The tuberous sclerosis complex proteins – a GRIPP on cognition and neurodevelopment

Tuberous sclerosis complex (TSC) is a multi-system disorder associated with mutations in the TSC1 (hamartin) or TSC2 (tuberin) genes. The neurocognitive features of TSC show wide variability and have generally been attributed to structural brain abnormalities and/or seizures. We review the fundamental roles of TSC1 and TSC2 in cell signalling and propose that because the hamartin–tuberin complex (hereafter referred to as TSC1–2) acts as a global regulator and integrator of a range of physiological processes (‘GRIPP’) the neurocognitive manifestations of TSC result directly from cell-signalling abnormalities. Under the GRIPP hypothesis, the spectrum of neurodevelopmental abnormalities is caused by the biochemical consequences of individual TSC1 and TSC2 mutations. Recognizing the importance of signalling disruption in the brain might improve our understanding of other neurocognitive disorders.