{"doi":"10.7554/elife.101969","title":"DYRK1A kinase triplication is the major cause of Otitis Media in Down Syndrome","abstract":"Abstract Down syndrome (DS), which arises from trisomy of the whole or part of chromosome 21 (Hsa21), is one of the most common genetic abnormalities in humans. DS manifests as a broad spectrum of phenotypic features, including hearing loss due to otitis media with effusion (OME), affecting around 50% of children with DS. We employed a panel of mouse models of DS comprising a nested series of duplications covering the regions of the mouse genome syntenic to Hsa21 in order to define the loci involved with OME in DS. We identified a major locus on mouse chromosome 16, containing only 12 genes, that causes OME. Within this region we demonstrate that normalizing the gene dosage of Dyrk1a restored the wild-type phenotype. Investigation of downstream pathways of DYRK1A uncovered a number of pathological mechanisms whereby DYRK1A triplication leads to middle ear inflammation and vascular leak. These include cross-talk of DYRK1A and TGFβ signaling and its impact on proinflammatory cytokines IL-6 and IL-17, as well as raised VEGF levels in the middle ear accompanied by increased Hif1a. We conclude that DYRK1A is a potential therapeutic target for OME in children with DS.","journal":"eLife","year":2025,"id":559989,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9104,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1355189,"name":"Amy Southern","orcid":null,"position":1,"is_corresponding":false},{"id":1213490,"name":"Pratik Vikhe","orcid":"0000-0002-1096-970X","position":2,"is_corresponding":false},{"id":488249,"name":"Eva Lana‐Elola","orcid":"0000-0003-3351-5820","position":3,"is_corresponding":false},{"id":489424,"name":"Sheona Watson-Scales","orcid":null,"position":4,"is_corresponding":false},{"id":819731,"name":"Dorota Gibbins","orcid":null,"position":5,"is_corresponding":false},{"id":1355190,"name":"Debbie Williams","orcid":null,"position":6,"is_corresponding":false},{"id":1083769,"name":"Thomas Purnell","orcid":"0000-0002-9551-7947","position":7,"is_corresponding":false},{"id":1355191,"name":"Philomena Mburu","orcid":null,"position":8,"is_corresponding":false},{"id":513485,"name":"Andrew Parker","orcid":"0000-0003-2620-2420","position":9,"is_corresponding":false},{"id":938003,"name":"Dominic P. Norris","orcid":"0000-0003-1628-504X","position":10,"is_corresponding":false},{"id":418603,"name":"Regie Lyn P. Santos‐Cortez","orcid":"0000-0002-9958-2535","position":11,"is_corresponding":false},{"id":749848,"name":"Brian W. Herrmann","orcid":"0000-0003-2247-4330","position":12,"is_corresponding":false},{"id":268820,"name":"Sara Wells","orcid":"0000-0002-0572-0600","position":13,"is_corresponding":false},{"id":1354861,"name":"Heena V. Lad","orcid":"0000-0001-9534-8891","position":14,"is_corresponding":false},{"id":238175,"name":"Elizabeth Fisher","orcid":"0000-0003-2850-9936","position":15,"is_corresponding":false},{"id":270081,"name":"Victor L. J. Tybulewicz","orcid":"0000-0003-2439-0798","position":16,"is_corresponding":false},{"id":368678,"name":"Steve D. M. Brown","orcid":"0000-0002-0617-4824","position":17,"is_corresponding":false},{"id":1354860,"name":"Hilda Tateossian","orcid":"0000-0001-7013-5806","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:55:39.010633Z","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":[]}