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Genetic dissection of triplicated chromosome 21 orthologs yields varying skeletal traits in Down syndrome model mice

Sloan, Kourtney; Thomas, Jared; Blackwell, Matthew; Voisard, Deanna; Lana-Elola, Eva; Watson-Scales, Sheona; Roper, Daniel L; ... Roper, Randall J; + view all (2023) Genetic dissection of triplicated chromosome 21 orthologs yields varying skeletal traits in Down syndrome model mice. Disease Models & Mechanisms , 16 (4) , Article dmm049927. 10.1242/dmm.049927. Green open access

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Abstract

Down syndrome (DS) phenotypes result from triplicated genes, but it is generally unknown how specific three copy human chromosome 21 (Hsa21) orthologous genes or interactions between genes affect these traits. A mouse mapping panel genetically dissecting Hsa21 syntenic regions was used to investigate the contributions and interactions triplicated Hsa21 orthologous genes on mouse chromosome 16 (Mmu16). Four-month-old femurs of male and female Dp9Tyb, Dp2Tyb, Dp3Tyb, Dp4Tyb, Dp5Tyb, Dp6Tyb, Ts1Rhr, and Dp1Tyb;Dyrk1a+/+/- mice were analyzed by micro-computed tomography and 3-point bending to assess skeletal structure and mechanical properties. Male and female Dp1Tyb mice, with the entire Hsa21 homologous region of Mmu16 in three copies, display specific bone deficits similar to humans with DS and were used as a baseline comparison for the other strains in the panel. Bone phenotypes varied based on triplicated gene content, sex, and bone compartment. Three copies of Dyrk1a played a sex-specific, essential role in trabecular deficits and may interact with other genes to influence cortical deficits related to DS. Triplicated genes in Dp9Tyb and Dp2Tyb mice improved some skeletal deficits. As triplicated genes may both improve and worsen bone deficits, it is important to understand the interaction between and molecular mechanisms of skeletal alterations affected by these genes.

Type: Article
Title: Genetic dissection of triplicated chromosome 21 orthologs yields varying skeletal traits in Down syndrome model mice
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/dmm.049927
Publisher version: http://doi.org/10.1242/dmm.049927
Language: English
Additional information: © 2023. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: Animal models, Down syndrome, Genetics, Skeletal deficits, Trisomy 21
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10169877
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