Genetic landscape of neurodevelopmental disorders associated with cortical malformation

Abstract

Genetic abnormalities in somatic cells are emerging as a novel mechanism in neurodevelopmental diseases with previously unknown causes, such as focal malformation of cortical development (FMCD). FMCDs are the leading cause of pediatric epilepsies, especially medically intractable ‘catastrophic’ epilepsy. We found that, within human FMCD-affected brain, morphologically defective neurons show activation of the RAS-MAPK or PI3K-AKT-mTOR pathway. It remains unclear how a mutation in the components of these signal transduction pathways involved in the pathogenesis of FMCD. Introducing the FMCD-causing mutations into mouse brain resulted in developmental defects and impaired hemispheric architecture associated with FMCS. Mutation-expressing neural progenitors showed molecular signatures associated with developmental defects. A potential future therapy may include pharmacologically targeting defective gene regulatory networks. The unique animal and stem cell models established in this study can further the molecular mechanisms of FMCD-associated seizures and the fundamental processes governing normal brain development and function.