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Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing (ID 1280)
Abstract BodyAutism spectrum disorders (ASD) are neurodevelopmental disorders that manifest as impaired social communication and restrictive and repetitive behaviors. The vast majority of ASD cases correspond to idiopathic ASD for which the 50% causality that is genetic resides on variants of about two hundred genes that individually have minimal penetrance. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment.
Cytoplasmic polyadenylation element binding proteins 1–4 (CPEB1–4) are RNA-binding proteins that regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity.
We found that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes.
Together, these data identify CPEB4 as a regulator of ASD risk genes.