Abstract
Trisomy 21 (Down syndrome, DS) is the most common human genetic anomaly associated with heart defects. Based on evolutionary conservation, DS-associated heart defects have been modeled in mice. By generating and analyzing mouse mutants carrying different genomic rearrangements in human chromosome 21 (Hsa21) syntenic regions, we found the triplication of the Tiam1–Kcnj6 region on mouse chromosome 16 (Mmu16) resulted in DS-related cardiovascular abnormalities. In this study, we developed two tandem duplications spanning the Tiam1–Kcnj6 genomic region on Mmu16 using recombinase-mediated genome engineering, Dp(16)3Yey and Dp(16)4Yey, spanning the 2.1 Mb Tiam1–Il10rb and 3.7 Mb Ifnar1–Kcnj6 regions, respectively. We found that Dp(16)4Yey/+, but not Dp(16)3Yey/+, led to heart defects, suggesting the triplication of the Ifnar1–Kcnj6 region is sufficient to cause DS-associated heart defects. Our transcriptional analysis of Dp(16)4Yey/+ embryos showed that the Hsa21 gene orthologs located within the duplicated interval were expressed at the elevated levels, reflecting the consequences of the gene dosage alterations. Therefore, we have identified a 3.7 Mb genomic region, the smallest critical genomic region, for DS-associated heart defects, and our results should set the stage for the final step to establish the identities of the causal gene(s), whose elevated expression(s) directly underlie this major DS phenotype.
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Acknowledgments
The authors would like to thank Dawei Fu and Hiromi Kasahara-Sagawa for their technical assistance. This study is supported in part by grants from the Children’s Guild Foundation and the NIH (R01HL91519, R01NS66072 and P30CA16056).
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C. Liu, M. Morishima and X. Jiang contributed equally to this work.
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Liu, C., Morishima, M., Jiang, X. et al. Engineered chromosome-based genetic mapping establishes a 3.7 Mb critical genomic region for Down syndrome-associated heart defects in mice. Hum Genet 133, 743–753 (2014). https://doi.org/10.1007/s00439-013-1407-z
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DOI: https://doi.org/10.1007/s00439-013-1407-z