Functional analysis of RNF213 gene identified by genome-wide association study

全基因组关联研究鉴定的RNF213基因的功能分析

• 批准号: 23390267
• 负责人: KURE Shigeo
• 金额: $ 12.56万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23390267/
• 关键词: 小児神経学; モヤモヤ病; 疾患感受性遺伝子; RNF213遺伝子; 血管内皮細胞; 内頚動脈結紮; ノックアウト・マウス; 発症機序

Moyamoya disease (MMD) manifests progressive bilateral internal carotid artery stenosis and abnormal collateral vessels. A genome-wide association study was performed, which showed a strong association of RNF213 locus in chromosome 17q25-ter with MMD risk. Mutational analysis of RNF213 revealed a founder mutation in 73% of non-familial MMD cases and 1.4% of controls; carriers of this mutation have increased risk of MMD. We developed a genetic testing method for this founder mutation.To understand the function of RNF213 gene, we generated a knockout mice by gene targeting. Homozygous mice were born and grew normally and no abnormality was found in cerebral vascular development. The we ligated the internal carotid artery and observed reactive hypertrophy of vascular wall. The homozygous mice lacked the reactive hyperplasia of intima cells, which was constantly observed in wild-type mice, suggesting that Rnf213 gene plays a role in proliferation of intima cells.

Moyamoya病（MMD）表现出进行性双侧颈内动脉狭窄和异常的副血管。进行了一项全基因组关联研究，该研究表明，染色体17q25-TE与MMD风险的RNF213基因座有很强的关联。 RNF213的突变分析显示，在73％的非家庭MMD病例和1.4％的对照中，创始人突变是一个突变。该突变的载体增加了MMD的风险。我们为该创始人突变开发了一种基因测试方法。要了解RNF213基因的功能，我们通过基因靶向产生了敲除小鼠。纯合小鼠出生并正常生长，并且在脑血管发育中没有发现异常。我们连接了颈内动脉，并观察到了血管壁的反应性肥大。纯合小鼠缺乏内膜细胞的反应性增生，在野生型小鼠中经常观察到，这表明RNF213基因在内膜细胞的增殖中起着作用。

项目成果

Identification of a susceptibility gene for Moyamoya disease

烟雾病易感基因的鉴定

• 发表时间: 2013
• 作者: Morita M;Kuba K;Ichikawa A;Nakayama M;Katahira J;Iwamoto R;Watanebe T;Sakabe S;Daidoji T;Nakamura S;Kadowaki A;Ohto T;Nakanishi H;Taguchi R;Nakaya T;Murakami M;Yoneda Y;Arai H;Kawaoka Y;Penninger JM;Arita M;Imai Y.;Tsuyusaki Y;中屋隆明;Kure S.
• 通讯作者: Kure S.

Paradoxical increase in seizure frequency with valproate in nonketotic hyperglycinemia

非酮症高甘氨酸血症患者服用丙戊酸钠后癫痫发作频率反而增加

• DOI: 10.1016/j.braindev.2011.01.005
• 发表时间: 2012
• 期刊: Brain Dev
• 作者: Morita M;Kuba K;Ichikawa A;Nakayama M;Katahira J;Iwamoto R;Watanebe T;Sakabe S;Daidoji T;Nakamura S;Kadowaki A;Ohto T;Nakanishi H;Taguchi R;Nakaya T;Murakami M;Yoneda Y;Arai H;Kawaoka Y;Penninger JM;Arita M;Imai Y.;Tsuyusaki Y
• 通讯作者: Tsuyusaki Y

モヤモヤ病の疾患感受性遺伝子の同定

烟雾病易感基因的鉴定

• 发表时间: 2011
• 作者: Kure S;Kamada F;Aoki Y;Abe Y;Kikuchi A;Komatsuzaki S;Kanno J;Matsubara Y;Touho H;Miyatake S;Matsumoto N.;呉繁夫
• 通讯作者: 呉繁夫

Temporal profile of de novo development of moyamoya vasculopathy in an adult : case report

成人烟雾病血管病从头发生的时间特征：病例报告

• 发表时间: 2012
• 期刊: Neurol Med Chir (Tokyo)
• 作者: Shimoda Y;Fujimura M;Inoue T;Shimizu H;Tominaga T.
• 通讯作者: Tominaga T.

モヤモヤ病遺伝的要因の解明-疾患感受性遺伝子と創始者変異の同定

阐明烟雾病的遗传因素——疾病易感基因和始祖突变的鉴定

• 发表时间: 2011
• 作者: 呉繁夫;鎌田文顕;青木洋子;阿部裕;新堀哲也;小松崎匠子;菊池敦生;菅野潤子;土屋滋;松原洋一
• 通讯作者: 松原洋一