title: Engineered chromosome-based genetic mapping establishes a 3.7 Mb critical genomic region for Down syndrome-associated heart defects in mice.
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.
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Liu
authors.forename: Masae
authors.initials: M
authors.lastname: Morishima
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Jiang
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.forename: Kai
authors.initials: K
authors.lastname: Meng
authors.forename: Debjit
authors.initials: D
authors.lastname: Ray
authors.forename: Annie
authors.initials: A
authors.lastname: Pao
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
authors.forename: Michael S
authors.initials: MS
authors.lastname: Parmacek
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Yu
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D033481:Chromosomes, Mammalian; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D004622:Embryo, Mammalian; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics; D018628:Gene Dosage; D005818:Genetic Engineering; D056426:Genetic Loci; D016678:Genome; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D010641:Phenotype; D011995:Recombination, Genetic; D026801:Synteny; 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