generation of epilepsy model animals harboring the same genetic defects identified in human epilepsy

产生具有与人类癫痫相同的遗传缺陷的癫痫模型动物

• 批准号: 12559010
• 负责人: HIROSE Shinichi
• 金额: $ 7.81万
• 依托单位: Fukuoka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12559010/
• 关键词: Epilepsy; Channel disease; transgenic animals; febrile seizures; ADNFLE; BFNC; GEFS+; GEFS+; 組換え動物; CEFS+

We have made the following discoveries based on the genetic analyses searching mutations of genes encoding ion channels expressed in the central nerve system. The specimens used were in the bank holding DNA samples obtained from patients with various epilepsy syndrome. Two novel mutations have been identified in the gene encoding a1 subunit of Na+ channel, SCN1A in patients with generalized epilepsy with febrile seizures plus (GEFS+). Furthermore, we found that the gene encoding a2 subunit of Na+ channel, SCN2A is associated with autosomal dominant epilepsy with febrile seizures plus. The mutation result in slow inactivation in the channel function thereby cause hyper inimitability of the channel. Exploiting the above results, we have generated transgenic animals (rats), which harboring the same mutations identified in human epilepsy. One of such animals, that bears a CHRNA4 mutation showed convulsions. Pharmacological and electrophysiological characteristics of the animals are currently investigated.

我们已经基于遗传分析搜索在中枢神经系统中表达的编码离子通道的基因的突变而获得了以下发现。所用的样本是从各种癫痫综合征患者中获得的DNA样本库中的样本。在全身性癫痫伴热性惊厥加重（GEFS+）患者中发现了两个新的Na+通道α 1亚单位SCN 1A基因突变。此外，我们还发现钠离子通道α 2亚基基因SCN 2A与常染色体显性遗传性癫痫伴热性惊厥附加症有关。突变导致通道功能缓慢失活，从而导致通道的高度不可模仿性。利用上述结果，我们已经产生了转基因动物（大鼠），其具有在人类癫痫中鉴定的相同突变。其中一只携带CHRNA4突变的动物表现出抽搐。目前正在研究动物的药理学和电生理学特征。

项目成果

Sugawara, T., E.Mazaki-Miyazaki, M.Ito, H.Nagafuji, G.Fukuma, A.Mitsudome, K.wada, S.Kaneko, S.Hirose, K.Yamakawa: "Na_v1.1 mutations cause febrile seizures associated with afebrile partial seizures"Neurology. 57. 703-705 (2001)

Sukawara, T., E.Mazaki-Miyazaki, M.Ito, H.Nagafuji, G.Fukuma, A.Mitsudome, K.wada, S.Kaneko, S.Hirose, K.Yamakawa：“Na_v1.1 突变导致发热

Ito, M., H.Nagafuji, H.Okazawa, K.Yamakawa, T.Sugawara, E.Mazaki-Miyazaki, S.Hirose, G.Fukuma, A.Mitsudome, K.Wada, S.Kaneko: "Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (Na^+)-channel α1 subunit gene, SCN1A"Epil

Ito, M., H.Nagafuji, H.Okazawa, K.Yamakawa, T.Sugarahara, E.Mazaki-Miyazaki, S.Hirose, G.Fukuma, A.Mitsudome, K.Wada, S.Kaneko：“常染色体显性遗传伴有热性惊厥的癫痫加上 (Na^+) 通道 α1 亚基基因 SCN1A"Epil 的错义突变

Hirose S., et al.: "The genetics of febrile seizures and related epilepsy syndromes"Brain Dev. (in press). (2003)

Hirose S. 等人：“热性惊厥和相关癫痫综合征的遗传学”Brain Dev。

Hirose S., et al.: "X-Linked mental retardation and epilepsy : Pathogenetic significance of ARX mutations"Brain Dev. 25. 161-165 (2003)

Hirose S. 等人：“X 连锁智力低下和癫痫：ARX 突变的病理遗传学意义”Brain Dev。

Okada M., et al.: "Age-dependennt modulation of hippocampal excitability by KCNQ-channels"Epilepsy Research. 58. 81-94 (2003)

Okada M. 等人：“KCNQ 通道对海马兴奋性的年龄依赖性调节”癫痫研究。