COMPREHENSIVE DNA DIAGNOSTIC SYSTEM FOR SINGLE GENE DISORDERS

非酮性高甘氨酸血症（NKH）是由线粒体甘氨酸切割系统缺陷引起的，以甘氨酸蓄积为特征。严重者出现昏迷和惊厥，轻度者出现精神发育迟滞和行为异常。甘氨酸在中枢神经系统中蓄积的后果在很大程度上仍然未知。目前尚无有效的治疗方法。我们在一例NKH患者中发现了一个具有显性负效应的GLDC突变。显性阴性GLDC cDNA的转基因表达产生两个小鼠系，其显示脑中甘氨酸水平的显著升高（#10-4 >#5-3）。通过表达正常GLDC还建立了另一个脑甘氨酸耗尽的转基因小鼠系#wP。与野生型C57 BL/6小鼠相比，具有甘氨酸积累的小鼠显示出轻度NKH的行为异常特征，表现为过度活跃（#10 -4）、攻击性（#10-4、#5 - 3）、焦虑（#10-4和#5 - 3）和易癫痫发作（#10-4、#5-3）。与此形成鲜明对比的是，#wP小鼠表现出运动、惊厥和焦虑样活动的显著减少。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，可改善高甘氨酸血症小鼠的多动和癫痫易感性。我们的研究结果表明甘氨酸作为一种行为调节剂和一种新的有效治疗轻度NKH的作用。

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.