DYRK1A kinase triplication is the major cause of Otitis Media in Down Syndrome

• DOI: 10.7554/elife.101969
• Publication Date: 2025-01-07T00:25:09Z
• Authors: Hilda Tateossian; Amy Southern; Pratik Vikhe; Eva Lana-Elola; Sheona Watson-Scales; Dorota Gibbins; Debbie Williams; Thomas Purnell; Philomena Mburu; Andrew Parker; Dominic P Norris; Regie Lyn P Santo...; Brian W Herrmann; Sara Wells; Heena V Lad; Elizabeth MC Fisher; Victor LJ Tybulewicz; Steve DM Brown
• Keywords: DYRK1A

Down syndrome (DS), which arises from trisomy of the whole or part chromosome 21 (Hsa21), is one most common genetic abnormalities in humans. DS manifests as a broad spectrum phenotypic features, including hearing loss due to otitis media with effusion (OME), affecting around 50% children DS. We employed panel mouse models comprising nested series duplications covering regions genome syntenic Hsa21 order define loci involved OME identified major locus on 16, containing only 12 genes, that causes OME. Within this region we demonstrate normalizing gene dosage Dyrk1a restored wild-type phenotype. Investigation downstream pathways DYRK1A uncovered number pathological mechanisms whereby triplication leads middle ear inflammation and vascular leak. These include cross-talk TGFβ signaling its impact proinflammatory cytokines IL-6 IL-17, well raised VEGF levels accompanied by increased Hif1a . conclude potential therapeutic target for