Abstract
Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by a progressive stenosis at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. Although its etiology is undetermined, recent genome-wide and locus-specific association studies identified RNF213 as an important susceptibility gene for MMD among East Asian population. A polymorphism in c.14576G>A in RNF213 was evident in almost all of the familial patients with MMD and 80% of sporadic cases, but the exact role of RNF213 polymorphism in the development of MMD remains unknown. To answer this question, we generated genetically engineered mice lacking Rnf213 by homologous recombination (Rnf213-knockout mice), as well as Rnf213-knock-in mice expressing a missense mutation in mouse Rnf213, p. R4828K, corresponding to human RNF213, p. R4859K, in MMD patients. Although both mice did not spontaneously develop MMD up to 64 weeks of age as shown by high-resolution magnetic resonance angiography and carbon black injection analysis of the circle of Willis, the biological response of these mice under a variety of insults, such as ischemia or immunological stimuli, provided new insights for the pathogenesis of this rare entity.
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References
Suzuki J, Takaku A. Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol. 1969;20:288–99.
Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis, Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (Spontaneous Occlusion of the Circle of Willis). Neurol Med Chir (Tokyo). 2012;52:245–66.
Ikeda H, Sasaki T, Yoshimoto T, Fukui M, Arinami T. Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet. 1999;64:533–7.
Inoue TK, Ikezaki K, Sasazuki T, Matsushima T, Fukui M. Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol. 2000;15:179–82.
Sakurai K, Horiuchi Y, Ikeda H, Ikezaki K, Yoshimoto T, Fukui M, et al. A novel susceptibility locus for moyamoya disease on chromosome 8q23. J Hum Genet. 2004;49:278–81.
Yamauchi T, Tada M, Houkin K, Tanaka T, Nakamura Y, Kuroda S, et al. Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke. 2000;31:930–5.
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.
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.
Wu Z, Jiang H, Zhang L, Xu X, Zhang X, Kang Z, et al. Molecular analysis of RNF213 gene for moyamoya disease in the Chinese Han population. PLoS One. 2012;7:e48179.
Miyatake S, Miyake N, Touho H, Nishimura-Tadaki A, Kondo Y, Okada I, et al. Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology. 2012;78:803–10.
Sonobe S, Fujimura M, Niizuma K, Nishijima Y, Ito A, Shimizu H, et al. Temporal profile of the vascular anatomy evaluated by 9.4-tesla magnetic resonance angiography and histopathological analysis in mice lacking RNF213; a susceptibility gene for moyamoya disease. Brain Res. 2014;1552:64–71.
Kanoke A, Fujimura M, Niizuma K, Ito A, Sakata H, Sato-Maeda M, et al. Temporal profile of the vascular anatomy evaluated by 9.4-tesla magnetic resonance angiography and histological analysis in mice with the R4859K mutation of RNF213, the susceptibility gene for moyamoya disease. Brain Res. 2015;1624:497–505.
Hitomi T, Habu T, Kobayashi H, Okuda H, Harada KH, Osafune K, et al. 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. Biochem Biophys Res Commun. 2013;438:13–9.
Kobayashi H, Yamazaki S, Takashima S, Liu W, Okuda H, Yan J, et al. Ablation of Rnf213 retards progression of diabetes in the Akita mouse. Biochem Biophys Res Commun. 2013;432:519–25.
Kuriyama S, Kusaka Y, Fujimura M, Wakai K, Tamakoshi K, Hashimoto S, et al. Prevalence and clinicoepidemiological features of moyamoya disease in Japan: findings from a nationwide epidemiological survey. Stroke. 2008;39:42–7.
Fujimura M, Sonobe S, Nishijima Y, Niizuma K, Sakata H, Kure S, et al. Genetics and biomarkers of moyamoya disease: significance of RNF213 as a susceptibility gene. J Stroke. 2014;16:65–72.
Godin D, Ivan E, Johnson C, Magid R, Galis ZS. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation. 2000;102:2861–6.
Ryoo S, Cha J, Kim SJ, Choi JW, Ki CS, Kim KH, et al. High-resolution magnetic resonance wall imaging findings of Moyamoya disease. Stroke. 2014;45:2457–60.
Sonobe S, Fujimura M, Niizuma K, Fujimura T, Furudate S, Nishijima Y, et al. Increased vascular MMP-9 in mice lacking RNF213; moyamoya disease susceptibility gene. Neuroreport. 2014;25:1442–6.
Fujimura M, Watanabe M, Narisawa A, Shimizu H, Tominaga T. Increased expression of serum matrix metalloproteinase-9 in patients with moyamoya disease. Surg Neurol. 2009;72:476–80.
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.
Kim SJ, Heo KG, Shin HY, Bang OY, Kim GM, Chung CS, et al. Association of thyroid autoantibodies with moyamoya-type cerebrovascular disease: a prospective study. Stroke. 2010;41:173–6.
Li H, Zhang ZS, Dong ZN, Ma MJ, Yang WZ, Han C, et al. Increased thyroid function and elevated thyroid autoantibodies in pediatric patients with moyamoya disease: a case-control study. Stroke. 2011;42:1138–9.
Kanoke A, Fujimura M, Niizuma K, Fujimura T, Kakizaki A, Ito A, et al. Temporal profile of magnetic resonance angiography and decreased ratio of regulatory T cells after immunological adjuvant administration to mice lacking RNF213, a susceptibility gene for moyamoya disease. Brain Res. 1642;2016:1–9.
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Fujimura, M., Kure, S., Tominaga, T. (2017). Pathological Investigation on RNF213: Animal Models of Rnf213-Knockout and Knock-in Mice. In: Koizumi, A., et al. Moyamoya Disease Explored Through RNF213. Current Topics in Environmental Health and Preventive Medicine. Springer, Singapore. https://doi.org/10.1007/978-981-10-2711-6_7
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DOI: https://doi.org/10.1007/978-981-10-2711-6_7
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