Molecular Analysis of Pathogenic Mutations causing Tuberous Sclerosis Complex

Basic data for this project

Description

Tuberous sclerosis complex (TSC) is a genetic disease characterized by benign tumors in multiple organs that lead to organ failure. The goal of this study is to rationalize the divers pathologies observed in tuberous sclerosis by understanding the effect of particular pathogenic point mutations in the affected proteins tuberin and hamartin (forming the TSC complex) on a molecular level and to correlate this information with different physiological outcomes. Due to the absence of structural and mechanistic information so far, these aspects have remained largely elusive. In our ongoing effort to determine the three-dimensional protein structure of the TSC complex, we have made significant progress in determining the crystal structures of TSC complex domains. This information provides the indispensable foundation for a systematic structure-guided approach to comprehensively characterize the effects of pathogenic point mutations. Our study will focus on investigating the influence of mutations on TSC complex structure and integrity, on molecular functions of the TSC complex and on TSC complex-dependent signaling pathways. We expect to not only gain novel insight into the mechanism of TSC complex function, but also the pathogenic processes that lead to the manifestation of tuberous sclerosis.