| First Author | Tateossian H | Year | 2025 |
| Journal | Elife | Mgi Jnum | J:361105 |
| Mgi Id | MGI:7856465 | Doi | 10.7554/eLife.101969.1 |
| Citation | Tateossian H, et al. (2025) DYRK1A kinase triplication is the major cause of Otitis Media in Down Syndrome. Elife |
| abstractText | 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. |
