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

Tateossian, H.; Southern, A.; Vikhe, P.; Lana-Elola, E.; Watson-Scales, S.; Gibbins, D.; Williams, D.; Purnell, T.; Mburu, P.; Parker, A.; Norris, D. P.; Santos-Cortez, R. L. P.; Herrmann, B. W.; Wells, S.; Lad, H. V.; Fisher, E.; Tybulewicz, V. L.; Brown, S. D. M.

doi:10.1101/2024.10.03.616443

bioRxiv · 10.1101/2024.10.03.616443

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

Tateossian, H.·Southern, A.·Vikhe, P.·Lana-Elola, E.·Watson-Scales, S.·Gibbins, D.·Williams, D.·Purnell, T.·Mburu, P.·Parker, A.·Norris, D. P.·Santos-Cortez, R. L. P.·Herrmann, B. W.·Wells, S.·Lad, H. V.·Fisher, E.·Tybulewicz, V. L.·Brown, S. D. M.

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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 TGF{beta} 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.

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Tateossian, H., Southern, A., Vikhe, P., Lana-Elola, E., Watson-Scales, S., Gibbins, D., Williams, D., Purnell, T., Mburu, P., Parker, A., Norris, D. P., Santos-Cortez, R. L. P., Herrmann, B. W., Wells, S., Lad, H. V., Fisher, E., Tybulewicz, V. L., Brown, S. D. M.. 2024-10-03. DYRK1A kinase triplication is the major cause of Otitis Media in Down Syndrome. https://doi.org/10.1101/2024.10.03.616443

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