Autism-like phenotype and risk gene-RNA deadenylation by CPEB4 mis-splicing

Common genetic contributions to autism spectrum disorder (ASD) reside in risk-gene variants that individually have minimal effect-sizes. Since neurodevelopment-perturbing environmental factors also underlie idiopathic-ASD, it is crucial to identify altered regulators able to orchestrate multiple ASD-risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1-4 (CPEB1-4) regulate translation of specific mRNAs by modulating their poly(A)-tail and participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD genes. Idiopathic-ASD brains show CPEB4 transcript isoform imbalance due to decreased inclusion of a neuronal-specific microexon together with a new molecular signature of global poly(A)-tail shortening that remarkably impacts high-confidence ASD-risk genes with concomitant reduction of their protein levels. Equivalent CPEB4 transcript isoform imbalance in mice mimics the mRNA-polyadenylation and protein level changes of ASD genes and induces ASD-like neuroanatomical, electrophysiological and behavioral phenotypes. Altogether, these data unravel CPEB4 as a novel regulator of ASD-risk genes.