{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T17:11:20Z","timestamp":1789665080016,"version":"4.0.1"},"reference-count":91,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T00:00:00Z","timestamp":1754524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Moyamoya disease (MMD) is primarily associated with genetic variants in RNF213. RNF213 p.R4810K (c.14429G&gt;A, p.Arg4810Lys) is a founder variant predominantly found in East Asian populations and is strongly associated with MMD, a rare cerebrovascular condition characterized by progressive stenosis of intracranial arteries and the development of abnormal collateral networks. Recent evidence suggests that RNF213 variants are also enriched in non-moyamoya intracranial arteriopathies, such as large-artery atherosclerotic stroke and intracranial arterial stenosis\/occlusion (ICASO), particularly in east Asian individuals with early-onset or cryptogenic stroke. This expanded phenotypic spectrum, termed RNF213-related vasculopathy (RRV), represents a distinct pathogenic entity that may involve unique pathogenic processes separate from traditional atherosclerosis. In this review, we synthesize current genetic, clinical, radiological, and experimental findings that delineate the unique features of RRV. Patients with RRV typically exhibit a lower burden of traditional vascular risk factors, negative vascular remodeling in the absence of atheromatous plaques, and an increased propensity for disease progression. RNF213 variants may compromise vascular resilience by impairing adaptive responses to hemodynamic stress. Furthermore, emerging cellular and animal model data indicate that RNF213 influences angiogenesis, lipid metabolism, and stress responses, offering mechanistic insights into its role in maintaining vascular integrity. Recognizing RRV as a distinct clinical entity has important implications for diagnosis, risk stratification, and the development of genome-informed therapeutic strategies.<\/jats:p>","DOI":"10.3390\/genes16080939","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T10:58:26Z","timestamp":1754564306000},"page":"939","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["RNF213-Related Vasculopathy: An Entity with Diverse Phenotypic Expressions"],"prefix":"10.3390","volume":"16","author":[{"given":"Takeshi","family":"Yoshimoto","sequence":"first","affiliation":[{"name":"Department of Stroke and Cerebrovascular Diseases, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9408-0560","authenticated-orcid":false,"given":"Sho","family":"Okune","sequence":"additional","affiliation":[{"name":"Department of Stroke and Cerebrovascular Diseases, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Stroke and Cerebrovascular Diseases, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Yamagami","sequence":"additional","affiliation":[{"name":"Department of Stroke and Cerebrovascular Diseases, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"},{"name":"Division of Stroke Prevention and Treatment, Institute of Medicine, University of Tsukuba, Tsukuba 305-8576, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Matsumaru","sequence":"additional","affiliation":[{"name":"Department of Stroke and Cerebrovascular Diseases, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"},{"name":"Department of Neurosurgery, Institute of Medicine, University of Tsukuba, Tsukuba 305-8576, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/S1474-4422(22)00165-X","article-title":"Moyamoya disease: Diagnosis and interventions","volume":"21","author":"Ihara","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/S1474-4422(08)70240-0","article-title":"Moyamoya disease: Current concepts and future perspectives","volume":"7","author":"Kuroda","year":"2008","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1056\/NEJMra0804622","article-title":"Moyamoya disease and moyamoya syndrome","volume":"360","author":"Scott","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Yoshimoto, T., Yamagami, H., and Matsumaru, Y. (2025). Recent advances in stroke genetics\u2014Unraveling the complexity of cerebral infarction: A brief review. Genes, 16.","DOI":"10.3390\/genes16010059"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/jhg.2010.132","article-title":"A genome-wide association study identifies RNF213 as the first Moyamoya disease gene","volume":"56","author":"Kamada","year":"2011","journal-title":"J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Liu, W., Morito, D., Takashima, S., Mineharu, Y., Kobayashi, H., Hitomi, T., Hashikata, H., Matsuura, N., Yamazaki, S., and Toyoda, A. (2011). Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022542"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s12199-015-0498-7","article-title":"A new horizon of moyamoya disease and associated health risks explored through RNF213","volume":"21","author":"Koizumi","year":"2016","journal-title":"Environ. Health Prev. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3200","DOI":"10.1161\/STROKEAHA.114.006244","article-title":"RNF213 rare variants in an ethnically diverse population with Moyamoya disease","volume":"45","author":"Cecchi","year":"2014","journal-title":"Stroke"},{"key":"ref_9","first-page":"49","article-title":"Moyamoya disease and syndromes: From genetics to clinical management","volume":"8","author":"Guey","year":"2015","journal-title":"Appl. Clin. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1097\/CM9.0000000000002985","article-title":"RNF213 in moyamoya disease: Genotype-phenotype association and the underlying mechanism","volume":"137","author":"Fang","year":"2024","journal-title":"Chin. Med. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1038\/ejhg.2017.92","article-title":"FREX consortium. Rare RNF213 variants in the C-terminal region encompassing the RING-finger domain are associated with moyamoya angiopathy in Caucasians","volume":"25","author":"Guey","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1212\/01.wnl.0000176066.33797.82","article-title":"Moyamoya disease in Washington State and California","volume":"65","author":"Uchino","year":"2005","journal-title":"Neurology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2","DOI":"10.5853\/jos.2015.01627","article-title":"Moyamoya disease: Epidemiology, clinical features, and diagnosis","volume":"18","author":"Kim","year":"2016","journal-title":"J. Stroke"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"307","DOI":"10.2176\/jns-nmc.2022-0072","article-title":"Diagnostic criteria for Moyamoya disease\u20142021 revised version","volume":"62","author":"Kuroda","year":"2022","journal-title":"Neurol. Med. Chir."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"299","DOI":"10.2176\/nmc.52.299","article-title":"Distribution of moyamoya disease susceptibility polymorphism p.R4810K in RNF213 in East and Southeast Asian populations","volume":"52","author":"Liu","year":"2012","journal-title":"Neurol. Med. Chir."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1161\/CIRCULATIONAHA.118.038439","article-title":"Moyamoya disease susceptibility variant RNF213 p.R4810K increases the risk of ischemic stroke attributable to large-artery atherosclerosis","volume":"139","author":"Okazaki","year":"2019","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s12199-017-0680-1","article-title":"Rare variants of RNF213 and moyamoya\/non-moyamoya intracranial artery stenosis\/occlusion disease risk: A meta-analysis and systematic review. Environ","volume":"22","author":"Liao","year":"2017","journal-title":"Health Prev. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Liao, X., Zhang, T., Li, B., Hu, S., Liu, J., Deng, J., Tan, H., and Yan, J. (2019). Rare RNF213 variants and the risk of intracranial artery stenosis\/occlusion disease in Chinese population: A case-control study. BMC Med. Genet., 20.","DOI":"10.1186\/s12881-019-0788-9"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3371","DOI":"10.1161\/STROKEAHA.112.663864","article-title":"Identification of a genetic variant common to moyamoya disease and intracranial major artery stenosis\/occlusion","volume":"43","author":"Miyawaki","year":"2012","journal-title":"Stroke"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s12199-012-0299-1","article-title":"P.R4810K, a polymorphism of RNF213, the susceptibility gene for moyamoya disease, is associated with blood pressure","volume":"18","author":"Koizumi","year":"2013","journal-title":"Environ. Health Prev. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1097\/HJH.0000000000002964","article-title":"The association between the Moyamoya disease susceptible gene RNF213 variant and incident cardiovascular disease in a general population: The Nagahama study","volume":"39","author":"Tabara","year":"2021","journal-title":"J. Hypertens."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Morimoto, T., Mineharu, Y., Ono, K., Takagi, Y., Nozaki, K., Fujioka, T., Miyamoto, S., Iihara, K., Kuwabara, Y., and Koizumi, A. (2017). Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0175649"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.jacasi.2023.05.002","article-title":"RNF213 p.R4810K variant increases the risk of vasospastic angina","volume":"3","author":"Ishiyama","year":"2023","journal-title":"JACC Asia"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Luo, Y., Cao, Z., Wu, S., and Sun, X. (2022). Ring finger protein 213 in Moyamoya disease with pulmonary arterial hypertension: A mini-review. Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.843927"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2045894018778155","DOI":"10.1177\/2045894018778155","article-title":"Rare variants in RNF213, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia-induced pulmonary hypertension in mice","volume":"8","author":"Kobayashi","year":"2018","journal-title":"Pulm. Circ."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s12199-016-0549-8","article-title":"Frequency of RNF213 p.R4810K, a susceptibility variant for moyamoya disease, and health characteristics of carriers in the Japanese population","volume":"21","author":"Cao","year":"2016","journal-title":"Environ. Health Prev. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e1783","DOI":"10.1212\/WNL.0000000000011653","article-title":"Association of de novo RNF213 variants with childhood onset Moyamoya disease and diffuse occlusive vasculopathy","volume":"96","author":"Pinard","year":"2021","journal-title":"Neurology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"303","DOI":"10.5853\/jos.2023.00297","article-title":"Genotype-phenotype correlation of the RNF213 R4810K variant in moyamoya disease","volume":"25","author":"Ok","year":"2023","journal-title":"J. Stroke"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e036333","DOI":"10.1161\/JAHA.124.036333","article-title":"Relationship between RNF213 p.R4810K and echocardiographic findings in patients with cerebrovascular diseases: A multicenter prospective cohort study","volume":"14","author":"Noda","year":"2025","journal-title":"J. Am. Heart Assoc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.healun.2019.08.022","article-title":"Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension","volume":"39","author":"Hiraide","year":"2020","journal-title":"J. Heart Lung Transplant."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.healun.2019.10.003","article-title":"Pulmonary arterial hypertension in the modern era: The intersection of genotype and phenotype","volume":"39","author":"Ruopp","year":"2020","journal-title":"J. Heart Lung Transplant."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hiraide, T., Suzuki, H., Momoi, M., Shinya, Y., Fukuda, K., Kosaki, K., and Kataoka, M. (2022). RNF213-associated vascular disease: A concept unifying various vasculopathies. Life, 12.","DOI":"10.3390\/life12040555"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1007\/s11427-018-9382-0","article-title":"A targeted sequencing approach to find novel pathogenic genes associated with sporadic aortic dissection","volume":"61","author":"Li","year":"2018","journal-title":"Sci. China Life Sci."},{"key":"ref_34","first-page":"e000298","article-title":"Association of the RNF213 p.R4810K variant with the outer diameter of cervical arteries in patients with ischemic stroke","volume":"2","author":"Yamaguchi","year":"2022","journal-title":"Stroke Vasc. Interv. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e016670","DOI":"10.1161\/JAHA.120.016670","article-title":"Prospective screening of extracranial systemic arteriopathy in young adults with Moyamoya disease","volume":"9","author":"Jee","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1002\/ajmg.a.38258","article-title":"RNF213 variants in a child with PHACE syndrome and moyamoya vasculopathy","volume":"173","author":"Schilter","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1111\/ene.14754","article-title":"Cutaneous manifestations in Moyamoya angiopathy: A review","volume":"28","author":"Mitri","year":"2021","journal-title":"Eur. J. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Eto, F., Yoshimoto, T., Okazaki, S., Nishimura, K., Ogura, S., Yamaguchi, E., Fukuma, K., Saito, S., Washida, K., and Koga, M. (2021). RNF213 p.R4810K (c.14429G > A) variant determines anatomical variations of the circle of Willis in cerebrovascular disease. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.681743"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e56185","DOI":"10.7554\/eLife.56185","article-title":"Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism","volume":"9","author":"Ahel","year":"2020","journal-title":"eLife"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1002\/ajmg.a.62215","article-title":"A new syndrome of moyamoya disease, kidney dysplasia, aminotransferase elevation, and skin disease associated with de novo variants in RNF213","volume":"185","author":"Strong","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.devcel.2015.12.015","article-title":"Endothelial RSPO3 controls vascular stability and pruning through non-canonical WNT\/Ca2+\/NFAT signaling","volume":"36","author":"Scholz","year":"2016","journal-title":"Dev. Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s12013-011-9159-7","article-title":"Phenotype switch of vascular smooth muscle cells after siRNA silencing of filamin","volume":"61","author":"Zhu","year":"2011","journal-title":"Cell Biochem. Biophys."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Mineharu, Y., and Miyamoto, S. (2021). RNF213 and GUCY1A3 in Moyamoya Disease: Key Regulators of Metabolism, Inflammation, and Vascular Stability. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.687088"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e002146","DOI":"10.1161\/JAHA.115.002146","article-title":"Biochemical and functional characterization of RNF213 (Mysterin) R4810K, a susceptibility mutation of moyamoya disease, in angiogenesis in vitro and in vivo","volume":"4","author":"Kobayashi","year":"2015","journal-title":"J. Am. Heart Assoc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5961","DOI":"10.1038\/s41467-024-50392-z","article-title":"RNF213 promotes Treg cell differentiation by facilitating K63-linked ubiquitination and nuclear translocation of FOXO1","volume":"15","author":"Yang","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12987-025-00649-6","article-title":"The role of the RING finger protein 213 gene in Moyamoya disease","volume":"22","author":"Deng","year":"2025","journal-title":"Fluids Barriers CNS"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.bbrc.2013.07.004","article-title":"Downregulation of Securin by the variant RNF213 R4810K (rs112735431, G>A) reduces angiogenic activity of induced pluripotent stem cell-derived vascular endothelial cells from moyamoya patients","volume":"438","author":"Hitomi","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1007\/s12975-019-00743-6","article-title":"Moyamoya disease and spectrums of RNF213 vasculopathy","volume":"11","author":"Bang","year":"2020","journal-title":"Transl Stroke Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1161\/STROKEAHA.120.032691","article-title":"Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function","volume":"53","author":"Roy","year":"2022","journal-title":"Stroke"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Ohkubo, K., Sakai, Y., Inoue, H., Akamine, S., Ishizaki, Y., Matsushita, Y., Sanefuji, M., Torisu, H., Ihara, K., and Sardiello, M. (2015). Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells. Sci. Rep., 5.","DOI":"10.1038\/srep13191"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5772","DOI":"10.1038\/s41467-021-26061-w","article-title":"Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity","volume":"12","author":"Thery","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/s41586-021-03566-4","article-title":"Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection","volume":"594","author":"Otten","year":"2021","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Choi, J., Inoue, R., Masuo, Y., Shimizu, Y., Sonomura, K., Kim, M., Kobayashi, H., Harada, K.H., Mineharu, Y., and Koizumi, A. (2025). RNF213 acts as a molecular switch for Cav-1 ubiquitination and phosphorylation in human cells. Cells, 14.","DOI":"10.3390\/cells14110775"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1177\/1747493016662039","article-title":"Caveolin-1, Ring finger protein 213, and endothelial function in Moyamoya disease","volume":"11","author":"Bang","year":"2016","journal-title":"Int. J. Stroke"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1161\/CIRCRESAHA.115.308269","article-title":"Endothelial mineralocorticoid receptor mediates diet-induced aortic stiffness in females","volume":"118","author":"Jia","year":"2016","journal-title":"Circ. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s11340-020-00666-6","article-title":"Arterial wall stiffening in caveolin-1 deficiency-induced pulmonary artery hypertension in mice","volume":"61","author":"Moreno","year":"2021","journal-title":"Exp. Mech."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/j.cardiores.2005.12.014","article-title":"Caveolins and the regulation of endothelial nitric oxide synthase in the heart","volume":"69","author":"Feron","year":"2006","journal-title":"Cardiovasc Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1038\/82176","article-title":"In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation","volume":"6","author":"Bucci","year":"2000","journal-title":"Nat. