Basic Research in Cardiology

, Volume 103, Issue 3, pp 216–227 | Cite as

Genes in congenital heart disease: atrioventricular valve formation

  • Irene C. Joziasse
  • Jasper J. van de Smagt
  • Kelly Smith
  • Jeroen Bakkers
  • Gert-Jan Sieswerda
  • Barbara J. M. Mulder
  • Peter A. Doevendans


Through the use of animal studies, many candidate genes (mainly encoding transcriptional factors and receptors) have been implicated in the development of congenital heart disease. Thus far, only a minority of these genes have been shown to carry mutations associated with congenital disease in humans, e.g., GATA 4, TBX-5, NOTCH1 and NKX2-5. Mutations in these genes can cause a variety of cardiac defects even within the same family. Conversely, similar phenotypes are observed for different gene mutations suggesting a common pathway. Multiple genes and genetic pathways have been related to atrioventricular valve formation, although most of these genes have not yet been demonstrated as causative in human atrioventricular valve defects. Key pathways include the epidermal growth factor receptor pathway and related interacting pathways, most importantly the pathway of UDP-glucose dehydrogenase, resulting ultimately in activation of Ras. Other examples of interacting pathways include that of Nodal/Cited2/Pitx2, Wnt, Notch and ECE. Further studies are needed to investigate the pathways which are crucial for atrioventricular valve formation in humans. Understanding the underlying molecular process of abnormal atrioventricular valve formation in patients with congenital heart disease may provide important insight, in the etiology and possibly into preventive or treatment regimes.

Key words

heart defects congenital valves genes genetic pathways 


  1. 1.
    Abu-Issa R, Smyth G, Smoak I, Yamamura K, Meyers EN (2002) Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse. Development 129:4613–4625PubMedGoogle Scholar
  2. 2.
    Alsan BH, Schultheiss TM (2002) Regulation of avian cardiogenesis by Fgf8 signaling. Development 129:1935–1943PubMedGoogle Scholar
  3. 3.
    Amendt BA, Semina EV, Alward WL (2000) Rieger syndrome: a clinical, molecular, and biochemical analysis. Cell Mol Life Sci 57:1652–1666PubMedGoogle Scholar
  4. 4.
    Arnold SJ, Maretto S, Islam A, Bikoff EK, Robertson EJ (2006) Dose-dependent Smad1, Smad5 and Smad8 signaling in the early mouse embryo. Dev Biol 296:104–118PubMedGoogle Scholar
  5. 5.
    Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776PubMedGoogle Scholar
  6. 6.
    Bakkers J, Kramer C, Pothof J, Quaedvlieg NE, Spaink HP, Hammerschmidt M (2004) Has2 is required upstream of Rac1 to govern dorsal migration of lateral cells during zebrafish gastrulation. Development 131:525–537PubMedGoogle Scholar
  7. 7.
    Bamford RN, Roessler E, Burdine RD, Saplakoglu U, dela Cruz J, Splitt M, Goodship JA, Towbin J, Bowers P, Ferrero GB, Marino B, Schier AF, Shen MM, Muenke M, Casey B (2000) Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet 26:365–369PubMedGoogle Scholar
  8. 8.
    Bamforth SD, Bragança J, Farthing CR, Schneider JE, Broadbent C, Michell AC, Clarke K, Neubauer S, Norris D, Brown NA, Anderson RH, Bhattacharya S (2004) Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway. Nat Genet 36:1189–1196PubMedGoogle Scholar
  9. 9.
    Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG, Seidman CE (1997) Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 15:30–35PubMedGoogle Scholar
  10. 10.
    Beis D, Bartman T, Jin SW, Scott IC, D’Amico LA, Ober EA, Verkade H, Frantsve J, Field HA, Wehman A, Baier H, Tallafuss A, Bally-Cuif L, Chen JN, Stainier DY, Jungblut B (2005) Genetic and cellular analyses of zebrafish atrioventricular cushion and valve development. Development 132:4193–4204PubMedGoogle Scholar
  11. 11.
