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Genetic analysis of Down syndrome-associated heart defects in mice

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An Erratum to this article was published on 10 April 2011

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.

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References

  • Abbag FI (2006) Congenital heart diseases and other major anomalies in patients with Down syndrome. Saudi Med J 27:219–222

    PubMed  Google Scholar 

  • Adams DJ, Biggs PJ, Cox T, Davies R, van der Weyden L, Jonkers J, Smith J, Plumb B, Taylor R, Nishijima I, Yu Y, Rogers J, Bradley A (2004) Mutagenic insertion and chromosome engineering resource (MICER). Nat Genet 36:867–871

    Article  PubMed  CAS  Google Scholar 

  • Akeson EC, Lambert JP, Narayanswami S, Gardiner K, Bechtel LJ, Davisson MT (2001) Ts65Dn-localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome. Cytogenet Cell Genet 93:270–276

    Article  PubMed  CAS  Google Scholar 

  • Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, Neilson JR, Chen L, Heit JJ, Kim SK, Yamasaki N, Miyakawa T, Francke U, Graef IA, Crabtree GR (2006) NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441:595–600

    Article  PubMed  CAS  Google Scholar 

  • Bedard E, Shore DF, Gatzoulis MA (2008) Adult congenital heart disease: a 2008 overview. Br Med Bull 85:151–180

    Article  PubMed  Google Scholar 

  • Birukova AA, Alekseeva E, Mikaelyan A, Birukov KG (2007a) HGF attenuates thrombin-induced endothelial permeability by Tiam1-mediated activation of the Rac pathway and by Tiam1/Rac-dependent inhibition of the Rho pathway. FASEB J 21:2776–2786

    Article  PubMed  CAS  Google Scholar 

  • Birukova AA, Malyukova I, Mikaelyan A, Fu P, Birukov KG (2007b) Tiam1 and betaPIX mediate Rac-dependent endothelial barrier protective response to oxidized phospholipids. J Cell Physiol 211:608–617

    Article  PubMed  CAS  Google Scholar 

  • Bradley A (1987) Production and analysis of chimaeric mice. In: Robertson E (ed) Teratocarcinomas and embryonic stem cells—a practical approach. IRL Press, Oxford, pp 113–151

    Google Scholar 

  • Bradley A, Zheng B, Liu P (1998) Thirteen years of manipulating the mouse genome: a personal history. Int J Dev Biol 42:943–950

    PubMed  CAS  Google Scholar 

  • Chang LW, Chen PY, Kuo PL, Chang FM (2001) Prenatal diagnosis of a fetus with megacystis and monosomy 21. Prenat Diagn 21:512–513

    Article  PubMed  CAS  Google Scholar 

  • Chaoui R, Heling KS, Sarioglu N, Schwabe M, Dankof A, Bollmann R (2005) Aberrant right subclavian artery as a new cardiac sign in second- and third-trimester fetuses with Down syndrome. Am J Obstet Gynecol 192:257–263

    Article  PubMed  Google Scholar 

  • Daliento L, Mazzotti E, Mongillo E, Rotundo M, Dalla Volta S (2002) Life expectancy and quality of life in adult patients with congenital heart disease. Ital Heart J 3:339–347

    PubMed  Google Scholar 

  • Davisson MT, Schmidt C, Akeson EC (1990) Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome. Prog Clin Biol Res 360:263–280

    PubMed  CAS  Google Scholar 

  • Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA (2003) DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 4:3

    Article  Google Scholar 

  • Dunlevy L, Bennett M, Slender A, Lana-Elola E, Tybulewicz VL, Fisher EM, Mohun T (2010) Down syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse. Cardiovasc Res 88:287–295

    Article  PubMed  CAS  Google Scholar 

  • Epstein CJ (1990) The consequences of chromosome imbalance. Am J Med Genet Suppl 7:31–37

    PubMed  CAS  Google Scholar 

  • Goodship J, Cross I, LiLing J, Wren C (1998) A population study of chromosome 22q11 deletions in infancy. Arch Dis Child 79:348–351

