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Deficiencies in the region syntenic to human 21q22.3 cause cognitive deficits in mice

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Abstract

Copy-number variation in the human genome can be disease-causing or phenotypically neutral. This type of genetic rearrangement associated with human chromosome 21 (Hsa21) underlies partial Monosomy 21 and Trisomy 21. Mental retardation is a major clinical manifestation of partial Monosomy 21. To model this human chromosomal deletion disorder, we have generated novel mouse mutants carrying heterozygous deletions of the 2.3- and 1.1-Mb segments on mouse chromosome 10 (Mmu10) and Mmu17, respectively, which are orthologous to the regions on human 21q22.3, using Cre/loxP-mediated chromosome engineering. Alterations of the transcriptional levels of genes within the deleted intervals reflect gene-dosage effects in the mutant mice. The analysis of cognitive behaviors shows that the mutant mice carrying the deletion on either Mmu10 or Mmu17 are impaired in learning and memory. Therefore, these mutants represent mouse models for Monosomy 21-associated mental retardation, which can serve as a powerful tool to study the molecular mechanism underlying the clinical phenotype and should facilitate efforts to identify the haploinsufficient causative genes.

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Acknowledgments

The authors thank Paul Szurek and Jeffrey LaDuca for their assistance. This project was supported in part by grants to Y. E. Yu from the Louis Sklarow Memorial Fund, the Jerome Lejeune Foundation, and the NIH (R0HL091519).

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Authors and Affiliations

  1. Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Tao Yu, Zhongyou Li, Chunhong Liu, Annie Pao, Sei-Ichi Matsui & Y. Eugene Yu

  2. Institute of Membrane and Systems Biology, University of Leeds, Leeds, LS2 8JT, UK

    Steven J. Clapcote

  3. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, M5G 1X5, Canada

    Allison R. Bechard & John C. Roder

  4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    Sandra Carattini-Rivera

  5. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, 77030, USA

    Antonio Baldini

  6. Department of Neurosciences, University of California at San Diego, School of Medicine, La Jolla, CA, 92093, USA

    William C. Mobley

  7. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK

    Allan Bradley

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  1. Tao Yu
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  3. Zhongyou Li
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  12. Allan Bradley
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  13. Y. Eugene Yu
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Correspondence to Y. Eugene Yu.

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Yu, T., Clapcote, S.J., Li, Z. et al. Deficiencies in the region syntenic to human 21q22.3 cause cognitive deficits in mice. Mamm Genome 21, 258–267 (2010). https://doi.org/10.1007/s00335-010-9262-x

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  • DOI: https://doi.org/10.1007/s00335-010-9262-x

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