Mutations in phosphatase and tensin homolog (PTEN) were first identified in a number of patients with different conditions (reviewed in Eng, 2003), together called PTEN hamartoma tumor syndromes (PHTS). Although relatively rare, PTEN mutations are consistently identified in non-syndromic ASDs comorbid with significant macrocephaly (Butler et al., 2005; Buxbaum et al., 2007), a feature observed in approximately 20% of all ASD cases (reviewed in Fombonne et al., 1999; Courchesne et al., 2003; Courschesne et al., 2011).The Pten protein normally functions as a protein and lipid phosphatase that negatively regulates the Akt signaling pathway, particularly by dephosphorylating phosphatidylinositol (3, 4, 5)-triphosphate (PIP3; Maehama and Dixon, 1998). Tuberin, the protein product of Tsc2, is one target of the Akt signaling pathway (Potter et al., 2002), which is inhibited following phosphorylation by Akt (Inoki et al., 2002). Thus, the PI3K/Akt signaling pathway increases mTORC1 activity and Pten, like the Tsc1 and Tsc2 products, normally inhibits mTORC1 activity.
