Genetica

, Volume 138, Issue 11–12, pp 1231–1240

Mutations of the GATA4 and NKX2.5 genes in Chinese pediatric patients with non-familial congenital heart disease

Article

Abstract

A number of mutations in GATA4 and NKX2.5 have been identified to be causative for a subset of familial congenital heart defects (CHDs) and a small number of sporadic CHDs. In this study, we evaluated common GATA4 and NKX2.5 mutations in 135 Chinese pediatric patients with non-familial congenital heart defects. Two novel mutations in the coding region of GATA4 were identified, namely, 487C>T (Pro163Ser) in exon 1 in a child with tetralogy of Fallot and 1220C>A (Pro407Gln) in exon 6 in a pediatric patient with outlet membranous ventricular septal defect. We also found 848C>A (Pro283Gln) in exon 2 of the NKX2.5 gene in a pediatric patient with ventricular septal defect, patent ductus arteriosus and aortic isthmus stenosis. None of the mutations was detected in healthy control subjects (n = 114). This study suggests that GATA4 and NKX2.5 missense mutations may be associated with congenital heart defects in pediatric Chinese patients. Further clinical studies with large samples are warranted.

Keywords

GATA4 NKX2.5 Congenital heart disease Mutation Pediatric patient 

Supplementary material

10709_2010_9522_MOESM1_ESM.doc (46 kb)
Supplementary material 1 (DOC 45 kb)

