COMPREHENSIVE DNA DIAGNOSTIC SYSTEM FOR SINGLE GENE DISORDERS

单基因疾病综合 DNA 诊断系统

基本信息

批准号：
15591080
负责人：
KURE Shigeo
金额：
$ 2.37万
依托单位：
TOHOKU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591080/
关键词：
hyperglycinemia NMDA glutamate receptor model mice inhibitory glycine receptor abnormal behavior seizure sencitivity hyperactivity increased aggresiveness グリシン脳症 NMDA受容体

项目摘要

Nonketotic hyperglycinemia (NKH) is caused by deficiency of the mitochondrial glycine cleavage system, and characterized by accumulation of glycine. Coma and convulsions develop in severe cases while psychomotor retardation and behavioral abnormalities in mild cases. Consequences of glycine accumulation in the central nervous system remain largely unknown. No effective therapy has been established. We identified a GLDC mutation with dominant-negative effect in a patient with NKH. Transgenic expression of the dominant-negative GLDC cDNA generated two mouse lines, which showed significant elevation of glycine level in brain (#10-4 >#5-3). Another transgenic mouse line #wP with depletion of cerebral glycine was also established by expressing normal GLDC. Mice with glycine accumulation showed behavioral abnormalities characteristic to mild NKH, being hyperactive (#10-4), aggressive (#10-4, #5-3), anxious (#10-4 and #5-3), and susceptible to seizures (#10-4, #5-3), as compared with wild type C57BL/6 mice. In sharp contrast, #wP mice showed significant reduction in locomotion, convulsiveness, and anxiety-like activity. Antagonists for the NMDA receptor glycine-binding site, but not an antagonist for the NMDA receptor channel, ameliorated hyperactivity and seizure susceptibility of hyperglycinemic mice. Our results suggest a role of glycine as a behavioral modulator and a novel effective treatment for mild NKH.

非酮症高甘氨酸血症（NKH）是由线粒体甘氨酸裂解系统缺陷引起的，其特征是甘氨酸积累。严重者会出现昏迷和抽搐，轻微者会出现精神运动迟缓和行为异常。甘氨酸在中枢神经系统中积累的后果仍然很大程度上未知。尚未建立有效的治疗方法。我们在 NKH 患者中发现了具有显性失活效应的 GLDC 突变。显性失活 GLDC cDNA 的转基因表达产生了两个小鼠系，其大脑中的甘氨酸水平显着升高（#10-4>#5-3）。还通过表达正常 GLDC 建立了另一个脑甘氨酸耗尽的转基因小鼠系#wP。甘氨酸积累的小鼠表现出轻度 NKH 特有的行为异常，即过度活跃 (#10-4)、攻击性 (#10-4、#5-3)、焦虑 (#10-4 和 #5-3)，并且容易受到与野生型 C57BL/6 小鼠相比，癫痫发作（#10-4、#5-3）。与此形成鲜明对比的是，#wP 小鼠表现出运动、抽搐和焦虑样活动显着减少。 NMDA 受体甘氨酸结合位点的拮抗剂，但不是 NMDA 受体通道的拮抗剂，可改善高甘氨酸小鼠的多动症和癫痫易感性。我们的结果表明甘氨酸具有行为调节剂的作用，并且是治疗轻度 NKH 的新型有效方法。