The tuberous sclerosis (TSC) genes, TSC1 and TSC2, encode hamartin and tuberin, respectively, and are putative tumor suppressor genes that were originally identified due to their involvement in the inherited autosomal dominant disorder tuberous sclerosis.
Our knowledge of TSC genetics and pathophysiology has expanded dramatically in recent years: two genetic loci were discovered in the 1990s and recent elucidation of TSC's interaction with the mTOR pathway has changed how we manage the disease.
Using mouse genetics, we find that at the lowest concentrations of metformin that inhibit hepatic mTORC1 signaling, this inhibition is dependent on AMPK and the tuberous sclerosis complex (TSC) protein complex (TSC complex).
Taken together, our studies raise the possibility of a gene × environment interaction between heterozygous TSC gene mutations and gestational immune activation in the pathogenesis of TSC-related ASD.
Analysis of TSC-associated hamartomas has shown loss of heterozygosity for the regions of chromosomes 9 and 16 known to harbour TSC genes, consistent with the occurrence of somatic 'second-hit' mutations.
TSC is caused by a germline heterozygous mutation in either TSC1 or TSC2, and TSC-LAM is thought to occur as a result of a somatic mutation (second hit) in addition to a germline mutation in TSC1 or TSC2 (first hit).
These data support the hypothesis that both the TSC genes act as tumour suppressors and that the manifestations of TSC in patients with germline TSC mutations rise from "second hit" somatic mutations inactivating the remaining normal copy of the TSC gene.