Molecular Analysis of Epilepsy Predisposition

DESCRIPTION (provided by applicant): Epilepsy is a complex disorder that affects over 15 million Americans. Despite the considerable clinical heterogeneity in the epilepsy phenotype it has been clearly established that predisposition to epilepsy can result from inherited mutations in specific genes. The epilepsy genes which were first described encoded voltage-gated sodium channels, SCN1A, SCN2A and SCN1B and a GABA receptor subunit, GABRG2. It is thought that the epilepsies associated with these genes result from enhanced excitability of neuronal membranes resulting from prolonged depolarization of the neuronal membranes. Recently it has been demonstrated, however, that another type of gene is involved in focal epilepsy of the temporal lobe. This is the LGI1 gene which was mutated in a small series of families showing linkage to chromosome region 10q24. The LGI1 gene is a putative transmembrane protein with homologies to a Drosophila gene which is involved in axon guidance during development of the brain. It is hypothesized that epilepsy in these cases results from abnormal brain development and provides an opportunity to investigate the function of this gene and its role in normal development as well as epilepsy. The P.l.'s group was responsible for the original cloning of the LGI1 gene which has also been shown to be involved in the progression of brain tumors. The phenotype involved in loss of LGI1 function in glial cells is an increased ability to migrate and invade local brain tissue which, again may be related to signals which ensure the orderly distribution of cells within the brain. We now propose to use a combination of cell and molecular approaches to characterize the function of this gene in order to improve our understanding of the events which give rise to epilepsy and possibly identify ways to treat it.