    Article  PubMed  CAS  Google Scholar 

  • Huang da W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44–57

    Article  PubMed  Google Scholar 

  • Joosten AM, De Vos S, Van Opstal D, Brandenburg H, Gaillard JL, Vermeij-Keers C (1997) Full monosomy 21, prenatally diagnosed by fluorescent in situ hybridization. Prenat Diagn 17:271–275

    Article  PubMed  CAS  Google Scholar 

  • Kahlem P, Sultan M, Herwig R, Steinfath M, Balzereit D, Eppens B, Saran NG, Pletcher MT, South ST, Stetten G, Lehrach H, Reeves RH, Yaspo ML (2004) Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of Down syndrome. Genome Res 14:1258–1267

    Article  PubMed  CAS  Google Scholar 

  • Korbel JO, Tirosh-Wagner T, Urban AE, Chen XN, Kasowski M, Dai L, Grubert F, Erdman C, Gao MC, Lange K, Sobel EM, Barlow GM, Aylsworth AS, Carpenter NJ, Clark RD, Cohen MY, Doran E, Falik-Zaccai T, Lewin SO, Lott IT, McGillivray BC, Moeschler JB, Pettenati MJ, Pueschel SM, Rao KW, Shaffer LG, Shohat M, Van Riper AJ, Warburton D, Weissman S, Gerstein MB, Snyder M, Korenberg JR (2009) The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. Proc Natl Acad Sci USA 106:12031–12036

    Article  PubMed  CAS  Google Scholar 

  • Korenberg JR, Chen XN, Schipper R, Sun Z, Gonsky R, Gerwehr S, Carpenter N, Daumer C, Dignan P, Disteche C (1994) Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc Natl Acad Sci USA 91:4997–5001

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Yu T, Morishima M, Pao A, LaDuca J, Conroy J, Nowak N, Matsui S, Shiraishi I, Yu Y (2007) Duplication of the entire 22.9-Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities. Hum Mol Genet 16:1359–1366

    Article  PubMed  CAS  Google Scholar 

  • Lignon JM, Bichler Z, Hivert B, Gannier FE, Cosnay P, del Rio JA, Migliore-Samour D, Malecot CO (2008) Altered heart rate control in transgenic mice carrying the KCNJ6 gene of the human chromosome 21. Physiol Genomics 33:230–239

    Article  PubMed  CAS  Google Scholar 

  • Liu P, Zhang H, McLellan A, Vogel H, Bradley A (1998) Embryonic lethality and tumorigenesis caused by segmental aneuploidy on mouse chromosome 11. Genetics 150:1155–1168

    PubMed  CAS  Google Scholar 

  • Lyle R, Gehrig C, Neergaard-Henrichsen C, Deutsch S, Antonarakis SE (2004) Gene expression from the aneuploid chromosome in a trisomy mouse model of down syndrome. Genome Res 14:1268–1274

    Article  PubMed  CAS  Google Scholar 

  • Lyle R, Bena F, Gagos S, Gehrig C, Lopez G, Schinzel A, Lespinasse J, Bottani A, Dahoun S, Taine L, Doco-Fenzy M, Cornillet-Lefebvre P, Pelet A, Lyonnet S, Toutain A, Colleaux L, Horst J, Kennerknecht I, Wakamatsu N, Descartes M, Franklin JC, Florentin-Arar L, Kitsiou S, Ait Yahya-Graison E, Costantine M, Sinet PM, Delabar JM, Antonarakis SE (2009) Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21. Eur J Hum Genet 17:454–466

    Article  PubMed  CAS  Google Scholar 

  • Marelli AJ, Therrien J, Mackie AS, Ionescu-Ittu R, Pilote L (2009) Planning the specialized care of adult congenital heart disease patients: from numbers to guidelines; an epidemiologic approach. Am Heart J 157:1–8

    Article  PubMed  Google Scholar 

  • Moore CS (2006) Postnatal lethality and cardiac anomalies in the Ts65Dn Down syndrome mouse model. Mamm Genome 17:1005–1012

    Article  PubMed  CAS  Google Scholar 

  • O’Doherty A, Ruf S, Mulligan C, Hildreth V, Errington ML, Cooke S, Sesay A, Modino S, Vanes L, Hernandez D, Linehan JM, Sharpe PT, Brandner S, Bliss TV, Henderson DJ, Nizetic D, Tybulewicz VL, Fisher EM (2005) An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science 309:2033–2037