    Boyer AS, Ayerinskas II, Vincent EB, McKinney LA, Weeks DL, Runyan RB (1999) TGFbeta2 and TGFbeta3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev Biol 208:530–545PubMedGoogle Scholar
  12. 12.
    Brade T, Männer J, Kühl M (2006) The role of Wnt signalling in cardiac development and tissue remodelling in the mature heart. Cardiovasc Res 72:198–209PubMedGoogle Scholar
  13. 13.
    Brewer AC, Alexandrovich A, Mjaatvedt CH, Shah AM, Patient RK, Pizzey JA (2005) GATA factors lie upstream of Nkx 2.5 in the transcriptional regulatory cascade that effects cardiogenesis. Stem Cells Dev 14:425–439PubMedGoogle Scholar
  14. 14.
    Brown CB, Boyer AS, Runyan RB, Barnett JV (1999) Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science 283:2080–2082PubMedGoogle Scholar
  15. 15.
    Brown CO, Chi X, Garcia-Gras E, Shirai M, Feng XH, Schwartz RJ (2004) The cardiac determination factor, Nkx2–5, is activated by mutual cofactors GATA-4 and Smad1/4 via a novel upstream enhancer. J Biol Chem 279:10659–10669PubMedGoogle Scholar
  16. 16.
    Camenisch TD, Schroeder JA, Bradley J, Klewer SE, McDonald JA (2002) Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2-ErbB3 receptors. Nat Med 8:850–855PubMedGoogle Scholar
  17. 17.
    Camenisch TD, Spicer AP, Brehm-Gibson T, Biesterfeldt J, Augustine ML, Calabro A Jr, Kubalak S, Klewer SE, McDonald JA (2000) Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J Clin Invest 106:349–360PubMedGoogle Scholar
  18. 18.
    Campbell M (1973) Incidence of cardiac malformations at birth and later, and neonatal mortality. Br Heart J 35:189–200PubMedGoogle Scholar
  19. 19.
    Chang H, Huylebroeck D, Verschueren K, Guo Q, Matzuk MM, Zwijsen A (1999) Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development 126:1631–1642PubMedGoogle Scholar
  20. 20.
    Chen D, Zhao M, Mundy GR (2004) Bone morphogenetic proteins. Growth Factors 22:233–241PubMedGoogle Scholar
  21. 21.
    Ching YH, Ghosh TK, Cross SJ, Packham EA, Honeyman L, Loughna S, Robinson TE, Dearlove AM, Ribas G, Bonser AJ, Thomas NR, Scotter AJ, Caves LS, Tyrrell GP, Newbury-Ecob RA, Munnich A, Bonnet D, Brook JD (2005) Mutation in myosin heavy chain 6 causes atrial septal defect. Nat Genet 37:423–428PubMedGoogle Scholar
  22. 22.
    Clouthier DE, Hosoda K, Richardson JA, Williams SC, Yanagisawa H, Kuwaki T, Kumada M, Hammer RE, Yanagisawa M (1998) Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 125:813–824PubMedGoogle Scholar
  23. 23.
    de la Pompa JL, Timmerman LA, Takimoto H, Yoshida H, Elia AJ, Samper E, Potter J, Wakeham A, Marengere L, Langille BL, Crabtree GR, Mak TW (1998) Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature 392:182–186PubMedGoogle Scholar
  24. 24.
    Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-[beta] family signalling. Nature 425:577–584PubMedGoogle Scholar
  25. 25.
    Digilio MC, Marino B, Toscano A, Giannotti A, Dallapiccola B (1999) Atrioventricular canal defect without Down syndrome: a heterogeneous malformation. Am J Med Genet 85:140–146PubMedGoogle Scholar
  26. 26.
    Dor Y, Camenisch TD, Itin A, Fishman GI, McDonald JA, Carmeliet P, Keshet E (2001) A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects. Development 128:1531–1538PubMedGoogle Scholar
  27. 27.
    Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M (1997) The cardiac transcription factors Nkx2–5 and GATA-4 are mutual cofactors. EMBO J 16:5687–5696PubMedGoogle Scholar
  28. 28.
    Eisenberg LM, Markwald RR (1995) Molecular regulation of atrioventricular valvuloseptal morphogenesis. Circ Res 77:1–6PubMedGoogle Scholar
  29. 29.
    Eldadah ZA, Hamosh A, Biery NJ, Montgomery RA, Duke M, Elkins R, Dietz HC (2001) Familial Tetralogy of Fallot caused by mutation in the jagged1 gene. Hum Mol Genet 10:163–169PubMedGoogle Scholar
  30. 30.
    Euler-Taimor G, Heger J (2006) The complex pattern of SMAD signaling in the cardiovascular system. Cardiovasc Res 69:15–25PubMedGoogle Scholar
  31. 31.
    Fischer A, Steidl C, Wagner TU, Lang E, Jakob PM, Friedl P, Knobeloch KP, Gessler M (2007) Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition. Circ Res 100:856–863PubMedGoogle Scholar
  32. 32.
    Flagg AE, Earley JU, Svensson EC (2007) FOG-2 attenuates endothelial-to-mesenchymal transformation in the endocardial cushions of the developing heart. Dev Biol 304:308–316PubMedGoogle Scholar
  33. 33.
    Gage PJ, Suh H, Camper SA (1999) Dosage requirement of Pitx2 for development of multiple organs. Development 126:4643–4651PubMedGoogle Scholar
  34. 34.
    Galvin KM, Donovan MJ, Lynch CA, Meyer RI, Paul RJ, Lorenz JN, Fairchild-Huntress V, Dixon KL, Dunmore JH, Gimbrone MA Jr, Falb D, Huszar D (2000) A role for smad6 in development and homeostasis of the cardiovascular system. Nat Genet 24:171–174PubMedGoogle Scholar
  35. 35.
    Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443–447PubMedGoogle Scholar
  36. 36.
    Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D (2005) Mutations in NOTCH1 cause aortic valve disease. Nature 437:270–274PubMedGoogle Scholar
  37. 37.
    Gassmann M, Casagranda F, Orioli D, Simon H, Lai C, Klein R, Lemke G (1995) Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378:390–394PubMedGoogle Scholar
  38. 38.
    Gaussin V, Morley GE, Cox L, Zwijsen A, Vance KM, Emile L, Tian Y, Liu J, Hong C, Myers D, Conway SJ, Depre C, Mishina Y, Behringer RR, Hanks MC, Schneider MD, Huylebroeck D, Fishman GI, Burch JB, Vatner SF (2005) Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus. Circ Res 97:219–226PubMedGoogle Scholar
  39. 39.
    Gaussin V, Van de Putte T, Mishina Y, Hanks MC, Zwijsen A, Huylebroeck D, Behringer RR, Schneider MD (2002) Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3. Proc Natl Acad Sci USA 99:2878–2883PubMedGoogle Scholar
  40. 40.
    Gitler AD, Zhu Y, Ismat FA, Lu MM, Yamauchi Y, Parada LF, Epstein JA (2003) Nf1 has an essential role in endothelial cells. Nat Genet 33:75–79PubMedGoogle Scholar
  41. 41.
    Goldmuntz E, Bamford R, Karkera JD, dela Cruze J, Roessler E, Muenke M (2002) CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle. Am J Hum Genet 70:776–780PubMedGoogle Scholar
  42. 42.
    Gong W, Gottlieb S, Collins J, Blescia A, Dietz H, Goldmuntz E, Donald-McGinn DM, Zackai EH, Emanuel BS, Driscoll DA, Budarf ML (2001) Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects. J Med Genet 38:E45PubMedGoogle Scholar
  43. 43.
    Heathcote K, Braybrook C, Abushaban L, Guy M, Khetyar ME, Patton MA, Carter ND, Scambler PJ, Syrris P (2005) Common arterial trunk associated with a homeodomain mutation of NKX2.6. Hum Mol Genet 14:585–593PubMedGoogle Scholar
  44. 44.