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1083\/jcb.201712120","article-title":"The AAA+ ATPase\/ubiquitin ligase mysterin stabilizes cytoplasmic lipid droplets","volume":"218","author":"Sugihara","year":"2019","journal-title":"J. Cell Biol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Yuan, Y., Jiang, L., Liu, Y., and Zhang, L. (2023). The emerging role of E3 ubiquitin ligase RNF213 as an antimicrobial host determinant. Front. Cell Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1205355"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e202000807","DOI":"10.26508\/lsa.202000807","article-title":"MMD-associated RNF213 SNPs encode dominant-negative alleles that globally impair ubiquitylation","volume":"5","author":"Bhardwaj","year":"2022","journal-title":"Life Sci. Alliance"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.brainres.2016.04.051","article-title":"Mutation of RNF213 a by TALEN causes abnormal angiogenesis and circulation defects in zebrafish","volume":"1644","author":"Wen","year":"2016","journal-title":"Brain Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.brainres.2014.01.011","article-title":"Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213: A susceptibility gene for moyamoya disease","volume":"1552","author":"Sonobe","year":"2014","journal-title":"Brain Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1016\/j.jstrokecerebrovasdis.2018.04.013","article-title":"RNF213 p.R4810K polymorphism and the risk of Moyamoya disease, intracranial major artery stenosis\/occlusion, and quasi-moyamoya disease: A meta-analysis","volume":"27","author":"Wang","year":"2018","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"105305","DOI":"10.1016\/j.jstrokecerebrovasdis.2020.105305","article-title":"Vascular smooth muscle cell derived from iPS cell of Moyamoya disease\u2014Comparative characterization with endothelial cell transcriptome","volume":"29","author":"Tokairin","year":"2020","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Hamauchi, S., Shichinohe, H., Uchino, H., Yamaguchi, S., Nakayama, N., Kazumata, K., Osanai, T., Abumiya, T., Houkin, K., and Era, T. (2016). Cellular Functions and Gene and Protein Expression Profiles in Endothelial Cells Derived from Moyamoya Disease-Specific iPS Cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163561"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1007\/s00701-012-1472-4","article-title":"Outer-diameter narrowing of the internal carotid and middle cerebral arteries in moyamoya disease detected on 3D constructive interference in steady-state MR image: Is arterial constrictive remodeling a major pathogenesis?","volume":"154","author":"Kaku","year":"2012","journal-title":"Acta Neurochir."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1161\/STROKEAHA.114.004761","article-title":"High-resolution magnetic resonance wall imaging findings of Moyamoya disease","volume":"45","author":"Ryoo","year":"2014","journal-title":"Stroke"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e011996","DOI":"10.1161\/JAHA.119.011996","article-title":"Ring finger protein 213 variant and plaque characteristics, vascular remodeling, and hemodynamics in patients with intracranial atherosclerotic stroke: A high-resolution magnetic resonance imaging and hemodynamic study","volume":"8","author":"Choi","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.5551\/jat.63379","article-title":"RNF213 p.R4810K variant carriers with intracranial arterial stenosis have a low atherosclerotic burden","volume":"29","author":"Ohara","year":"2022","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1161\/01.STR.22.3.312","article-title":"Probability of stroke: A risk profile from the Framingham Study","volume":"22","author":"Wolf","year":"1991","journal-title":"Stroke"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1161\/STROKEAHA.108.521419","article-title":"The Essen stroke risk score predicts recurrent cardiovascular events: A validation within the REduction of Atherothrombosis for Continued Health (REACH) registry","volume":"40","author":"Weimar","year":"2009","journal-title":"Stroke"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.5551\/jat.48843","article-title":"Development of a cardiovascular disease risk prediction model using the Suita Study, a population-based prospective cohort study in Japan","volume":"27","author":"Nakai","year":"2020","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"117281","DOI":"10.1016\/j.atherosclerosis.2023.117281","article-title":"Association of thyroid peroxidase antibody with the RNF213 p.R4810K variant in ischemic stroke\/transient ischemic attack","volume":"382","author":"Yoshimoto","year":"2023","journal-title":"Atherosclerosis"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Duntas, L.H., and Brenta, G. (2018). A renewed focus on the association between thyroid hormones and lipid metabolism. