The co-occurrence of ASD and Tuberous Sclerosis Complex (TSC) has been recognized for many years. Features of ASD are present in 25-50% of individuals with TSC, a neurodevelopmental disorder caused by mutations in tumor suppressor genesTSC1 and TSC2, encoding hamartin and tuberin respectively. Tuberin and hamartin function together to inhibit mTOR signaling, which regulates protein synthesis and cell growth. In addition to being a critical regulator of cell growth, mTOR signaling plays an essential role in neural plasticity and synapse function. Naturally occurring mutations, resulting in inactivation or downregulation of the tuberin-hamartin complex through phosphorylation, lead to aberrant activation of mTOR signaling. Haploinsufficiency or a reduction in TSC proteins has been shown to be sufficient for perturbations of synapse function. Neurofibromatosis type 1 (NF1), is another common inherited neurocutaneous disorder associated with cognitive, attention and learning deficits. NF1 deficiency results in tuberin inactivation through phosphorylation, and subsequent mTOR activation. Similarly, brain-derived neurotrophic factor (BDNF) phosphorylates tuberin and induces mTORdependent local protein synthesis in neurons. Pam (Protein Associated with Myc), a large protein that we identified as an interactor of the TSC2 protein tuberin, is highly conserved across many species and has the highest expression in brain. Pam homologs in Drosophila and C. elegans are neuron-specific and function as synaptic growth regulators. PTEN is another important upstream regulator of mTOR signaling, and mutations in PTEN result in tuberin phosphorylation and mTOR activation. We hypothesize that aberrant hyperactivation of mTOR in neurons is a common causal pathway for learning and other cognitive deficits associated with TSC and NF1, and increases risk for ASD. Further, we hypothesize that inherited variations in one or more genes that influence mTOR signaling, TSC1, TSC2, NF1, BDNF, Pam and PTEN will be associated with risk for ASD.