    Hogan PG, Chen L, Nardone J, Rao A (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 17:2205–2232PubMedGoogle Scholar
  45. 45.
    Hurlstone AF, Haramis AP, Wienholds E, Begthel H, Korving J, Van Eeden F, Cuppen E, Zivkovic D, Plasterk RH, Clevers H (2003) The Wnt/beta-catenin pathway regulates cardiac valve formation. Nature 425:633–637PubMedGoogle Scholar
  46. 46.
    Ichida M, Finkel T (2001) Ras regulates NFAT3 activity in cardiac myocytes. J Biol Chem 276:3524–3530PubMedGoogle Scholar
  47. 47.
    Iwamoto R, Yamazaki S, Asakura M, Takashima S, Hasuwa H, Miyado K, Adachi S, Kitakaze M, Hashimoto K, Raab G, Nanba D, Higashiyama S, Hori M, Klagsbrun M, Mekada E (2003) Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc Natl Acad Sci USA 100:3221–3226PubMedGoogle Scholar
  48. 48.
    Jackson LF, Qiu TH, Sunnarborg SW, Chang A, Zhang C, Patterson C, Lee DC (2003) Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling. EMBO J 22:2704–2716PubMedGoogle Scholar
  49. 49.
    Jiao K, Kulessa H, Tompkins K, Zhou Y, Batts L, Baldwin HS, Hogan BL (2003) An essential role of Bmp4 in the atrioventricular septation of the mouse heart. Genes Dev 17:2362–2367PubMedGoogle Scholar
  50. 50.
    Jiao K, Langworthy M, Batts L, Brown CB, Moses HL, Baldwin HS (2006) Tgf{beta} signaling is required for atrioventricular cushion mesenchyme remodeling during in vivo cardiac development. Development 133:4585–4593PubMedGoogle Scholar
  51. 51.
    Johnson EN, Lee YM, Sander TL, Rabkin E, Schoen FJ, Kaushal S, Bischoff J (2003) NFATc1 mediates vascular endothelial growth factor-induced proliferation of human pulmonary valve endothelial cells. J Biol Chem 278:1686–1692PubMedGoogle Scholar
  52. 52.
    Joziasse IC, Smith K, van der Smagt JJ, Mulder BJ, Bakkers J, Doevendans PA (2007) Abstract 2133: Mutations in Alk2 are associated with congenital atrioventricular valve-and septal defects. Circulation 116:IIGoogle Scholar
  53. 53.
    Kaartinen V, Dudas M, Nagy A, Sridurongrit S, Lu MM, Epstein JA (2004) Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells. Development 131:3481–3490PubMedGoogle Scholar
  54. 54.
    Kim RY, Robertson EJ, Solloway MJ (2001) Bmp6 and Bmp7 are required for cushion formation and septation in the developing mouse heart. Dev Biol 235:449–466PubMedGoogle Scholar
  55. 55.
    Kioussi C, Briata P, Baek SH, Rose DW, Hamblet NS, Herman T, Ohgi KA, Lin C, Gleiberman A, Wang J, Brault V, Ruiz-Lozano P, Nguyen HD, Kemler R, Glass CK, Wynshaw-Boris A, Rosenfeld MG (2002) Identification of a Wnt/Dvl/beta-Catenin –> Pitx2 pathway mediating cell-type-specific proliferation during development. Cell 111:673–685PubMedGoogle Scholar
  56. 56.
    Kitamura K, Miura H, Miyagawa-Tomita S, Yanazawa M, Katoh-Fukui Y, Suzuki R, Ohuchi H, Suehiro A, Motegi Y, Nakahara Y, Kondo S, Yokoyama M (1999) Mouse Pitx2 deficiency leads to anomalies of the ventral body wall, heart, extra- and periocular mesoderm and right pulmonary isomerism. Development 126:5749–5758PubMedGoogle Scholar
  57. 57.