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00511"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"76","DOI":"10.2174\/1874192401105010076","article-title":"Effects of thyroid dysfunction on lipid profile","volume":"5","author":"Rizos","year":"2011","journal-title":"Open Cardiovasc. Med. J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"511","DOI":"10.3803\/EnM.2023.1915","article-title":"Lipid variability induces endothelial dysfunction by increasing inflammation and oxidative stress","volume":"39","author":"Rhee","year":"2024","journal-title":"Endocrinol. Metab."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.2147\/DMSO.S458233","article-title":"Association of biomarkers for dyslipidemia, inflammation, and oxidative stress with endothelial dysfunction in obese youths: A case-control study","volume":"17","author":"Sharma","year":"2024","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3026","DOI":"10.1161\/STROKEAHA.117.018227","article-title":"Added value of vessel wall magnetic resonance imaging for differentiation of nonocclusive intracranial vasculopathies","volume":"48","author":"Shibata","year":"2017","journal-title":"Stroke"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1179\/1743132815Y.0000000069","article-title":"Vascular remodeling of the circle of Willis in moyamoya disease","volume":"37","author":"Mikami","year":"2015","journal-title":"Neurol. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"777","DOI":"10.3171\/2016.11.JNS161650","article-title":"Angiographic features of hemorrhagic moyamoya disease with high recurrence risk: A supplementary analysis of the Japan Adult Moyamoya Trial","volume":"128","author":"Funaki","year":"2018","journal-title":"J. Neurosurg."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Macvanin, M.T., Gluvic, Z., Zafirovic, S., Gao, X., Essack, M., and Isenovic, E.R. (2023). The protective role of nutritional antioxidants against oxidative stress in thyroid disorders. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1092837"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"323","DOI":"10.2478\/jomb-2014-0044","article-title":"Association between thyroid hormones, lipids and oxidative stress markers in subclinical hypothyroidism","volume":"34","author":"Cheserek","year":"2015","journal-title":"J. Med. Biochem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.jstrokecerebrovasdis.2017.11.037","article-title":"Thyroid autoantibodies and the clinical presentation of moyamoya disease: A prospective study","volume":"27","author":"Lanterna","year":"2018","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.atherosclerosis.2018.11.032","article-title":"TPO-Ab plays a role in arterial remodeling in patients with intracranial stenosis","volume":"280","author":"Zhang","year":"2019","journal-title":"Atherosclerosis"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1161\/STROKEAHA.109.562264","article-title":"Association of thyroid autoantibodies with moyamoya-type cerebrovascular disease: A prospective study","volume":"41","author":"Kim","year":"2010","journal-title":"Stroke"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1212\/WNL.0b013e318249f71f","article-title":"Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease","volume":"78","author":"Miyatake","year":"2012","journal-title":"Neurology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/jhg.2012.105","article-title":"Sibling cases of moyamoya disease having homozygous and heterozygous c.14576G>A variant in RNF213 showed varying clinical course and severity","volume":"57","author":"Miyatake","year":"2012","journal-title":"J. Hum. Genet."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e200029","DOI":"10.1212\/NXG.0000000000200029","article-title":"Effect of the RNF213 p.R4810K variant on the progression of intracranial artery stenosis: A 15-year follow-up study","volume":"8","author":"Okazaki","year":"2022","journal-title":"Neurol. Genet."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e039002","DOI":"10.1161\/JAHA.124.039002","article-title":"Balloon pulmonary angioplasty in heterozygous RNF213 p.Arg4810Lys variant carriers diagnosed with chronic thromboembolic pulmonary hypertension","volume":"14","author":"Kiko","year":"2025","journal-title":"J. Am. Heart Assoc."},{"key":"ref_91","first-page":"e000396","article-title":"Impact of the RNF213 p.R4810K variant on endovascular therapy for large-vessel occlusion stroke","volume":"2","author":"Yoshimoto","year":"2022","journal-title":"Stroke Vasc. Interv. 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