UC San Diego

Autism spectrum disorders (ASDs) are a group of complex neurodevelopmental disorders of high prevalence in the United States, affecting 1 in 68 children. ASDs demonstrate a strong genetic component and share a common core set of symptoms, yet are etiologically genetically heterogeneous. An increasing number of genetic variants have been implicated in ASDs, and the functional study of these variants will be critical for the elucidation of autism pathophysiology. The advent of induced pluripotent stem cell (iPSC) technology has allowed for the generation of human cellular disease models containing individual patient genomes. Here, we report a de novo balanced translocation disrupting the TRPC6 gene in a non-syndromic autistic individual. Using multiple models, including dental pulp cells, iPSCs, and mice, we demonstrate that TRPC6 reduction leads to altered neuronal development, morphology and function. The observed phenotypes could then be rescued by restoration of TRPC6 levels and by treatment with insulin-like growth factor-1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway may benefit from these drugs. We also show that MECP2, the causative gene in Rett syndrome, affects TRPC6 expression levels, suggesting common pathways among ASDs. Genetic sequencing of TRPC6 in large ASD and control cohorts revealed significantly more nonsynonymous mutations in the ASD population, identifying two instances of loss-of-function mutations with incomplete penetrance. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrates the potential of iPSCs to model genetically complex sporadic diseases