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

我们一直关注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相关基因和遗传异常。还检查了具有这种遗传异常的离子通道或受体的电生理学。在目前赠款的帮助下，我们从日本各地的癫痫患者及其家人那里收集了样本，并配备了所需的设备。通过寻找儿童癫痫的遗传异常，确定了几个编码离子通道的基因的突变。鉴定出这种突变的基因包括CHRNA4（编码乙酰胆碱受体亚基的基因）、KCNQ 2和3（编码钾通道亚基的基因）、GABRG 2（编码GABAA受体亚基的基因）和SCN 1A和2A（编码钠通道亚基的基因）。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SCN 1A突变，这些突变可用于诊断这种癫痫。我们已经克隆了啮齿动物的cDNA的离子通道对应于人类离子通道的突变鉴定和证明的电生理功能障碍所造成的突变与重建的离子通道。此外，基于所获得的知识和克隆，我们已经产生了携带对应于所鉴定的人类突变的突变的啮齿动物模型。啮齿动物模型表现出与癫痫个体相似的癫痫表型。与用于制作动物模型的补助金一起，目前的补助金已经修改，并重新申请新的科学补助金。一项新的赠款已经得到资助，因此应该进一步扩大结果，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.