    Article  PubMed  Google Scholar 

  • O’Gorman S, Dagenais NA, Qian M, Marchuk Y (1997) Protamine-Cre recombinase transgenes efficiently recombine target sequences in the male germ line of mice, but not in embryonic stem cells. Proc Natl Acad Sci USA 94:14602–14607

    Article  PubMed  Google Scholar 

  • Olson LE, Richtsmeier JT, Leszl J, Reeves RH (2004) A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science 306:687–690

    Article  PubMed  CAS  Google Scholar 

  • Pillutla P, Shetty KD, Foster E (2009) Mortality associated with adult congenital heart disease: trends in the US population from 1979 to 2005. Am Heart J 158:874–879

    Article  PubMed  Google Scholar 

  • Prescott K, Ivins S, Hubank M, Lindsay E, Baldini A, Scambler P (2005) Microarray analysis of the Df1 mouse model of the 22q11 deletion syndrome. Hum Genet 116:486–496

    Article  PubMed  CAS  Google Scholar 

  • Ramirez-Solis R, Davis AC, Bradley A (1993) Gene targeting in embryonic stem cells. Methods Enzymol 225:855–878

    Article  PubMed  CAS  Google Scholar 

  • Ramirez-Solis R, Liu P, Bradley A (1995) Chromosome engineering in mice. Nature 378:720–724

    Article  PubMed  CAS  Google Scholar 

  • Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS, Schmidt C, Bronson RT, Davisson MT (1995) A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet 11:177–184

    Article  PubMed  CAS  Google Scholar 

  • Robertson E (1987) Embryo-derived stem cell lines. In: Robertson E (ed) Teratocarcinomas and embryonic stem cells—a practical approach. IRL Press, Oxford, pp 77–112

    Google Scholar 

  • Roizen NJ, Patterson D (2003) Down’s syndrome. Lancet 361:1281–1289

    Article  PubMed  Google Scholar 

  • Roofthooft MT, van Meer H, Rietman WG, Ebels T, Berger RM (2008) Down syndrome and aberrant right subclavian artery. Eur J Pediatr 167:1033–1036

    Article  PubMed  Google Scholar 

  • Rowe RD, Uchida IA (1961) Cardiac malformation in mongolism: a prospective study of 184 mongoloid children. Am J Med 31:726–735

    Article  PubMed  CAS  Google Scholar 

  • Saeed AI, Bhagabati NK, Braisted JC, Liang W, Sharov V, Howe EA, Li J, Thiagarajan M, White JA, Quackenbush J (2006) TM4 microarray software suite. Methods Enzymol 411:134–193

    Article  PubMed  CAS  Google Scholar 

  • Shinohara T, Tomizuka K, Miyabara S, Takehara S, Kazuki Y, Inoue J, Katoh M, Nakane H, Iino A, Ohguma A, Ikegami S, Inokuchi K, Ishida I, Reeves RH, Oshimura M (2001) Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down’s syndrome. Hum Mol Genet 10:1163–1175

    Article  PubMed  CAS  Google Scholar 

  • Sinet PM, Theophile D, Rahmani Z, Chettouh Z, Blouin JL, Prieur M, Noel B, Delabar JM (1994) Mapping of the Down syndrome phenotype on chromosome 21 at the molecular level. Biomed Pharmacother 48:247–252

    Article  PubMed  CAS  Google Scholar 

  • Singleton PA, Dudek SM, Chiang ET, Garcia JG (2005) Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1, and alpha-actinin. FASEB J 19:1646–1656

    Article  PubMed  CAS  Google Scholar 

  • Torfs CP, Christianson RE (1998) Anomalies in Down syndrome individuals in a large population-based registry. Am J Med Genet 77:431–438

    Article  PubMed  CAS  Google Scholar 

  • Verheugt CL, Uiterwaal CS, van der Velde ET, Meijboom FJ, Pieper PG, van Dijk AP, Vliegen HW, Grobbee DE, Mulder BJ (2010) Mortality in adult congenital heart disease. Eur Heart J 31:1220–1229

