title: Genetic analysis of Down syndrome-associated heart defects in mice.
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.
authors: Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
authors: Chunhong
authors: C
authors: Liu
authors: Masae
authors: M
authors: Morishima
authors: Tao
authors: T
authors: Yu
authors: Sei-Ichi
authors: S
authors: Matsui
authors: Li
authors: L
authors: Zhang
authors: Dawei
authors: D
authors: Fu
authors: Annie
authors: A
authors: Pao
authors: Alberto C
authors: AC
authors: Costa
authors: Katheleen J
authors: KJ
authors: Gardiner
authors: John K
authors: JK
authors: Cowell
authors: Norma J
authors: NJ
authors: Nowak
authors: Normal J
authors: NJ
authors: Nowak
authors: Michael S
authors: MS
authors: Parmacek
authors: Ping
authors: P
authors: Liang
authors: Antonio
authors: A
authors: Baldini
authors: Y Eugene
authors: YE
authors: Yu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics*; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics; D020440:Gene Duplication / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D017384:Sequence Deletion / Q000235:genetics; D026801:Synteny / Q000235:genetics; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D020662:Guanine Nucleotide Exchange Factors; C497069:Kcnj6 protein, mouse; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513260:Tiam1 protein, mouse