TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review

Abstract

Tuberous sclerosis complex is an autosomal dominant disorder characterized by skin manifestations and formation of multiple tumors in different organs, mainly in the central nervous system. Tuberous sclerosis is caused by the mutation of one of two tumor suppressor genes, TSC1 or TSC2. Currently, the development of novel techniques and great advances in high-throughput genetic analysis made mutation screening of the TSC1 and TSC2 genes more widely available. Extensive studies of the TSC1 and TSC2 genes in patients with TSC worldwide have revealed a wide spectrum of mutations. Consequently, the discovery of the underlying genetic defects in TSC has furthered our understanding of this complex genetic disorder, and genotype-phenotype correlations are becoming possible, although there are still only a few clearly established correlations. This review focuses on the main symptoms and genetic alterations described in TSC patients from 13 countries in three continents, as well as on genotype-phenotype correlations established to date. The determination of genotype-phenotype correlations may contribute to the establishment of successful personalized treatment for TSC.

Figure 1. TSC1 and TSC2 gene structure, domains and distribution of point mutations. (A) Schematic representation of TSC1 and TSC2 exons and the domains of hamartin and tuberin, respectively, codified by them. The symbols represent the number of different mutations described at each exon. (B) The graph shows the percentage of the total number of described mutations that occur at each TSC1 and TSC2 exon.

Figure 2. The role of the TSC2:TSC1 complex in the mTOR pathway. PI3K is activated by growth factors through direct interaction with receptors or through interaction with scaffolding adaptors, such as the IRS proteins. These interactions recruit PI3K to its substrate PtdIns(4,5)P2 (PIP2), allowing generation of the lipid second messenger PtdIns(3,4,5)P3 (PIP3). Akt and PDK1 are recruited to the cell plasma membrane through association with PIP3. This allows Akt to be activated through phosphorylation on Thr308 by PDK1 and Ser473 by mTORC2 (not shown). Once active, Akt phosphorylates many downstream targets, including multiple sites on TSC2. Phosphorylation of TSC2 impairs the GTPase activity of the TSC2:TSC1 complex, allowing Rheb-GTP to accumulate. Rheb-GTP in excess activates high levels of mTORC1, which in turn phosphorylates and inhibits 4E-BP1 and activates S6K1 and S6K2. By this way, mTORC1 influences on cell growth, translation factors activation and cell nutrition.