TSC1

TSC1 is located on chromosome 9q34 and consists of 23 exons, which encode the 130 kDa TSC1 protein, hamartin. The first two exons containing the 5 ′ UTR, and 3-21 is the main coding region, containing three alternative splicing forms (PMID: 2882085, PMID: 9242607). TSC2 is the first cloned TSC causative gene, located on chromosome 16p13.3 and consists of 42 exons which encode the 200 kDa TSC2 protein, tuberin. Exon 1 does not contain coding sequences, exons 2 – 42 encode functional proteins, and TSC2 has seven different alternative splicing isoforms (PMID: 26703369). TSC1 and TSC2, along with TBC1D7, form a heterotrimeric complex (the TSC protein complex) in a 2:2:1 ratio (PMID: 26798146, PMID: 22795129), which inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PMID: 28215400), which in turn affects the PI3K/mTOR/AKT pathway, thereby inhibiting protein synthesis and cell growth as well as regulating cellular autophagy (PMID: 18722121). Each TSC2 consists of a HEAT repeat domain (HEAT), a dimerization domain (DD), followed by a C-terminal GAP catalytic domain (GAP), and activated RHEB can activate mTOR1, while the GAP domain can act on the GTP-bound Ras homolog RHEB-GTP to hydrolyze it, thereby converting RHEB-GTP into an inactive GDP-bound form and blocking the activation of mTOR (PMID: 12869586, PMID: 27226234). Exons 16, 23, 33,and 40 are the most frequently mutated and constitute more than a quarter of all observed TSC2 pathogenic variants (PMID: 26703369). TSC1 can interact with the C-terminal domain of TSC2 through the N-terminal domain to maintain the stability of the TSC complex, and The C-terminal domain of Tsc1 (998-1,164 aa) forms a homodimer and binds to both protomers of the Hsp90 middle domain. This ensures inhibition of both subunits of the Hsp90 dimer and prevents the activating co-chaperone Aha1 from binding the middle domain of Hsp90, inhibiting its ATPase activity and preventing TSC2 ubiquitination and proteasomal degradation(PMID: 29127155, PMID: 33037995, PMID: 18411301). Inactivating pathogenic variants in either the TSC1 or the TSC2 gene, leading to uncontrolled binding of RHEB to GTP (active form), sustained activation of RHEB, and hyperactivation of the mTOR pathway, resulting in dysregulation of protein synthesis and cell growth (PMID: 27226234, PMID: 12869586, PMID: 33436626). This leads to a variety of diseases such as autosomal dominant tuberous sclerosis complex (TSC), subependymal giant cell astrocytoma(SEGAs), and hemangiomas.

TSC complexes have a tumor suppressors effect, and mutations in TSC1 and TSC2 lose their inhibitory effect on RHEB, thus activating the mTOR-related pathway leading to cancer development. Therefore, mTOR inhibitors are mainly used clinically to treat TSC mutation-related diseases, mainly including everolimus and sirolimus. A clinical study showed that patients with hemangioma treated with sirolimus for 12 months showed a reduction in lesion size of approximately 30% ,with less cytotoxic effects, and allowing for continued dosing (PMID: 18184959). Everolimus, an analogue of sirolimus, was first evaluated in the placebo-controlled EXIST-1 and EXIST-2 trials for SEGA and renal angiomyolipoma with favorable response rates and was therefore approved by the FDA as first-line treatment for renal angiomas larger than 3 cm in adult patients with TSC(PMID: 23312829, PMID: 26156073). A later evaluation showed a similar response to everolimus regardless of the type of mutation in TSC1 and TSC2 (PMID: 26540169). At the same time, everolimus may have a therapeutic effect on TSC-induced epilepsy (PMID: 22000822, PMID: 23798472), and case reports have shown that in metastatic RCC, suntinib and everolimus can be combined. For patients with hemangiomas that cannot be treated with mTOR inhibitors or have contraindications, treatment with corticosteroids should be followed by embolization (PMID: 24053983). Vigabatrin is recommended as first-line treatment for infantile spasms in tuberous sclerosis complex (TSC), rather than using non-TSC-related corticosteroids. Vigabatrin prevents the metabolism of GABA by irreversibly inhibiting GABA transaminase (GABA-T), enhancing inhibitory neurotransmission, and possibly also reducing mTOR activation (PMID: 23437388). The mechanism of vigabatrin in the treatment of infantile spasms in TSC is unknown. However, vigabatrin is a particularly effective treatment for infantile spasms in TSC, with a ∼95% efficacy in stopping infantile spasms in TSC patients (PMID: 26227562). Many inhibitors targeting the activation of the mTOR pathway and the autophagic response are also in clinical trials (PMID: 21482669, PMID: 28415776).