Genetic analysis of Down syndrome-associated heart defects in mice

Chunhong Liu, Masae Morishima, Tao Yu, Sei Ichi Matsui, Li Zhang, Dawei Fu, Annie Pao, Alberto C. Costa, Katheleen J. Gardiner, John Kenneth Cowell, Normal J. Nowak, Michael S. Parmacek, Ping Liang, Antonio Baldini, Y. Eugene Yu

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33 Scopus citations

Abstract

Human trisomy 21, the chromosomal basis of Down syndrome (DS), is the most common genetic cause of heart defects. Regions on human chromosome 21 (Hsa21) are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this study, we have analyzed the impact of duplications of each syntenic region on cardiovascular development in mice and have found that only the duplication on Mmu16, i.e., Dp(16)1Yey, is associated with heart defects. Furthermore, we generated two novel mouse models carrying a 5.43-Mb duplication and a reciprocal deletion between Tiam1 and Kcnj6 using chromosome engineering, Dp(16Tiam1-Kcnj6)Yey/+ and Df(16Tiam1-Kcnj6)Yey/+, respectively, within the 22.9-Mb syntenic region on Mmu16. We found that Dp(16Tiam1-Kcnj6)Yey/+, but not Dp(16)1Yey/Df(16Tiam1-Kcnj6)Yey, resulted in heart defects, indicating that triplication of the Tiam1-Knj6 region is necessary and sufficient to cause DS-associated heart defects. Our transcriptional analysis of Dp(16Tiam1-Kcnj6)Yey/+ embryos confirmed elevated expression levels for the genes located in the Tiam-Kcnj6 region. Therefore, we established the smallest critical genomic region for DS-associated heart defects to lay the foundation for identifying the causative gene(s) for this phenotype.

Original languageEnglish (US)
Pages (from-to)623-632
Number of pages10
JournalHuman Genetics
Volume130
Issue number5
DOIs
Publication statusPublished - Nov 2011

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Liu, C., Morishima, M., Yu, T., Matsui, S. I., Zhang, L., Fu, D., ... Yu, Y. E. (2011). Genetic analysis of Down syndrome-associated heart defects in mice. Human Genetics, 130(5), 623-632. https://doi.org/10.1007/s00439-011-0980-2