{"doi":"10.1093/hmg/ddae174","title":"Dysregulation of alternative splicing is a transcriptomic feature of patient-derived fibroblasts from CAG repeat expansion spinocerebellar ataxias","abstract":"The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of rare dominantly inherited neurodegenerative diseases characterized by progressive ataxia. The most common mutation seen across the SCAs is a CAG repeat expansion, causative for SCA1, 2, 3, 6, 7, 12 and 17. We recently identified dysregulation of alternative splicing as a novel, presymptomatic transcriptomic hallmark in mouse models of SCAs 1, 3 and 7. In order to understand if dysregulation of alternative splicing is a transcriptomic feature of patient-derived cell models of CAG SCAs, we performed RNA sequencing and transcriptomic analysis in patient-derived fibroblast cell lines of SCAs 1, 3 and 7. We identified widespread and robust dysregulation of alternative splicing across all CAG expansion SCA lines investigated, with disease relevant pathways affected, such as microtubule-based processes, transcriptional regulation, and DNA damage and repair. Novel disease-relevant alternative splicing events were validated across patient-derived fibroblast lines from multiple CAG SCAs and CAG containing reporter cell lines. Together this study demonstrates that dysregulation of alternative splicing represents a novel and shared pathogenic process in CAG expansion SCA1, 3 and 7 and can potentially be used as a biomarker across patient models of this group of devastating neurodegenerative diseases.","journal":"Human Molecular Genetics","year":2024,"id":451999,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1054619,"name":"Claudia D. Lennon","orcid":null,"position":1,"is_corresponding":false},{"id":531650,"name":"John D. Cleary","orcid":"0000-0001-7599-5995","position":2,"is_corresponding":false},{"id":692060,"name":"Hannah K. Shorrock","orcid":"0000-0001-9647-7230","position":3,"is_corresponding":false},{"id":335265,"name":"J. Andrew Berglund","orcid":"0000-0002-5198-2724","position":4,"is_corresponding":false},{"id":1054106,"name":"Asmer Aliyeva","orcid":"0000-0002-5202-5977","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T02:02:50.407779Z","pmid":"39589088","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":[]}