TSC2 deletion

Chordomas presenting in early childhood in the sacral location have been reported as a rare manifestation of tuberous sclerosis complex. The combination of these findings led to a diagnosis of tuberous sclerosis, confirmed with the finding of a heterozygous TSC2 gene deletion; treatment with sirolimus resulted in regression of cardiac rhabdomyomas and hypopigmented macules.

The disease is caused by mutations in Tsc1 or Tsc2 genes, which lead to altered cell signal transduction, most prominently hyperactivation of the mechanistic target of rapamycin (mTOR) pathway... We have established a scalable platform to characterize Tsc2 mutations. Our model replicates key phenotypes seen in patient tissue samples and other Tsc2 mutation models, such as enlarged neuronal soma size and altered signal transduction, that can be rescued by gene replacement. In the future, this testing platform will allow us to rapidly establish genotype-phenotype relationships for patient-specific Tsc2 mutations, making a personalized medicine approach for TSC feasible.

Furthermore, hyperactivation of mTOR signaling was relieved by rapamycin. Immunohistochemistry of clinical samples confirmed frequent TSC2 loss in HCC. Thus, our study revealed that genetic alterations cause TSC2 loss of function and result in the hyperactivation of mTOR, and high frequency of TSC2 truncating mutations around RAP_GAP domain may be one of the reasons for the hyperactivation of mTOR in HCC patients.