Mutational Analysis of Cell Types in Tuberous Sclerosis Complex (TSC)

Abstract

Abstract : Tuberous sclerosis complex (TSC) is an autosomal disorder resulting from mutations in the TSC1 or TSC2 genes that is associated with epilepsy, cognitive disability, and autism. TSC1/TSC2 gene mutations lead to developmental alterations in brain structure known as tubers in over 80% of TSC patients. Loss of TSC1 or TSC2 function in tubers results from biallelic TSC gene inactivation and leads to activation of the mTOR cascade as evidenced by phosphorylation of ribosomal S6 protein (P-S6). We demonstrate that there are numerous cytoarchitectural abnormalities in non-tuber brain areas in post-mortem TSC brain. Many of these regions exhibit aberrant phosphorylation of the ribosomal S6 protein (phospho-S6 or P-S6), a marker for enhanced mTOR signaling. We find P-S6 expression in cortex as well as subcortical regions. We have defined mTOR activation in fetal TSC brain tissue. Single cell mutational analysis of these regions reveals somatic mutations suggesting that even though these lesions are distinct from tubers, they arise by biallelic gene inactivation. We have generated two new in vitro TSC models and have identified several new proteins that are upregulated in TSC.