Tuberous sclerosis complex (TSC) is a genetic disease caused by mutations in either the TSC1 or TSC2 genes. Patients with TSC have hamartomas – benign collections of abnormally differentiated cells – in organs throughout the body. In the brain, hamartomas are associated with intractable epilepsy, autism, behavioral problems and mental retardation.
Seok-Hyung Kim, Kevin Ess, and colleagues have now generated a zebrafish model of TSC, with a mutation in the tsc2 gene. They reported in the March issue of Disease Models & Mechanisms that zebrafish with two mutant copies of tsc2 died during early larval development with enlarged cells in the brain and liver. Their forebrains were poorly organized and had higher levels of TORC1, a protein whose action is normally blocked by tsc2. Transplanted mutant cells were able to mislocalize normal cells in the forebrain, which may help explain the formation of brain hamartomas in patients with TSC.
A zebrafish model will greatly facilitate new approaches to study TSC and hopefully result in the identification of new therapies.