    König K, Will JC, Berger F, Müller D, Benson DW (2006) Familial congenital heart disease, progressive atrioventricular block and the cardiac homeobox transcription factor gene NKX2.5: : identification of a novel mutation. Clin Res Cardiol 95:499–503PubMedGoogle Scholar
  58. 58.
    Kumar A, Novoselov V, Celeste AJ, Wolfman NM, ten Dijke P, Kuehn MR (2001) Nodal signaling uses activin and transforming growth factor-beta receptor-regulated Smads. J Biol Chem 276:656–661PubMedGoogle Scholar
  59. 59.
    Kurihara Y, Kurihara H, Oda H, Maemura K, Nagai R, Ishikawa T, Yazaki Y (1995) Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1. J Clin Invest 96:293–300PubMedGoogle Scholar
  60. 60.
    Lakkis MM, Epstein JA (1998) Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart. Development 125:4359–4367PubMedGoogle Scholar
  61. 61.
    Langford K, Sharland G, Simpson J (2005) Relative risk of abnormal karyotype in fetuses found to have an atrioventricular septal defect (AVSD) on fetal echocardiography. Prenat Diagn 25:137–139PubMedGoogle Scholar
  62. 62.
    Liebner S, Cattelino A, Gallini R, Rudini N, Iurlaro M, Piccolo S, Dejana E (2004) Beta-catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse. J Cell Biol 166:359–367PubMedGoogle Scholar
  63. 63.
    Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X (2002) Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108:837–847PubMedGoogle Scholar
  64. 64.
    Loffredo CA, Chokkalingam A, Sill AM, Boughman JA, Clark EB, Scheel J, Brenner JI (2004) Prevalence of congenital cardiovascular malformations among relatives of infants with hypoplastic left heart, coarctation of the aorta, and d-transposition of the great arteries. Am J Med Genet A 124:225–230PubMedGoogle Scholar
  65. 65.
    McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB (2006) NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 79:169–173PubMedGoogle Scholar
  66. 66.
    Metcalfe K, Rucka AK, Smoot L, Hofstadler G, Tuzler G, McKeown P, Siu V, Rauch A, Dean J, Dennis N, Ellis I, Reardon W, Cytrynbaum C, Osborne L, Yates JR, Read AP, Donnai D, Tassabehji M (2000) Elastin: mutational spectrum in supravalvular aortic stenosis. Eur J Hum Genet 8:955–963PubMedGoogle Scholar
  67. 67.
    Meyers EN, Martin GR (1999) Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH. Science 285:403–406PubMedGoogle Scholar
  68. 68.
    Miquerol L, Langille BL, Nagy A (2000) Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development 127:3941–3946PubMedGoogle Scholar
  69. 69.
    Mjaatvedt CH, Yamamura H, Capehart AA, Turner D, Markwald RR (1998) The Cspg2 gene, disrupted in the hdf mutant, is required for right cardiac chamber and endocardial cushion formation. Dev Biol 202:56–66PubMedGoogle Scholar
  70. 70.
    Mohamed SA, Aherrahrou Z, Liptau H, Erasmi AW, Hagemann C, Wrobel S, Borzym K, Schunkert H, Sievers HH, Erdmann J (2006) Novel missense mutations (p.T596M and p.P1797H) in NOTCH1 in patients with bicuspid aortic valve. Biochem Biophys Res Commun 345:1460–1465PubMedGoogle Scholar
  71. 71.
    Molin DG, Bartram U, Van der Heiden K, Van Iperen L, Speer CP, Hierck BP, Poelmann RE, Gittenberger-de-Groot AC (2003) Expression patterns of Tgfbeta1–3 associate with myocardialisation of the outflow tract and the development of the epicardium and the fibrous heart skeleton. Dev Dyn 227:431–444PubMedGoogle Scholar
  72. 72.
    Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN (1998) A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93:215–228PubMedGoogle Scholar
  73. 73.
    Moorman A, Webb S, Brown NA, Lamers W, Anderson RH (2003) Development of the heart: (1) formation of the cardiac chambers and arterial trunks. Heart 89:806–814PubMedGoogle Scholar
  74. 74.
