Molecular Studies of mTOR and Tau pathways in Focal Cortical Dysplasia

Abstract

Epilepsy is one of the most common neurological diseases, affecting 1.5 -2.0 % of the world population. Several types of malformations of cortical development (MCD), including Focal Cortical Dysplasia (FCD), cause epilepsy and are associated with the occurrence of refractory seizures. FCD is characterized by cortical architecture abnormalities observed in other MCD, such as Tuberous Sclerosis (TS) and Hemimegalencephaly (HME). FCD, TS and HME also show aberrant expression of genes belonging to mTOR signaling pathway. Potential involvement of Tau pathway was reported in patients with FCD. Therefore, the similarity in histological features and molecular pathways suggests that pathogenic mechanisms could be common to these three disorders. Furthermore, somatic mosaic mutations have been indentified in patients with TS and HME. The identification of somatic mutations in a mosaic state might contribute to the understanding of complex diseases such as DCF; however, they are not usually detected by traditional methods such Sanger sequencing. Recently, Next-generation sequencing (NGS) technology has been reported to allow detection of somatic mutations in a mosaic state in the central nervous system. The objective of this project is to investigate whether somatic mosaic mutations in genes belonging to the mTOR and Tau pathways are involved in the molecular etiology of the FCD. Deep Sequencing by NGS will be performed in genomic DNA of both FCD resected brain tissue and peripheral blood of patients in order to assess whether the somatic mutations are restricted to the central nervous system. Exon capturing of candidate genes will be performed with Nextera Custom Enrichment Kit (Illumina) kit and NGS will be performed on a MiSeq bench top sequencing machine. This project intends to contribute to the understanding of the genetic and molecular etiology of FCD as well as in other diseases whose somatic mosaicism is potentially involved.