TSC and LAM
Tuberous Sclerosis Complex (TSC) is affecting 1 in every 5,800 individuals without bias for gender, race, or ethnic background. It is estimated that the number of TSC patients is 1.2-1.5 million worldwide, and 75-100 thousand in the US. TSC is a tumor suppressor syndrome with benign tumors in multiple organs including the brain, skin, kidney, lungs, retina, and heart. TSC is caused by mutations in the tumor suppressor genes TSC1 and TSC2. There is no strong genotype/phenotype correlation, although TSC2-associated disease seems to be more severe. The severity of the symptoms is variable, with some patients only mildly affected and others having severe cognitive and developmental delay, autism, or bleeding kidney tumors. Treatment is symptomatic.
Lymphangioleiomyomatosis is a disease of progressive cystic lung degeneration found almost exclusively in women. The sporadic form of LAM (sLAM) is very rare, affecting 3-5 individuals per one million. The estimated worldwide number of sLAM patients is 20,000-40,000. Another form of LAM is the TSC-associated LAM, which affects about half of all female TSC patients over the age of 40. LAM it is caused by proliferation of smooth muscle-like cells in the lungs. Patients present with shortness of breath, often have multiple lung collapses, and become oxygen dependent. End-stage LAM patients can undergo lung transplantation. About 60-70% of LAM patients have kidney angiomyolipomas. Sporadic LAM is caused by mutations in TSC2.
The identification of mTOR as downstream target of TSC1 and TSC2, led to the first clinical trials and eventual approval of the mTOR inhibitors sirolimus (rapamycin) and everolimus (RAD001) as treatment for TSC and LAM.
How TSC1 and TSC2 function
The genes TSC1 and TSC2 encode for two proteins, named hamartin and tuberin, respectively. Tuberin (200 kDa) contains a GTPase-activating protein domain at its COOH-terminus. Hamartin (130 kDa) contains a COOH-terminal RhoA activation domain. Hamartin and tuberin participate in a large mutlimeric protein complex. Tuberin (TSC2) negatively regulates the small GTPase Rheb. Upon growth factor stimulation tuberin is subjected to inhibitory phosphorylation by multiple kinases, including AKT/PKB, ERK1/2 and MK2, leading to Rheb activation and increase in the activity of the mammalian target of rapamycin (mTOR) which regulates mRNA translation, ribosome biogenesis, macromolecule synthesis, cell growth, authophagy, angiogenesis, and apoptosis. Additionally, Rheb negatively regulates B-Raf kinase which participates in differentiation. Upon energy starvation and hypoxia, tuberin is positively regulated by AMPK. Therefore, the hamartin/tuberin complex plays a central role in integrating signals from different extracellular stimuli. (reviewed in Astrinidis and Henske 2005 Oncogene)
Lymphangioleiomyomatosis is a disease of progressive cystic lung degeneration found almost exclusively in women. The sporadic form of LAM (sLAM) is very rare, affecting 3-5 individuals per one million. The estimated worldwide number of sLAM patients is 20,000-40,000. Another form of LAM is the TSC-associated LAM, which affects about half of all female TSC patients over the age of 40. LAM it is caused by proliferation of smooth muscle-like cells in the lungs. Patients present with shortness of breath, often have multiple lung collapses, and become oxygen dependent. End-stage LAM patients can undergo lung transplantation. About 60-70% of LAM patients have kidney angiomyolipomas. Sporadic LAM is caused by mutations in TSC2.
The identification of mTOR as downstream target of TSC1 and TSC2, led to the first clinical trials and eventual approval of the mTOR inhibitors sirolimus (rapamycin) and everolimus (RAD001) as treatment for TSC and LAM.
How TSC1 and TSC2 function
The genes TSC1 and TSC2 encode for two proteins, named hamartin and tuberin, respectively. Tuberin (200 kDa) contains a GTPase-activating protein domain at its COOH-terminus. Hamartin (130 kDa) contains a COOH-terminal RhoA activation domain. Hamartin and tuberin participate in a large mutlimeric protein complex. Tuberin (TSC2) negatively regulates the small GTPase Rheb. Upon growth factor stimulation tuberin is subjected to inhibitory phosphorylation by multiple kinases, including AKT/PKB, ERK1/2 and MK2, leading to Rheb activation and increase in the activity of the mammalian target of rapamycin (mTOR) which regulates mRNA translation, ribosome biogenesis, macromolecule synthesis, cell growth, authophagy, angiogenesis, and apoptosis. Additionally, Rheb negatively regulates B-Raf kinase which participates in differentiation. Upon energy starvation and hypoxia, tuberin is positively regulated by AMPK. Therefore, the hamartin/tuberin complex plays a central role in integrating signals from different extracellular stimuli. (reviewed in Astrinidis and Henske 2005 Oncogene)
Updated 5 March 2018