    Moorman AF, Christoffels VM (2003) Cardiac chamber formation: development, genes, and evolution. Physiol Rev 83:1223–1267PubMedGoogle Scholar
  75. 75.
    Moorman AF, Christoffels VM (2003) Development of the cardiac conduction system: a matter of chamber development. Novartis Found Symp 250:25–34. Discussion 34–43, 276–279Google Scholar
  76. 76.
    Muncke N, Jung C, Rudiger H, Ulmer H, Roeth R, Hubert A, Goldmuntz E, Driscoll D, Goodship J, Schon K, Rappold G (2003) Missense mutations and gene interruption in PROSIT240, a novel TRAP240-like gene, in patients with congenital heart defect (transposition of the great arteries). Circulation 108:2843–2850PubMedGoogle Scholar
  77. 77.
    Nowotschin S, Liao J, Gage PJ, Epstein JA, Campione M, Morrow BE (2006) Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field. Development 133:1565–1573PubMedGoogle Scholar
  78. 78.
    Okubo A, Miyoshi O, Baba K, Takagi M, Tsukamoto K, Kinoshita A, Yoshiura K, Kishino T, Ohta T, Niikawa N, Matsumoto N (2004) A novel GATA4 mutation completely segregated with atrial septal defect in a large Japanese family. J Med Genet 41:e97PubMedGoogle Scholar
  79. 79.
    Özcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hübner N, Chien KR, Birchmeier C, Garratt AN (2002) Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci USA 99:8880–8885PubMedGoogle Scholar
  80. 80.
    Person AD, Garriock RJ, Krieg PA, Runyan RB, Klewer SE (2005) Frzb modulates Wnt-9a-mediated beta-catenin signaling during avian atrioventricular cardiac cushion development. Dev Biol 278:35–48PubMedGoogle Scholar
  81. 81.
    Phelan SA, Ito M, Loeken MR (1997) Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis. Diabetes 46:1189–1197PubMedGoogle Scholar
  82. 82.
    Pizzuti A, Sarkozy A, Newton AL, Conti E, Flex E, Digilio MC, Amati F, Gianni D, Tandoi C, Marino B, Crossley M, Dallapiccola B (2003) Mutations of ZFPM2/FOG2 gene in sporadic cases of tetralogy of Fallot. Hum Mutat 22:372–377PubMedGoogle Scholar
  83. 83.
    Poelmann RE, Gittenberger-de Groot AC (2005) Apoptosis as an instrument in cardiovascular development. Birth Defects Res C Embryo Today 75:305–313PubMedGoogle Scholar
  84. 84.
    Potts JD, Dagle JM, Walder JA, Weeks DL, Runyan RB (1991) Epithelial-mesenchymal transformation of embryonic cardiac endothelial cells is inhibited by a modified antisense oligodeoxynucleotide to transforming growth factor beta 3. Proc Natl Acad Sci USA 88:1516–1520PubMedGoogle Scholar
  85. 85.
    Potts JD, Runyan RB (1989) Epithelial-mesenchymal cell transformation in the embryonic heart can be mediated, in part, by transforming growth factor beta. Dev Biol 134:392–401PubMedGoogle Scholar
  86. 86.
    Qing M, Görlach A, Schumacher K, Wöltje M, Vazquez-Jimenez JF, Hess J, Seghaye MC (2007) The hypoxia-inducible factor HIF-1 promotes intramyocardial expression of VEGF in infants with congenital cardiac defects. Basic Res Cardiol 102:224–232PubMedGoogle Scholar
  87. 87.
    Reamon-Buettner SM, Borlak J (2004) TBX5 mutations in non-Holt-Oram syndrome (HOS) malformed hearts. Hum Mutat 24:104PubMedGoogle Scholar
  88. 88.
    Reamon-Buettner SM, Borlak J (2004) Somatic NKX2–5 mutations as a novel mechanism of disease in complex congenital heart disease. J Med Genet 41:684–690PubMedGoogle Scholar
  89. 89.