References

  1. Akcaboy MI, Cengiz FB, Inceoglu B, Ucar T, Atalay S, Tutar E, Tekin M (2008) The effect of p.Arg25Cys alteration in NKX2–5 on conotruncal heart anomalies: mutation or polymorphism? Pediatr Cardiol 29:126–129CrossRefPubMedGoogle Scholar
  2. Azpiazu N, Frasch M (1993) Tinman and bagpipe: two homeo box genes that determine cell fates in the dorsal mesoderm of Drosophila. Genes Dev 7:1325–1340CrossRefPubMedGoogle Scholar
  3. Bartlett H, Veenstra GJ, Weeks DL (2010) Examining the cardiac NK-2 genes in early heart development. Pediatr Cardiol 31:335–341CrossRefPubMedGoogle Scholar
  4. Benson DW, Silberbach GM, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S, Smalls O, Johnson MC, Watson MS, Seidman JG, Seidman CE, Plowden J, Kugler JD (1999) Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest 104:1567–1573CrossRefPubMedGoogle Scholar
  5. Bentham J, Bhattacharya S (2008) Genetic mechanisms controlling cardiovascular development. Ann N Y Acad Sci 1123:10–19CrossRefPubMedGoogle Scholar
  6. Biben C, Weber R, Kesteven S, Stanley E, McDonald L, Elliott DA, Barnett L, Koentgen F, Robb L, Feneley M, Harvey RP (2000) Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5. Circ Res 87:888–895PubMedGoogle Scholar
  7. Bodmer R (1993) The gene tinman is required for specification of the heart and visceral muscles in Drosophila. Development 118:719–729PubMedGoogle Scholar
  8. Brown CO 3rd, 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 279:10659–10669CrossRefPubMedGoogle Scholar
  9. Chen MW, Pang YS, Guo Y, Pan JH, Liu BL, Shen J, Liu TW (2010a) GATA4 mutations in Chinese patients with congenital cardiac septal defects. Pediatr Cardiol 31:85–89CrossRefPubMedGoogle Scholar
  10. Chen Y, Mao J, Sun Y, Zhang Q, Cheng HB, Yan WH, Choy KW, Li H (2010b) A novel mutation of GATA4 in a familial atrial septal defect. Clin Chim Acta 411:1741–1745CrossRefPubMedGoogle Scholar
  11. Clark KL, Yutzey KE, Benson DW (2006) Transcription factors and congenital heart defects. Annu Rev Physiol 68:97–121CrossRefPubMedGoogle Scholar
  12. D’Amato E, Giacopelli F, Giannattasio A, D’Annunzio G, Bocciardi R, Musso M, Lorini R, Ravazzolo R (2010) Genetic investigation in an Italian child with an unusual association of atrial septal defect, attributable to a new familial GATA4 gene mutation, and neonatal diabetes due to pancreatic agenesis. Diabet Med 27:1195–1200CrossRefPubMedGoogle Scholar
  13. Dai YS, Cserjesi P, Markham BE, Molkentin JD (2002) The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism. J Biol Chem 277:24390–24398CrossRefPubMedGoogle Scholar
  14. Ding JD, Li KR, Zhang XL, Yao YY, Reng LQ, Tao SY, Fang X, Ma GS (2009) Preliminary exploration of transcription factor Nkx2.5 mutations and congenital heart diseases. Zhonghua Yi Xue Za Zhi 89:1114–1116PubMedGoogle Scholar
  15. 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 16:5687–5696CrossRefPubMedGoogle Scholar
  16. Elliott DA, Kirk EP, Yeoh T, Chandar S, McKenzie F, Taylor P, Grossfeld P, Fatkin D, Jones O, Hayes P, Feneley M, Harvey RP (2003) Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome. J Am Coll Cardiol 41:2072–2076CrossRefPubMedGoogle Scholar
  17. Esposito G, Grutter G, Drago F, Costa MW, De Santis A, Bosco G, Marino B, Bellacchio E, Lepri F, Harvey RP, Sarkozy A, Dallapiccola B (2009) Molecular analysis of PRKAG2, LAMP2, and NKX2-5 genes in a cohort of 125 patients with accessory atrioventricular connection. Am J Med Genet A 149A:1574–1577CrossRefPubMedGoogle Scholar
  18. 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 424:443–447CrossRefPubMedGoogle Scholar
  19. Gioli-Pereira L, Pereira AC, Mesquita SM, Xavier-Neto J, Lopes AA, Krieger JE (2010) NKX2.5 mutations in patients with non-syndromic congenital heart disease. Int J Cardiol 138:261–265CrossRefPubMedGoogle Scholar
