Delineating the molecular pathway and pathogenic mechanism underlying autosomal dominant lateral temporal epilepsy (ADLTE)

The proposed project aims to identify novel genes causing autosomal dominant lateral temporal epilepsy (ADLTE) to delineate the entire set of proteins that are involved in the development of ADLTE. We recently discovered the second gene causing ADLTE, RELN, a known gene encoding the protein Reelin. Homozygous mutations in this gene cause lissencephaly with cerebellar hypoplasia, a recessive disorder associated with brain cortex abnormalities and seizures. Together, Reelin and LGI1 heterozygous mutations are found about half of the ADLTE families. The proposed project aims to identify novel ADLTE genes by exploiting the exome variant dataset from 10 families without RELN and LGI1 we developed previously and by analyzing 12 additional ADLTE families by exome sequencing. In this effort, we will also use bioinformatic analysis of proteins interacting with LGI1 or Reelin to facilitate the identification of pathogenic mutations in affected family members among the bulk of DNA variants detected by exome sequencing. This analysis will lead to the identification of other genes for ADLTE, thus identifying the set of proteins which are involved in the mechanisms underlying ADLTE. We will also study the pathogenic mechanism leading to ADLTE by using induced pluripotent stem cells (iPSC) technology which allows differentiation in vitro of neuronal cells from patient's skin fibroblasts. This system is particularly useful for analyzing cell types that are not accessible for investigation, such as neurons. Using this cell system will develop a model for RELN and LGI1 mutations to define whether ADLTE results from a defect in synaptic transmission or during neuronal maturation in early life.''