Kearney J A, Plummer N W, Smith M R, Kapur J, Cummins T R, Waxman S G, Goldin A L, Meisler M H
Department of Human Genetics, University of Michigan, 4909 Buhl Box 0618, Ann Arbor, MI 48109-0618, USA.
Neuroscience. 2001;102(2):307-17. doi: 10.1016/s0306-4522(00)00479-6.
The GAL879-881QQQ mutation in the cytoplasmic S4-S5 linker of domain 2 of the rat brain IIA sodium channel (Na(v)1.2) results in slowed inactivation and increased persistent current when expressed in Xenopus oocytes. The neuron-specific enolase promoter was used to direct in vivo expression of the mutated channel in transgenic mice. Three transgenic lines exhibited seizures, and line Q54 was characterized in detail. The seizures in these mice began at two months of age and were accompanied by behavioral arrest and stereotyped repetitive behaviors. Continuous electroencephalogram monitoring detected focal seizure activity in the hippocampus, which in some instances generalized to involve the cortex. Hippocampal CA1 neurons isolated from presymptomatic Q54 mice exhibited increased persistent sodium current which may underlie hyperexcitability in the hippocampus. During the progression of the disorder there was extensive cell loss and gliosis within the hippocampus in areas CA1, CA2, CA3 and the hilus. The lifespan of Q54 mice was shortened and only 25% of the mice survived beyond six months of age. Four independent transgenic lines expressing the wild-type sodium channel were examined and did not exhibit any abnormalities. The transgenic Q54 mice provide a genetic model that will be useful for testing the effect of pharmacological intervention on progression of seizures caused by sodium channel dysfunction. The human ortholog, SCN2A, is a candidate gene for seizure disorders mapped to chromosome 2q22-24.
大鼠脑IIA钠通道（Na(v)1.2）结构域2胞质S4-S5连接区中的GAL879-881QQQ突变，在非洲爪蟾卵母细胞中表达时会导致失活减慢和持续性电流增加。神经元特异性烯醇化酶启动子用于指导突变通道在转基因小鼠体内的表达。三个转基因品系出现癫痫发作，对Q54品系进行了详细表征。这些小鼠的癫痫发作始于两个月大时，伴有行为停滞和刻板重复行为。连续脑电图监测检测到海马体中的局灶性癫痫活动，在某些情况下会扩散至累及皮层。从症状前的Q54小鼠分离出的海马CA1神经元表现出持续性钠电流增加，这可能是海马体兴奋性过高的基础。在疾病进展过程中，海马体CA1、CA2、CA3区和海马门区域出现广泛的细胞丢失和胶质增生。Q54小鼠的寿命缩短，只有25%的小鼠存活超过6个月。对四个表达野生型钠通道的独立转基因品系进行了检查，未发现任何异常。转基因Q54小鼠提供了一个遗传模型，可用于测试药物干预对钠通道功能障碍引起的癫痫发作进展的影响。人类同源基因SCN2A是一种癫痫疾病的候选基因，定位于染色体2q22-24。