  20. Goldmuntz E, Geiger E, Benson DW (2001) NKX2.5 mutations in patients with tetralogy of fallot. Circulation 104:2565–2568CrossRefPubMedGoogle Scholar
  21. Gutierrez-Roelens I, Sluysmans T, Gewillig M, Devriendt K, Vikkula M (2002) Progressive AV-block and anomalous venous return among cardiac anomalies associated with two novel missense mutations in the CSX/NKX2-5 gene. Hum Mutat 20:75–76CrossRefPubMedGoogle Scholar
  22. Hirayama-Yamada K, Kamisago M, Akimoto K, Aotsuka H, Nakamura Y, Tomita H, Furutani M, Imamura S, Takao A, Nakazawa M, Matsuoka R (2005) Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect. Am J Med Genet A 135:47–52PubMedGoogle Scholar
  23. Hobbs CA, Cleves MA, Keith C, Ghaffar S, James SJ (2005) NKX2.5 and congenital heart defects: a population-based study. Am J Med Genet A 134A:223–225CrossRefPubMedGoogle Scholar
  24. Hoffman JI, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39:1890–1900CrossRefPubMedGoogle Scholar
  25. Hosoda T, Komuro I, Shiojima I, Hiroi Y, Harada M, Murakawa Y, Hirata Y, Yazaki Y (1999) Familial atrial septal defect and atrioventricular conduction disturbance associated with a point mutation in the cardiac homeobox gene CSX/NKX2-5 in a Japanese patient. Jpn Circ J 63:425–426CrossRefPubMedGoogle Scholar
  26. Huang WY, Cukerman E, Liew CC (1995) Identification of a GATA motif in the cardiac α-myosin heavy-chain-encoding gene and isolation of a human GATA-4 cDNA. Gene 155:219–223CrossRefPubMedGoogle Scholar
  27. Ikeda Y, Hiroi Y, Hosoda T, Utsunomiya T, Matsuo S, Ito T, Inoue J, Sumiyoshi T, Takano H, Nagai R, Komuro I (2002) Novel point mutation in the cardiac transcription factor CSX/NKX2.5 associated with congenital heart disease. Circ J 66:561–563CrossRefPubMedGoogle Scholar
  28. Kasahara H, Lee B, Schott JJ, Benson DW, Seidman JG, Seidman CE, Izumo S (2000) Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease. J Clin Invest 106:299–308CrossRefPubMedGoogle Scholar
  29. Kasahara H, Usheva A, Ueyama T, Aoki H, Horikoshi N, Izumo S (2001) Characterization of homo- and heterodimerization of cardiac Csx/Nkx2.5 homeoprotein. J Biol Chem 276:4570–4580CrossRefPubMedGoogle Scholar
  30. Ko LJ, Engel JD (1993) DNA-binding specificities of the GATA transcription factor family. Mol Cell Biol 13:4011–4022PubMedGoogle Scholar
  31. Komuro I, Izumo S (1993) Csx: a murine homeobox-containing gene specifically expressed in the developing heart. Proc Natl Acad Sci USA 90:8145–8149CrossRefPubMedGoogle Scholar
  32. Kuo CT, Morrisey EE, Anandappa R, Sigrist K, Lu MM, Parmacek MS, Soudais C, Leiden JM (1997) GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 11:1048–1060CrossRefPubMedGoogle Scholar
  33. Lee Y, Shioi T, Kasahara H, Jobe SM, Wiese RJ, Markham BE, Izumo S (1998) The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression. Mol Cell Biol 18:3120–3129PubMedGoogle Scholar
  34. Liang Q, Wiese RJ, Bueno OF, Dai YS, Markham BE, Molkentin JD (2001) The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes. Mol Cell Biol 21:7460–7469CrossRefPubMedGoogle Scholar
  35. Liu XY, Yang YQ, Yang Y, Lin XP, Chen YH (2009a) Mutation of NKX2-5 gene in patients with atrial septal defect. Zhonghua Er Ke Za Zhi 47:696–700PubMedGoogle Scholar
  36. Liu XY, Yang YQ, Yang Y, Lin XP, Chen YH (2009b) Novel NKX2-5 mutations identified in patients with congenital ventricular septal defects. Zhonghua Yi Xue Za Zhi 89:2395–2399PubMedGoogle Scholar
  37. Lyons I, Parsons LM, Hartley L, Li R, Andrews JE, Robb L, Harvey RP (1995) Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev 9:1654–1666CrossRefPubMedGoogle Scholar
  38. McElhinney DB, Geiger E, Blinder J, Benson DW, Goldmuntz E (2003) NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol 42:1650–1655CrossRefPubMedGoogle Scholar
