Abstract
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by NOTCH3, primarily affects small cerebral arteries; however, stenosis of major intracranial arteries has occasionally been reported. Recent studies identified a close association between the c.14576G>A (p.R4859K, rs112735431) variant of the ring finger protein 213 (RNF213) gene and sporadic intracranial arterial stenosis (ICAS). To determine whether RNF213 is associated with ICAS in CADASIL, we genotyped rs112735431 for 124 patients with CADASIL. The c.14576G>A carrier rate in CADASIL patients with ICAS (4/17; 23.5%) was significantly higher compared with those without ICAS (2/107; 1.9%) (P = 0.0032). Among patients with ICAS, frequency of territorial infarction was significantly higher in c.14576G>A carriers (75.0%) than in non-carriers (20.0%) (P = 0.0410). In addition, rate of ≥50% stenosis or occlusion tended to be higher in c.14576G>A carriers (4/4; 100%) than in non-carriers (6/13; 46.2%) (P = 0.1029). We conclude that RNF213 is a gene associated with susceptibility to ICAS in CADASIL patients. MRA follow-up and close observation are necessary for CADASIL patients with the RNF213 variant, as they may be predisposed to ICAS.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. Lancet Neurol. 2009;8:643–53.
Davous P. CADASIL: a review with proposed diagnostic criteria. Eur J Neurol. 1998;5:219–33.
Kang HG, Kim JS. Intracranial arterial disease in CADASIL patients. J Neurol Sci. 2015;359:347–50.
Carvalho M, Oliveira A, Azevedo E, Bastos-Leite AJ. Intracranial arterial stenosis. J Stroke Cerebrovasc Dis. 2014;23:599–609.
Miyawaki S, Imai H, Takayanagi S, Mukasa A, Nakatomi H, Saito N. Identification of a genetic variant common to moyamoya disease and intracranial major artery stenosis/occlusion. Stroke. 2012;43:3371–4.
Bang OY, Chung JW, Cha J, Lee MJ, Yeon JY, Ki CS, et al. A polymorphism in RNF213 is a susceptibility gene for intracranial atherosclerosis. PLoS ONE. 2016;11:e0156607.
Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS ONE. 2011;6:e22542.
Kamada F, Aoki Y, Narisawa A, Abe Y, Komatsuzaki S, Kikuchi A, et al. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet. 2011;56:34–40.
Fukui M, Kono S, Sueishi K, Ikezaki K. Moyamoya disease. Neuropathology. 2000;20:S61–64.
Ito A, Fujimura M, Niizuma K, Kanoke A, Sakata H, Morita-Fujimura Y, et al. Enhanced post-ischemic angiogenesis in mice lacking RNF213; a susceptibility gene for moyamoya disease. Brain Res. 2015;1594:310–20.
Mizuta I, Watanabe-Hosomi A, Koizumi T, Mukai M, Hamano A, Tomii Y, et al. New diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy in Japan. J Neurol Sci. 2017;381:62–67.
Choi EJ, Choi CG, Kim JS. Large cerebral artery involvement in CADASIL. Neurology. 2005;65:1322–4.
Uehara T, Tabuchi M, Mori E. Frequency and clinical correlates of occlusive lesions of cerebral arteries in Japanese patients without stroke. Cerebrovasc Dis. 1998;8:267–72.
Bae HJ, Lee J, Park JM, Kwon O, Koo JS, Kim BK, et al. Risk factors of intracranial cerebral atherosclerosis among asymptomatics. Cerebrovasc Dis. 2007;24:355–60.
Acknowledgements
This work was supported by the construction and application of a database for CADASIL, a hereditary small-vessel disease, by the Japan Agency for Medical Research and Development (AMED), and by a grant-in-aid for Research on Intractable Disease “Research group on medical infrastructure for adult-onset leukoencephalopathy” from the Japanese Ministry of Health, Labor, and Welfare, Japan. We thank all participants in this study. This work forms part of the master’s thesis of Yeung WTE.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Yeung, W.T.E., Mizuta, I., Watanabe-Hosomi, A. et al. RNF213-related susceptibility of Japanese CADASIL patients to intracranial arterial stenosis. J Hum Genet 63, 687–690 (2018). https://doi.org/10.1038/s10038-018-0428-9
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s10038-018-0428-9
This article is cited by
-
Signaling pathways and molecular mechanisms involved in the onset and progression of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); a focus on Notch3 signaling
The Journal of Headache and Pain (2025)
-
Ring finger protein 213 c.14576G>A mutation is not involved in internal carotid artery and middle cerebral artery dysplasia
Scientific Reports (2021)
