{"doi":"10.1101/2022.09.22.508890","title":"Pathogenic mis-splicing of <i>CPEB4</i> in schizophrenia","abstract":"ABSTRACT Schizophrenia (SCZ) is caused by a complex interplay of polygenic risk and environmental factors, which might alter regulators of gene expression leading to pathogenic mis-expression of SCZ risk genes. The RNA binding protein family CPEB (CPEB1, CPEB2, CPEB3, CPEB4) regulates the translation of target RNAs bearing CPE sequences in their 3’UTR (approximately 40% of overall genes). We previously identified CPEB4 as a key dysregulated translational regulator in autism spectrum disorder (ASD), proving that its neuronal-specific microexon (exon 4) is mis-spliced in brains of ASD probands, leading to concerted underexpression of a plethora of high confidence ASD-risk genes. The genetic and pathogenic mechanisms shared between SCZ and ASD make it plausible that mis-splicing of CPEB4 might occur also in SCZ patients, leading to downstream altered brain expression of multiple SCZ-related genes. In this study, we first analyzed Psychiatric Genomics Consortium GWAS data and found significant enrichment of SCZ-associated genes for CPEB4-binder transcripts. We also found decreased inclusion of CPEB4 microexon in postmortem prefrontal cortex of SCZ probands. This mis-splicing is associated with decreased protein levels of SCZ-associated genes that are targets of CPEB4. Interestingly, this happens specifically in individuals with low exposure to antipsychotic medication. Finally, we show that mild overexpression of a CPEB4 transcript lacking exon 4 (CPEB4Δ4) in mice suffices to induce decreased protein levels of SCZ genes targeted by CPEB4; these mice are also characterized by SCZ-linked behaviors. In summary, this study identifies aberrant CPEB4 splicing and downstream mis-expression of SCZ-risk genes as a novel etiological mechanism in SCZ.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":304361,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9599,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":263898,"name":"Antonio F. Pardiñas","orcid":"0000-0001-6845-7590","position":1,"is_corresponding":false},{"id":997181,"name":"Alberto Parras","orcid":"0000-0003-0999-2600","position":2,"is_corresponding":false},{"id":671276,"name":"Ivó H. Hernández","orcid":"0000-0001-9656-6508","position":3,"is_corresponding":false},{"id":997182,"name":"María Santos‐Galindo","orcid":"0000-0003-2725-6228","position":4,"is_corresponding":false},{"id":997183,"name":"Sara Picó","orcid":"0000-0003-3022-8084","position":5,"is_corresponding":false},{"id":784825,"name":"Luís F. Callado","orcid":"0000-0001-9941-012X","position":6,"is_corresponding":false},{"id":997184,"name":"Ainara Elorza","orcid":"0000-0003-4617-1924","position":7,"is_corresponding":false},{"id":997739,"name":"Gonzalo Fernández‐Miranda","orcid":null,"position":8,"is_corresponding":false},{"id":997185,"name":"Eulàlia Belloc","orcid":"0000-0002-1059-3546","position":9,"is_corresponding":false},{"id":263899,"name":"James Walters","orcid":"0000-0002-6980-4053","position":10,"is_corresponding":false},{"id":1159,"name":"Michael C O'Donovan","orcid":"0000-0001-7073-2379","position":11,"is_corresponding":false},{"id":901729,"name":"Claudio Toma","orcid":"0000-0003-3901-7507","position":12,"is_corresponding":false},{"id":997740,"name":"Raúl Méndez","orcid":null,"position":13,"is_corresponding":false},{"id":784826,"name":"J. Javier Meana","orcid":"0000-0002-7913-6714","position":14,"is_corresponding":false},{"id":1100,"name":"Michael J. Owen","orcid":"0000-0003-4798-0862","position":15,"is_corresponding":false},{"id":671282,"name":"José J. Lucas","orcid":"0000-0003-1597-3916","position":16,"is_corresponding":false},{"id":997180,"name":"Ivana Ollà","orcid":"0000-0002-1029-2065","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T00:32:32.651796Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}