Identification of the responsible genes for childhood epilepsies targeting at channels and receptors expressed in the brain

我们一直专注于在中枢神经系统中表达的离子通道和受体的编码基因，以寻找儿童癫痫发病机制的负责基因和遗传异常。并对离子通道或受体进行了电生理检查。在这笔赠款的帮助下，我们从日本各地的癫痫患者及其家属那里收集了样本，并配备了所需的设备。通过寻找儿童癫痫的遗传异常，发现了编码离子通道的几个基因的一些突变。鉴定出这种突变的基因包括编码乙酰胆碱受体亚基的基因CHRNA4，编码钾通道亚基的基因KCNQ2和3，编码GABAA受体亚基的基因GABRG2，编码钠通道亚基的基因SCN1A和2A。特别是，在婴儿期严重肌阵挛性癫痫患者中发现了超过40个SCN1A突变，这种突变可以用来诊断这种癫痫。我们克隆了啮齿类动物的离子通道cDNA，其中突变鉴定并证明了由重构离子通道突变引起的电生理功能障碍。此外，基于所获得的知识和克隆，我们已经生成了啮齿动物模型，该模型具有与所鉴定的人类突变相对应的突变。啮齿动物模型表现出与癫痫患者相似的癫痫表型。连同用于制作动物模型的赠款，目前的赠款已被修改，并重新申请新的科学赠款。一项新的拨款已经获得资助，因此将进一步扩大研究结果，以检查癫痫的发病机制。

We have been focusing on the genes encoding ion channels and receptors expressed in the central nerve system in search of the responsible genes and genetic abnormalities for the pathogenesis of childhood epilepsies. The electrophysiology was also examined on the ion channels or receptors bearing such genetic abnormalities. With the aid of the present grant, we have collected samples from individuals with epilepsies from all over Japan and their families and been resourced with required equipment. Through the search for genetic abnormalities underlying childhood epilepsies, a number of mutations of several genes encoding ion channels were identified. The genes where such mutations were identified include CHRNA4, a gene encoding a subunit of acetylcholine receptor, KCNQ2 and 3, genes encoding subunits of potassium channels, GABRG2, a gene encoding a subunit of GABAA receptor and SCN1A and 2A, genes encoding subunits of sodium channel. In particular, over 40 mutations of SCN1A were found in patients with severe myoclonic epilepsy in infancy and such mutation may be used to make a diagnosis of this epilepsy. We have cloned rodent cDNA for ion channels corresponding to human ion channels where the mutations identified and demonstrated electrophysiological dysfunctions resulting from the mutations with reconstituted ion channels. Furthermore, based upon the knowledge obtained and clones, we have generated rodent models which bear mutations corresponding to the human mutations identified. The rodent model exhibited epilepsy phenotypes similar to those seen in individuals with epilepsy. In conjunction with the grant for generating animal models, the present grant had been modified and reapplied for a new scientific grant. A new grant has been funded and thus should extend the results further to examining the pathogeneses of epilepsies.