    Rivera-Feliciano J, Tabin CJ (2006) Bmp2 instructs cardiac progenitors to form the heart-valve-inducing field. Dev Biol 295:580–588PubMedGoogle Scholar
  90. 90.
    Roberts KE, McElroy JJ, Wong WPK, Yen E, Widlitz A, Barst RJ, Knowles JA, Morse JH (2004) BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 24:371–374PubMedGoogle Scholar
  91. 91.
    Robinson SW, Morris CD, Goldmuntz E, Reller MD, Jones MA, Steiner RD, Maslen CL (2003) Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet 72:1047–1052PubMedGoogle Scholar
  92. 92.
    Samanék M (2000) Congenital heart malformations: prevalence, severity, survival, and quality of life. Cardiol Young 10:179–185PubMedCrossRefGoogle Scholar
  93. 93.
    Sanford LP, Ormsby I, Gittenberger-de Groot AC, Sariola H, Friedman R, Boivin GP, Cardell EL, Doetschman T (1997) TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 124:2659–2670PubMedGoogle Scholar
  94. 94.
    Schlange T, Arnold HH, Brand T (2002) BMP2 is a positive regulator of Nodal signaling during left-right axis formation in the chicken embryo. Development 129:3421–3429PubMedGoogle Scholar
  95. 95.
    Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG (1998) Congenital heart disease caused by mutations in the transcription factor NKX2–5. Science 281:108–111PubMedGoogle Scholar
  96. 96.
    Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP (2006) Germline KRAS mutations cause Noonan syndrome. Nat Genet 38:331–336PubMedGoogle Scholar
  97. 97.
    Sepulveda JL, Belaguli N, Nigam V, Chen CY, Nemer M, Schwartz RJ (1998) GATA-4 and Nkx-2.5 coactivate Nkx-2 DNA binding targets: role for regulating early cardiac gene expression. Mol Cell Biol 18:3405–3415PubMedGoogle Scholar
  98. 98.
    Sheffield VC, Pierpont ME, Nishimura D, Beck JS, Burns TL, Berg MA, Stone EM, Patil SR, Lauer RM (1997) Identification of a complex congenital heart defect susceptibility locus by using DNA pooling and shared segment analysis. Hum Mol Genet 6:117–121PubMedGoogle Scholar
  99. 99.
    Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700PubMedGoogle Scholar
  100. 100.
    Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, Annunziata N, Doetschmann T (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359:693–699PubMedGoogle Scholar
  101. 101.
    Sirard C, de la Pompa JL, Elia A, Itie A, Mirtsos C, Cheung A, Hahn S, Wakeham A, Schwartz L, Kern SE, Rossant J, Mak TW (1998) The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev 12:107–119PubMedGoogle Scholar
  102. 102.
    Sperling S, Grimm CH, Dunkel I, Mebus S, Sperling HP, Ebner A, Galli R, Lehrach H, Fusch C, Berger F, Hammer S (2005) Identification and functional analysis of CITED2 mutations in patients with congenital heart defects. Hum Mutat 26:575–582PubMedGoogle Scholar
  103. 103.
    Stenvers KL, Tursky ML, Harder KW, Kountouri N, matayakul-Chantler S, Grail D, Small C, Weinberg RA, Sizeland AM, Zhu HJ (2003) Heart and liver defects and reduced transforming growth factor beta2 sensitivity in transforming growth factor beta type III receptor-deficient embryos. Mol Cell Biol 23:4371–4385PubMedGoogle Scholar
  104. 104.
    Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD (2001) Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465–468PubMedGoogle Scholar
  105. 105.
    Timmerman LA, Grego-Bessa J, Raya A, Bertrán E, Pérez-Pomares JM, Diez J, Aranda S, Palomo S, McCormick F, Izpisúa-Belmonte JC, de la Pompa JL (2004) Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 18:99–115PubMedGoogle Scholar
  106. 106.