    Article  PubMed  Google Scholar 

  • Williams RG, Pearson GD, Barst RJ, Child JS, del Nido P, Gersony WM, Kuehl KS, Landzberg MJ, Myerson M, Neish SR, Sahn DJ, Verstappen A, Warnes CA, Webb CL (2006) Report of the National Heart, Lung, and Blood Institute Working Group on research in adult congenital heart disease. J Am Coll Cardiol 47:701–707

    Article  PubMed  Google Scholar 

  • Williams AD, Mjaatvedt CH, Moore CS (2008) Characterization of the cardiac phenotype in neonatal Ts65Dn mice. Dev Dyn 237:426–435

    Article  PubMed  Google Scholar 

  • Yu Y, Bradley A (2001) Engineering chromosomal rearrangements in mice. Nat Rev Genet 2:780–790

    Article  PubMed  CAS  Google Scholar 

  • Yu YE, Morishima M, Pao A, Wang DY, Wen XY, Baldini A, Bradley A (2006) A deficiency in the region homologous to human 17q21.33-q23.2 causes heart defects in mice. Genetics 173:297–307

    Article  PubMed  CAS  Google Scholar 

  • Yu T, Li Z, Jia Z, Clapcote SJ, Liu C, Li S, Asrar S, Pao A, Chen R, Fan N, Carattini-Rivera S, Bechard AR, Spring S, Henkelman RM, Stoica G, Matsui S, Nowak NJ, Roder JC, Chen C, Bradley A, Yu YE (2010) A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions. Hum Mol Genet 19:2780–2791

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Zhongyou Li, Jeffrey Conroy and Jeffrey LaDuca for their assistance and Richard DiCioccio and Paula Jones for their helpful suggestions on the manuscript. This study is supported in part by grants to Y.E. Yu from the Children’s Guild Foundation and the NIH (R01HL091519).

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Authors and Affiliations

  1. Children’s Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA

    Chunhong Liu, Tao Yu, Sei-Ichi Matsui, Li Zhang, Dawei Fu, Annie Pao, John K. Cowell, Normal J. Nowak & Y. Eugene Yu

  2. New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY, 14263, USA

    Normal J. Nowak & Y. Eugene Yu

  3. Department of Cellular and Molecular Biology, Roswell Park Division of Graduate School, State University of New York at Buffalo, Buffalo, NY, 14263, USA

    Normal J. Nowak & Y. Eugene Yu

  4. Department of Anatomy and Developmental Biology, Department of Pediatric Cardiology, Tokyo Women’s Medical University, Tokyo, Japan

    Masae Morishima

  5. Division of Clinical Pharmacology and Toxicology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, 80045, USA

    Alberto C. Costa

  6. Department of Pediatrics, Intellectual and Developmental Disability Research Center, Human Medical Genetics and Neuroscience Programs, University of Colorado Denver, Aurora, CO, 80045, USA

    Katheleen J. Gardiner

  7. MCG Cancer Center, School of Medicine, Medical College of Georgia, Augusta, GA, 30912, USA

    John K. Cowell

  8. University of Pennsylvania Cardiovascular Institute, Philadelphia, PA, 19104, USA

    Michael S. Parmacek

  9. Department of Biological Sciences, Brock University, St. Catharines, ON, L2S 3A1, Canada

    Ping Liang

  10. Institute of Biosciences and Technologies, Texas A&M University, Houston, TX, 77843, USA

    Antonio Baldini

  11. Institute of Genetics and Biophysics, National Research Council, 80131, Naples, Italy

    Antonio Baldini

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  1. Chunhong Liu
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  2. Masae Morishima
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  3. Tao Yu
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  4. Sei-Ichi Matsui
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  5. Li Zhang
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  11. Normal J. Nowak
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  15. Y. Eugene Yu
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Correspondence to Y. Eugene Yu.

Additional information

C. Liu, M. Morishima and T. Yu contributed equally to this work.

An erratum to this article can be found at http://dx.doi.org/10.1007/s00439-011-0982-0

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Liu, C., Morishima, M., Yu, T. et al. Genetic analysis of Down syndrome-associated heart defects in mice. Hum Genet 130, 623–632 (2011). https://doi.org/10.1007/s00439-011-0980-2

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