COMPREHENSIVE DNA DIAGNOSTIC SYSTEM FOR SINGLE GENE DISORDERS

非酮症高血糖症(NKH)是由线粒体甘氨酸裂解系统缺陷引起的，以甘氨酸蓄积为特征。重症患者会出现昏迷和抽搐，而轻度患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蓄积的后果在很大程度上仍不清楚。目前还没有建立有效的治疗方法。我们在1例NKH患者中发现了一种具有显性-负效应的GLDC突变。转基因表达显性阴性的GLDC基因产生了两个小鼠品系，它们的大脑甘氨酸水平显著升高(#10-4和#5-3)。通过表达正常的GLDC，建立了另一株脑甘氨酸缺失的转基因小鼠#WP。与野生型C57BL/6小鼠相比，甘氨酸蓄积小鼠表现出轻度NKH的行为异常，表现为多动(#10-4)、攻击性(#10-4、#5-3)、焦虑(#10-4、#5-3)、易癫痫发作(#10-4、#5-3)。与此形成鲜明对比的是，#WP小鼠的活动、抽搐和类焦虑活动显著减少。NMDA受体甘氨酸结合部位的拮抗剂，但不是NMDA受体通道的拮抗剂，可以改善高血糖小鼠的多动和癫痫敏感性。我们的结果提示甘氨酸作为一种行为调节剂的作用和一种治疗轻度NKH的新的有效方法。

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.