  39. Molkentin JD (2000) The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem 275:38949–38952CrossRefPubMedGoogle Scholar
  40. 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 93:215–228CrossRefPubMedGoogle Scholar
  41. Morin S, Charron F, Robitaille L, Nemer M (2000) GATA-dependent recruitment of MEF2 proteins to target promoters. EMBO J 19:2046–2055CrossRefPubMedGoogle Scholar
  42. Morrisey EE, Ip HS, Tang Z, Parmacek MS (1997) GATA-4 activates transcription via two novel domains that are conserved within the GATA-4/5/6 subfamily. J Biol Chem 272:8515–8524CrossRefPubMedGoogle Scholar
  43. Mwinyi J, Hofmann Y, Pedersen RS, Nekvindova J, Cavaco I, Mkrtchian S, Ingelman-Sundberg M (2010a) The transcription factor GATA-4 regulates cytochrome P4502C19 gene expression. Life Sci 86:699–706CrossRefPubMedGoogle Scholar
  44. Mwinyi J, Nekvindova J, Cavaco I, Hofmann Y, Pedersen RS, Landman E, Mkrtchian S, Ingelman-Sundberg M (2010b) New insights into the regulation of CYP2C9 gene expression: the role of the transcription factor GATA-4. Drug Metab Dispos 38:415–421CrossRefPubMedGoogle Scholar
  45. Nemer G, Fadlalah F, Usta J, Nemer M, Dbaibo G, Obeid M, Bitar F (2006) A novel mutation in the GATA4 gene in patients with Tetralogy of Fallot. Hum Mutat 27:293–294CrossRefPubMedGoogle Scholar
  46. 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:e97CrossRefPubMedGoogle Scholar
  47. Pikkarainen S, Tokola H, Kerkela R, Ruskoaho H (2004) GATA transcription factors in the developing and adult heart. Cardiovasc Res 63:196–207CrossRefPubMedGoogle Scholar
  48. Poirier O, Nicaud V, McDonagh T, Dargie HJ, Desnos M, Dorent R, Roizes G, Schwartz K, Tiret L, Komajda M, Cambien F (2003) Polymorphisms of genes of the cardiac calcineurin pathway and cardiac hypertrophy. Eur J Hum Genet 11:659–664CrossRefPubMedGoogle Scholar
  49. Posch MG, Perrot A, Schmitt K, Mittelhaus S, Esenwein EM, Stiller B, Geier C, Dietz R, Gessner R, Ozcelik C, Berger F (2008) Mutations in GATA4, NKX2.5, CRELD1, and BMP4 are infrequently found in patients with congenital cardiac septal defects. Am J Med Genet A 146A:251–253CrossRefPubMedGoogle Scholar
  50. Posch MG, Boldt LH, Polotzki M, Richter S, Rolf S, Perrot A, Dietz R, Ozcelik C, Haverkamp W (2010) Mutations in the cardiac transcription factor GATA4 in patients with lone atrial fibrillation. Eur J Med Genet 53:201–203CrossRefPubMedGoogle Scholar
  51. Pu WT, Ishiwata T, Juraszek AL, Ma Q, Izumo S (2004) GATA4 is a dosage-sensitive regulator of cardiac morphogenesis. Dev Biol 275:235–244CrossRefPubMedGoogle Scholar
  52. Rajagopal SK, Ma Q, Obler D, Shen J, Manichaikul A, Tomita-Mitchell A, Boardman K, Briggs C, Garg V, Srivastava D, Goldmuntz E, Broman KW, Benson DW, Smoot LB, Pu WT (2007) Spectrum of heart disease associated with murine and human GATA4 mutation. J Mol Cell Cardiol 43:677–685CrossRefPubMedGoogle Scholar
  53. Reamon-Buettner SM, Borlak J (2005) GATA4 zinc finger mutations as a molecular rationale for septation defects of the human heart. J Med Genet 42:e32CrossRefPubMedGoogle Scholar
  54. Reamon-Buettner SM, Borlak J (2010) NKX2-5: an update on this hypermutable homeodomain protein and its role in human congenital heart disease (CHD). Hum MutatGoogle Scholar
  55. Reamon-Buettner SM, Cho SH, Borlak J (2007) Mutations in the 3′-untranslated region of GATA4 as molecular hotspots for congenital heart disease (CHD). BMC Med Genet 8:38CrossRefPubMedGoogle Scholar
  56. Rivera-Feliciano J, Lee KH, Kong SW, Rajagopal S, Ma Q, Springer Z, Izumo S, Tabin CJ, Pu WT (2006) Development of heart valves requires Gata4 expression in endothelial-derived cells. Development 133:3607–3618CrossRefPubMedGoogle Scholar
  57. Rojas A, Kong SW, Agarwal P, Gilliss B, Pu WT, Black BL (2008) GATA4 is a direct transcriptional activator of cyclin D2 and Cdk4 and is required for cardiomyocyte proliferation in anterior heart field-derived myocardium. Mol Cell Biol 28:5420–5431CrossRefPubMedGoogle Scholar