    Tremblay KD, Dunn NR, Robertson EJ (2001) Mouse embryos lacking Smad1 signals display defects in extra-embryonic tissues and germ cell formation. Development 128:3609–3621PubMedGoogle Scholar
  107. 107.
    van der Velde ET, Vriend JW, Mannens MM, Uiterwaal CS, Brand R, Mulder BJ (2005) CONCOR, an initiative towards a national registry and DNA-bank of patients with congenital heart disease in the Netherlands: rationale, design, and first results. Eur J Epidemiol 20:549–557PubMedGoogle Scholar
  108. 108.
    Veeman MT, Axelrod JD, Moon RT (2003) A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell 5:367–377PubMedGoogle Scholar
  109. 109.
    Vigetti D, Ori M, Viola M, Genasetti A, Karousou E, Rizzi M, Pallotti F, Nardi I, Hascall VC, De Luca G, Passi A (2006) Molecular cloning and characterization of UDP-glucose dehydrogenase from the amphibian Xenopus laevis and its involvement in hyaluronan synthesis. J Biol Chem 281:8254–8263PubMedGoogle Scholar
  110. 110.
    Walsh EC, Stainier DY (2001) UDP-glucose dehydrogenase required for cardiac valve formation in zebrafish. Science 293:1670–1673PubMedGoogle Scholar
  111. 111.
    Wang J, Sridurongrit S, Dudas M, Thomas P, Nagy A, Schneider MD, Epstein JA, Kaartinen V (2005) Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart. Dev Biol 286:299–310PubMedGoogle Scholar
  112. 112.
    Ware SM, Peng J, Zhu L, Fernbach S, Colicos S, Casey B, Towbin J, Belmont JW (2004) Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Am J Hum Genet 74:93–105PubMedGoogle Scholar
  113. 113.
    Weninger WJ, Floro KL, Bennett MB, Withington SL, Preis JI, Barbera JP, Mohun TJ, Dunwoodie SL (2005) Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development. Development 132:1337–1348PubMedGoogle Scholar
  114. 114.
    Yanagisawa H, Hammer RE, Richardson JA, Emoto N, Williams SC, Takeda S, Clouthier DE, Yanagisawa M (2000) Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development. J Clin Invest 105:1373–1382PubMedGoogle Scholar
  115. 115.
    Yanagisawa H, Yanagisawa M, Kapur RP, Richardson JA, Williams SC, Clouthier DE, de Wit D, Emoto N, Hammer RE (1998) Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development 125:825–836PubMedGoogle Scholar
  116. 116.
    Zatyka M, Priestley M, Ladusans EJ, Fryer AE, Mason J, Latif F, Maher ER (2005) Analysis of CRELD1 as a candidate 3p25 atrioventicular septal defect locus (AVSD2). Clin Genet 67:526–528PubMedGoogle Scholar
  117. 117.
    Zhang H, Bradley A (1996) Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122:2977–2986PubMedGoogle Scholar
  118. 118.
    Zhao F, Lufkin T, Gelb BD (2003) Expression of Tfap2d, the gene encoding the transcription factor Ap-2 delta, during mouse embryogenesis. Gene Expr Patterns 3:213–217PubMedGoogle Scholar
  119. 119.
    Zhao F, Weismann CG, Satoda M, Pierpont ME, Sweeney E, Thompson EM, Gelb BD (2001) Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation. Am J Hum Genet 69:695–703PubMedGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Irene C. Joziasse
    • 1
  • Jasper J. van de Smagt
    • 2
  • Kelly Smith
    • 3
  • Jeroen Bakkers
    • 3
  • Gert-Jan Sieswerda
    • 1
  • Barbara J. M. Mulder
    • 4
  • Peter A. Doevendans
    • 1
  1. 1.Dept. of Cardiology E03.511University Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Dept. of Medical GeneticsUniversity Medical Center UtrechtUtrechtThe Netherlands
  3. 3.Hubrecht LaboratoryUtrechtThe Netherlands
  4. 4.Dept. of CardiologyAmsterdam Medical CenterAmsterdamThe Netherlands

Personalised recommendations