Developmental mechanisms of epilepsy in sebaceous nevus syndrome caused by dysregulation of RAS/MAPK pathway

Abstract

Sebaceous nevus syndrome is a neuro-cutaneous disorder that shows neurological symptoms such as epilepsy, mental retardation, and cerebral defect and with the skin lesion called nevus sebaceous. Recently, it has been reported that sebaceous nevus syndrome is caused by somatic mutation of KRAS and HRAS during development. We found that the mis-activation of RAS/MAPK pathway resulted in neurological defects associated with sebaceous nevus syndrome. Activation of RAS/MAPK pathway by ectopic over-expression of KRAS p.G12V in developing mouse brain caused nodular heterotopia and emergence of dysmorphic neuron in adolescence. We also found similar cellular phenotype by using human embryonic stem cell-derived neuronal progenitor cells. Our data indicate that activation of RAS/MAPK pathway in developing excitatory neuron cause cellular aggregation of dysmorphic neurons. We will determine whether the nodular heterotopia is formed by cell autonomous way or non-autonomous way, using double UP vector system. The nodular heterotopia by constitutive activation of KRAS may be connected to epileptogenesis and other neurological defects of patients with RASopathies including sebaceous nevus syndrome. Using human embryonic stem cell-derived neuronal progenitor cells, we aim to characterize the gene expression profile that may explain the underlying molecular mechanisms of neurological defects caused by the mis-regulation of RAS/MAPK pathway.