TSC1 TSC2

About TSC1 TSC2

TSC1, encoding hamartin on chromosome 9q34.13, and TSC2, encoding tuberin on chromosome 16p13.3, produce proteins that form a complex acting as a GTPase activating protein for the small GTPase Rheb, thereby inhibiting mTORC1, a master regulator of cell growth and metabolism. Pathogenic variants in either gene cause tuberous sclerosis complex, an autosomal dominant disorder affecting roughly 1 in 6,000 births, with about two thirds of cases arising from new variants and TSC2 variants generally causing more severe disease. Features include benign growths called hamartomas in many organs: cortical tubers associated with epilepsy, including infantile spasms, autism, and intellectual disability, subependymal nodules and subependymal giant cell astrocytomas, renal angiomyolipomas, cardiac rhabdomyomas in infants, lymphangioleiomyomatosis of the lungs, mainly in women, and skin lesions such as hypomelanotic macules, facial angiofibromas, and shagreen patches. The condition was described by the French neurologist Desire Magloire Bourneville in 1880. Understanding of the TSC complex helped clarify how mTOR is regulated, and mTOR inhibitors such as everolimus and sirolimus are used to treat several TSC manifestations, including astrocytomas, angiomyolipomas, lymphangioleiomyomatosis, and some forms of seizures.