  58. Sadowski SL (2009) Congenital cardiac disease in the newborn infant: past, present, and future. Crit Care Nurs Clin North Am 21:37–48, viGoogle Scholar
  59. Sarkozy A, Conti E, Neri C, D’Agostino R, Digilio MC, Esposito G, Toscano A, Marino B, Pizzuti A, Dallapiccola B (2005) Spectrum of atrial septal defects associated with mutations of NKX2.5 and GATA4 transcription factors. J Med Genet 42:e16CrossRefPubMedGoogle Scholar
  60. 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 281:108–111CrossRefPubMedGoogle Scholar
  61. Sepulveda JL, Vlahopoulos S, Iyer D, Belaguli N, Schwartz RJ (2002) Combinatorial expression of GATA4, Nkx2-5, and serum response factor directs early cardiac gene activity. J Biol Chem 277:25775–25782CrossRefPubMedGoogle Scholar
  62. Stallmeyer B, Fenge H, Nowak-Gottl U, Schulze-Bahr E (2010) Mutational spectrum in the cardiac transcription factor gene NKX2.5 (CSX) associated with congenital heart disease. Clin Genet 78:533–540Google Scholar
  63. Tanaka M, Kasahara H, Bartunkova S, Schinke M, Komuro I, Inagaki H, Lee Y, Lyons GE, Izumo S (1998) Vertebrate homologs of tinman and bagpipe: roles of the homeobox genes in cardiovascular development. Dev Genet 22:239–249CrossRefPubMedGoogle Scholar
  64. Tanaka M, Chen Z, Bartunkova S, Yamasaki N, Izumo S (1999) The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development 126:1269–1280PubMedGoogle Scholar
  65. Tang ZH, Xia L, Chang W, Li H, Shen F, Liu JY, Wang Q, Liu MG (2006) Two novel missense mutations of GATA4 gene in Chinese patients with sporadic congenital heart defects. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 23:134–137PubMedGoogle Scholar
  66. Tomita-Mitchell A, Maslen CL, Morris CD, Garg V, Goldmuntz E (2007) GATA4 sequence variants in patients with congenital heart disease. J Med Genet 44:779–783CrossRefPubMedGoogle Scholar
  67. Turbay D, Wechsler SB, Blanchard KM, Izumo S (1996) Molecular cloning, chromosomal mapping, and characterization of the human cardiac-specific homeobox gene hCsx. Mol Med 2:86–96PubMedGoogle Scholar
  68. Watanabe Y, Benson DW, Yano S, Akagi T, Yoshino M, Murray JC (2002) Two novel frameshift mutations in NKX2.5 result in novel features including visceral inversus and sinus venosus type ASD. J Med Genet 39:807–811CrossRefPubMedGoogle Scholar
  69. White RA, Dowler LL, Pasztor LM, Gatson LL, Adkison LR, Angeloni SV, Wilson DB (1995) Assignment of the transcription factor GATA4 gene to human chromosome 8 and mouse chromosome 14: Gata4 is a candidate gene for Ds (disorganization). Genomics 27:20–26CrossRefPubMedGoogle Scholar
  70. Zeisberg EM, Ma Q, Juraszek AL, Moses K, Schwartz RJ, Izumo S, Pu WT (2005) Morphogenesis of the right ventricle requires myocardial expression of Gata4. J Clin Invest 115:1522–1531CrossRefPubMedGoogle Scholar
  71. Zhang W, Li X, Shen A, Jiao W, Guan X, Li Z (2008) GATA4 mutations in 486 Chinese patients with congenital heart disease. Eur J Med Genet 51:527–535CrossRefPubMedGoogle Scholar
  72. Zhang W, Li X, Shen A, Jiao W, Guan X, Li Z (2009a) Screening NKX2.5 mutation in a sample of 230 Han Chinese children with congenital heart diseases. Genet Test Mol Biomarkers 13:159–162CrossRefPubMedGoogle Scholar
  73. Zhang WM, Li XF, Ma ZY, Zhang J, Zhou SH, Li T, Shi L, Li ZZ (2009b) GATA4 and NKX2.5 gene analysis in Chinese Uygur patients with congenital heart disease. Chin Med J (Engl) 122:416–419Google Scholar

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© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.The Obstetrics and Gynecology HospitalFudan UniversityShanghaiChina
  2. 2.Department of Pharmaceutical Sciences, School of PharmacyUniversity of South FloridaTampaUSA

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