caa a22 4500 44586107X CHVBK 20180317145443.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s00439-011-0980-2 doi (NATIONALLICENCE)springer-10.1007/s00439-011-0980-2 Genetic analysis of Down syndrome-associated heart defects in mice [Elektronische Daten] [Chunhong Liu, Masae Morishima, Tao Yu, Sei-Ichi Matsui, Li Zhang, Dawei Fu, Annie Pao, Alberto Costa, Katheleen Gardiner, John Cowell, Normal Nowak, Michael Parmacek, Ping Liang, Antonio Baldini, Y. Yu] 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. Springer-Verlag, 2011 Liu Chunhong Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut Morishima Masae Department of Anatomy and Developmental Biology, Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan aut Yu Tao Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut Matsui Sei-Ichi Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut Zhang Li Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut Fu Dawei Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut Pao Annie Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut Costa Alberto Division of Clinical Pharmacology and Toxicology, Department of Medicine, University of Colorado School of Medicine, 80045, Aurora, CO, USA aut Gardiner Katheleen Department of Pediatrics, Intellectual and Developmental Disability Research Center, Human Medical Genetics and Neuroscience Programs, University of Colorado Denver, 80045, Aurora, CO, USA aut Cowell John Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut Nowak Normal Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut Parmacek Michael University of Pennsylvania Cardiovascular Institute, 19104, Philadelphia, PA, USA aut Liang Ping Department of Biological Sciences, Brock University, L2S 3A1, St. Catharines, ON, Canada aut Baldini Antonio Institute of Biosciences and Technologies, Texas A&M University, 77843, Houston, TX, USA aut Yu Y. Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut Human Genetics Springer-Verlag 130/5(2011-11-01), 623-632 0340-6717 130:5<623 2011 130 439 https://doi.org/10.1007/s00439-011-0980-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-011-0980-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Liu Chunhong Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Morishima Masae Department of Anatomy and Developmental Biology, Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan aut NATIONALLICENCE 700 1- Yu Tao Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Matsui Sei-Ichi Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Zhang Li Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Fu Dawei Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Pao Annie Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Costa Alberto Division of Clinical Pharmacology and Toxicology, Department of Medicine, University of Colorado School of Medicine, 80045, Aurora, CO, USA aut NATIONALLICENCE 700 1- Gardiner Katheleen Department of Pediatrics, Intellectual and Developmental Disability Research Center, Human Medical Genetics and Neuroscience Programs, University of Colorado Denver, 80045, Aurora, CO, USA aut NATIONALLICENCE 700 1- Cowell John Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Nowak Normal Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Parmacek Michael University of Pennsylvania Cardiovascular Institute, 19104, Philadelphia, PA, USA aut NATIONALLICENCE 700 1- Liang Ping Department of Biological Sciences, Brock University, L2S 3A1, St. Catharines, ON, Canada aut NATIONALLICENCE 700 1- Baldini Antonio Institute of Biosciences and Technologies, Texas A&M University, 77843, Houston, TX, USA aut NATIONALLICENCE 700 1- Yu Y. Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, 14263, Buffalo, NY, USA aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 130/5(2011-11-01), 623-632 0340-6717 130:5<623 2011 130 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer