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The impact of Mmu17 non-Hsa21 orthologous genes in the Ts65Dn mouse model of Down syndrome: the “gold standard” refuted

  • Faycal Guedj
    Prenatal Genomics and Fetal Therapy (PGT) Section, Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD, United States
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  • Elise Kane
    Prenatal Genomics and Fetal Therapy (PGT) Section, Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD, United States
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  • Lauren A. Bishop
    Prenatal Genomics and Fetal Therapy (PGT) Section, Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD, United States
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  • Jeroen L.A. Pennings
    Center for Health Protection, National Institute for Public Health and the Environment, Bilthoven, Netherlands
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  • Yann Herault
    Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Translational Medicine and Neurogenetics, Strasbourg, France
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  • Diana W. Bianchi
    Corresponding author: Diana W. Bianchi, MD, , Phone: (+1) 301-655-2890
    Prenatal Genomics and Fetal Therapy (PGT) Section, Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD, United States

    Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, United States
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      Despite successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome, translation to humans has failed. This raises questions about the appropriateness of the Ts65Dn mouse as the “gold standard.” We used the novel Ts66Yah mouse that carries an extra chromosome and the identical segmental Mmu16 trisomy as Ts65Dn without the Mmu17 non-orthologous region.


      Forebrains from embryonic day 18.5 Ts66Yah and Ts65Dn mice, along with euploid littermate controls, were used for gene expression and pathway analyses. Behavioral experiments were performed in neonatal and adult mice. Since male Ts66Yah mice are fertile, parent of origin transmission of the extra chromosome was studied.


      Forty-five protein coding genes mapped to the Ts65Dn Mmu17 non-orthologous region; 71-82% are expressed during forebrain development. Several of these genes are uniquely overexpressed in Ts65Dn embryonic forebrain producing major differences in dysregulated genes and pathways. Despite these differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in commonly dysregulated disomic genes and pathways. Delays in motor development, communication and olfactory spatial memory were present in Ts66Yah but more pronounced in Ts65Dn neonates. Adult Ts66Yah mice showed milder working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved.


      Our findings suggest that triplication of the non-orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may explain why preclinical trials that used this model have unsuccessfully translated to human therapies.

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