title: A new horizon of moyamoya disease and associated health risks explored through RNF213.
abstract: The cerebrovascular disorder moyamoya disease (MMD) was first described in 1957 in Japan, and is typically considered to be an Asian-specific disease. However, it is globally recognized as one of the major causes of childhood stroke. Although several monogenic diseases are known to be complicated by Moyamoya angiopathy, the ring finger protein 213 gene (RNF213) was identified as a susceptibility gene for MMD. RNF213 is unusual, because (1) it induces MMD with no other recognizable phenotypes, (2) the RNF213 p.R4810K variant is an Asian founder mutation common to Japanese, Korean and Chinese with carrier rates of 0.5-2% of the general population but a low penetrance, and (3) it encodes a relatively largest proteins with a dual AAA+ ATPase and E3 Ligase activities. In this review, we focus on the genetics and genetic epidemiology of RNF213, the pathology of RNF213 R4810K, and the molecular functions of RNF213, and also address the public health contributions to current unresolved issues of MMD. We also emphasize the importance of a more updated definition for MMD, of qualified cohort studies based on genetic epidemiology and an awareness of the ethical issues associated with genetic testing of carriers.
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. Koizumi.akio.5v@kyoto-u.ac.jp.
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Hatasu
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Preventive Medicine, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, 216-8511, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hitomi
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Kouji H
authors.initials: KH
authors.lastname: Harada
authors.affiliation: Laboratory of Nutritional Sciences, Department of Food Science and Nutrition, Mukogawa Women's University, Ikebirakicho 4-46, Nishinomiya, 663-8558, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Habu
authors.affiliation: Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Shohab
authors.initials: S
authors.lastname: Youssefian
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D009072:Moyamoya Disease / Q000235:genetics* / Q000473:pathology*; D018570:Risk Assessment; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases
keywords: Angiogenesis; Asian founder mutation; Hypoxia; Moyamoya disease; RNF213 R4810K