Genetic analysis of Down syndrome-associated heart defects in mice.

Human trisomy 21, the chromosomal basis of Down syndrome (DS), is the most common genetic cause of heart defects. Regions on human chromosome 21 (Has21) 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(Tiam1-Kcnj6)Yey/+ and Df(Tiam1-Kcnj6)Yey/+, respectively, within the 22.9-Mb syntenic region on Mmu16. We found that Dp(Tiam1-Kcnj6)Yey/+, but not Dp(16)1Yey/Df(Tiam1-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(Tiam1-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.

人类21三体，即唐氏综合征（DS）的染色体基础，是心脏缺陷最常见的遗传病因。人类21号染色体（Has21）上的区域与小鼠10号（Mmu10）、16号（Mmu16）和17号（Mmu17）染色体上的三个区域存在同线性保守关系。在这项研究中，我们分析了每个同线性区域的重复对小鼠心血管发育的影响，发现只有Mmu16上的重复，即Dp(16)1Yey，与心脏缺陷有关。此外，我们利用染色体工程技术在Mmu16上22.9 Mb的同线性区域内构建了两个新的小鼠模型，分别携带在Tiam1和Kcnj6之间的5.43 Mb重复和反向缺失，即Dp(Tiam1 - Kcnj6)Yey/+和Df(Tiam1 - Kcnj6)Yey/+。我们发现Dp(Tiam1 - Kcnj6)Yey/+会导致心脏缺陷，而Dp(16)1Yey/Df(Tiam1 - Kcnj6)Yey则不会，这表明Tiam1 - Knj6区域的三倍化对于导致DS相关心脏缺陷是必要且充分的。我们对Dp(Tiam1 - Kcnj6)Yey/+胚胎的转录分析证实了位于Tiam - Kcnj6区域的基因表达水平升高。因此，我们确定了与DS相关心脏缺陷最小的关键基因组区域，为识别这种表型的致病基因奠定了基础。