) → Code Discovery → paperFindGithubRepo → githubRepoInspect → curated list of 3 repos with variant calling pipelines.
Automated Workflows
Deep Research workflow conducts systematic review of 50+ RNF213 papers: searchPapers → citationGraph → GRADE all abstracts → structured report on ethnic prevalence. DeepScan applies 7-step analysis with CoVe checkpoints to verify p.R4810K penetrance claims across Liu et al. (2011) and Cecchi et al. (2014). Theorizer generates hypotheses on RNF213 ATPase inhibition for therapy from Kobayashi et al. (2015) mechanisms.
Frequently Asked Questions
What defines RNF213's role in Moyamoya disease?
RNF213 p.R4810K is the strongest susceptibility variant identified by GWAS at 17q25.3, acting as an AAA+ ATPase that impairs vascular development (Liu et al., 2011, 697 citations).
What methods study RNF213 variants?
GWAS, Sanger sequencing, and functional assays like HUVEC angiogenesis measure impacts; in vivo zebra fish models test vascular defects (Liu et al., 2011; Kobayashi et al., 2015, 154 citations).
What are key papers on RNF213?
Liu et al. (2011, 697 citations) discovered the gene; Kobayashi et al. (2015, 154 citations) detailed biochemical functions; Cecchi et al. (2014, 149 citations) assessed global variants.
What open problems exist?
Non-Asian rare variants' contributions, full ATPase mechanism in stenosis, and prospective testing for treatment stratification lack resolution (Mertens et al., 2021, 122 citations; Gonzalez et al., 2023, 124 citations).
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