Cell biology and pathophysiology. The pathology of tuberous sclerosis complex reflects abnormalities in cell size, number, morphology, and location, implying multiple roles of the genes. Wild TSC2 and TSC1 function as tumor suppressor genes. With the mutation of either one, their defective product is unable to inactivate the tumor growth caused by a second random somatic cell mutation (loss of heterozygosity). The multifocal nature of tuberous sclerosis complex is best explained by the Knudson 2-hit hypothesis, where the second hit is a somatic mutation that completely abrogates TSC1-TSC2 function by accelerating the effect of the first systemic hit/mutation. Both alleles of TSC1 or TSC2 have to be inactivated for development of tumors, ie, loss of heterozygosity.
The protein products tuberin and hamartin function together in cellular signaling pathways (Van Slegtenhorst et al 1997; 1998), forming a TSC2:TSC1 tumor suppressor complex. The tuberin-hamartin complex is purported to participate in protein translation, cell growth, proliferation, adhesion, migration, and intracellular trafficking. The TSC2:TSC1 complex is the principal cellular inhibitor of the mammalian target of rapamycin, mTOR (Orlova and Crino 2010). Thus, mutation of hamartin or tuberin in tuberous sclerosis complex leads to hyperactivation of the downstream mTOR pathway and the associated kinase signaling cascades and translational factors, resulting in increased cell growth and proliferation. Tuberin and hamartin are coexpressed in several cells, including kidney, brain, lung, and pancreas, and mutations in either hamartin or tuberin lead to a single disorder.
By sharing homology with a GTPase activating protein for Rap 1 and GTPase Rheb (Ras homologue enhanced in brain), the tuberin-hamartin complex inactivates GTP-bound Rheb (Zhang 2003). Active Rheb is an upstream positive modulator of the mammalian target of rapamycin (mTOR) (Tee et al 2003). Therefore, a loss of function mutation in TSC1-TSC2 will enhance Rheb, activate mTOR constitutively, and critically upregulate cell growth and proliferation through p70S6kinase (Kwiatkowski et al 2002), ribosomal S6 proteins, and eukaryotic initiation factor 4E binding protein 1 (4E-BP1).
Mammalian target of rapamycin, mTOR, exists as 2 complexes with differing functions. mTOR complex 1 (mTORC 1) with its cofactor, Raptor (regulatory associated protein of mTOR), activates mTOR’s protein kinase domain and is sensitive to rapamycin. This activation results in increased mRNA transcription and protein synthesis. TSC mutation leads to loss of inhibition of mTORC1. This causes constitutive activation of mTOR and, in turn, abnormal cellular proliferation and differentiation, producing the hamartomatous lesions of tuberous sclerosis complex. mTOR complex 2 (mTORC 2), with its cofactor Rictor (rapamycin insensitive component of mTOR), regulates protein synthesis in a manner distinct from mTORC1 and is unaffected by Rheb or rapamycin.
Loss of TSC1 or TSC2 in mature postmitotic hippocampal neurons in vitro causes enlarged somas, abnormal dendritic spines, and enhancement of glutamatergic neurotransmission. Elevated extracellular glutamate levels are assumed to contribute to excitotoxic neuronal death, abnormal glutamatergic synaptic physiology, and impaired behavioral conditioning and learning (Napolioni et al 2009). It has been shown that the seizure activity often originates from the mildly hypometabolic regions adjacent to the cortical tubers rather than directly from the tuber in humans.