title: 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.
abstract: Moyamoya disease (MMD) is a chronic, occlusive cerebrovascular disease with an unknown etiology. Recent genome-wide and locus-specific association studies identified the RNF213 gene (RNF213) as an important susceptibility gene of MMD among East Asian populations; however, the mechanism by which an abnormality in RNF213 leads to MMD has not yet been elucidated. Therefore, we herein generated Rnf213-knock-in mice (RNF213-KI) expressing a missense mutation in mouse Rnf213, p. R4828K, on Exon 61, corresponding to human RNF213, p. R4859K, on Exon 60, in MMD patients, and investigated whether they developed MMD. We assessed the temporal profile of intracranial arteries by 9.4-T magnetic resonance angiography (MRA) continuously in the same mouse up to 64 weeks of age. The ratios of the outer diameter of the internal carotid artery (ICA)/basilar artery (BA) and middle cerebral artery (MCA)/BA were evaluated histopathologically. The common carotid arteries (CCA) were sectioned and arterial wall thickness/thinness was evaluated by Elastica-Masson staining before and after CCA ligation, which selectively induced vascular hyperplasia. The results obtained showed that RNF213-KI grew normally, with no significant difference being observed in MRA findings or the anatomy of the circle of Willis between homozygous RNF213-KI and wild-type (Wt) littermates. Furthermore, no significant difference was noted in the diameter of the intracranial vasculature (ICA/BA; p=0.82, MCA/BA; p=0.27) or in vascular remodeling after CCA ligation. Therefore, RNF213-KI did not spontaneously develop MMD. Multiple secondary insults such as environmental factors may contribute to the onset of MMD in addition to genetic factors.
authors: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Atsushi
authors: A
authors: Kanoke
authors: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: fujimur@nsg.med.tohoku.ac.jp.
authors: Miki
authors: M
authors: Fujimura
authors: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Kuniyasu
authors: K
authors: Niizuma
authors: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Akira
authors: A
authors: Ito
authors: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Hiroyuki
authors: H
authors: Sakata
authors: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Mika
authors: M
authors: Sato-Maeda
authors: Department of Molecular Biology, Tohoku University Institute of Aging and Cancer, Sendai, Japan.
authors: Yuiko
authors: Y
authors: Morita-Fujimura
authors: Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Shigeo
authors: S
authors: Kure
authors: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Teiji
authors: T
authors: Tominaga
mesh_terms: D000251:Adenosine Triphosphatases; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000235:genetics; D001808:Blood Vessels / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D008239:Lysine / Q000235:genetics; D018810:Magnetic Resonance Angiography; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009072:Moyamoya Disease / Q000235:genetics / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D001120:Arginine; C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases; D008239:Lysine
keywords: Knock-in mice; Magnetic resonance angiography (MRA); Moyamoya disease; RNF213