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

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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.