Articlehttps://doi.org/10.1038/s41586-018-0423-5Autism-likephenotypeandriskgenemRNAdeadenylationbyCPEB4mis-splicingAlbertoParras1,2,HéctorAnta3,4,MaríaSantos-Galindo1,2,VivekSwarup5,Ainaraelorza1,2,Josél.Nieto-González2,6,SaraPicó1,2,ivóH.Hernández1,2,7,Juani.Díaz-Hernández1,2,eulàliaBelloc4,Annierodolosse4,NeelroopN.Parikshak5,OlgaPeñagarikano5,8,9,rafaelFernández-chacón2,6,Manuelirimia10,11,PilarNavarro3,DanielH.Geschwind5,raúlMéndez4,12*&JoséJ.lucas1,2*Commongeneticcontributionstoautismspectrumdisorder(ASD)resideinriskgenevariantsthatindividuallyhaveminimaleffectsizes.AsenvironmentalfactorsthatperturbneurodevelopmentalsounderlieidiopathicASD,itiscrucialtoidentifyalteredregulatorsthatcanorchestratemultipleASDriskgenesduringneurodevelopment.Cytoplasmicpolyadenylationelementbindingproteins1–4(CPEB1–4)regulatethetranslationofspecificmRNAsbymodulatingtheirpoly(A)-tailsandtherebyparticipateinembryonicdevelopmentandsynapticplasticity.HerewefindthatCPEB4bindstranscriptsofmosthigh-confidenceASDriskgenes.ThebrainsofindividualswithidiopathicASDshowimbalancesinCPEB4transcriptisoformsthatresultfromdecreasedinclusionofaneuron-specificmicroexon.Inaddition,9%ofthetranscriptomeshowsreducedpoly(A)-taillength.Notably,thispercentageismuchhigherforhigh-confidenceASDriskgenes,correlatingwithreducedexpressionoftheproteinproductsofASDriskgenes.AnequivalentimbalanceinCPEB4transcriptisoformsinmicemimicsthechangesinmRNApolyadenylationandproteinexpressionofASDriskgenesandinducesASD-likeneuroanatomical,electrophysiologicalandbehaviouralphenotypes.Together,thesedataidentifyCPEB4asaregulatorofASDriskgenes.ASDishighlyheritable1.However,despitetheimportanceofgeneticdeterminantsinASD,environmentalfactorsthatperturbneurodevel-opmentalsocontributetoitsdevelopment2–4.AminorityofASDcasesaresyndromicformscausedbyhighlypenetrantsingle-genemutationsorchromosomalabnormalities;theseformsareoftencharacterizedbyadditionalphenotypes,suchasintellectualdisability,epilepsyandcran-iofaciald...
