Tuberous sclerosis complex and the mTOR pathway

Tuberous sclerosis complex (TSC) is a neurocutaneous disease characterized by the growth of hamartomas in many tissues and organs. The most prominent neurological manifestation of TSC is epileptic seizures. Two causative genes have been identifi ed: TSC1 at 9q34 and TSC2 at 16p13.3. TSC1 encodes for hamartin and TSC2 encodes for tuberin. Tuberin contains a small region of homology to the GTPase activating protein. Rapamycin (developed as an antifungal agent) has regulatory effects on cell growth and proliferation via its inhibitory action on a key protein mammalian target of rapamycin (mTOR). Hamartin and tuberin are two major regulatory proteins that negatively modulate mTOR via inhibiting GTPase RHEB. Therefore, mutations of either TSC1 or TSC2 genes cause the same disease TSC. Since rapamycin inhibit mTOR pathway, rapamycin and other mTOR inhibitors are thought to be a new treatment for TSC. Recently increasing data are indicating that rapamycin is effective in various hamartomas in TSC patients. mTOR inhibitors may provide new treatment of TSC, and therapeutic outcomes are encouraging so far. Although several clinical trials have been conducted for the effi cacy of rapamycin and other mTOR inhibitor everolimus, well designed multicenter trials are necessary in the near future.