Pediatric Cardiology

, Volume 32, Issue 2, pp 193–201 | Cite as

Novel NKX2-5 Mutations in Patients With Familial Atrial Septal Defects

  • Xing-Yuan Liu
  • Juan Wang
  • Yi-Qing Yang
  • Yang-Yang Zhang
  • Xiao-Zhong Chen
  • Wei Zhang
  • Xiao-Zhou Wang
  • Jing-Hao Zheng
  • Yi-Han Chen
Original Article

Abstract

Atrial septal defect (ASD) is a common cardiovascular malformation and an important contributor to substantial morbidity and mortality. Increasing evidence demonstrates that mutated NKX2-5, a gene encoding a homeobox transcription factor crucial to cardiogenesis, is a significant genetic determinant for congenital ASD. Nevertheless, the genetic basis for ASD in a majority of ASD patients remains largely unknown. In the current study, the entire coding region of NKX2-5 was sequenced initially for 58 unrelated probands with familial ASD. The relatives of the probands harboring identified mutations and 200 unrelated control individuals were subsequently genotyped. Three novel heterozygous NKX2-5 mutations (p.P43GfsX59, p.C46 W, and p.S179F) were identified respectively in three families with autosomal dominantly inherited ASD. These mutations, absent in 200 control individuals, cosegregated with ASD in the families that had complete penetrance. The findings expand the spectrum of mutations in NKX2-5 linked to ASD and contribute to genetic counseling, clinical interventions, and prenatal prevention of ASD for individuals with genetic susceptibility.

Keywords

Atrial septal defect Genetics Transcription factor 

References

  1. 1.
    Akazawa H, Komuro I (2005) Cardiac transcription factor Csx/NKX2-5: its role in cardiac development and diseases. Pharmacol Ther 107:252–268CrossRefPubMedGoogle Scholar
  2. 2.
    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
  3. 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. 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. 5.
    Chen MW, Pang YS, Guo Y, Pan JH, Liu BL, Shen J, Liu TW (2010) GATA4 mutations in Chinese patients with congenital cardiac septal defects. Pediatr Cardiol 31:85–89CrossRefPubMedGoogle Scholar
  6. 6.
    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 37:423–428CrossRefPubMedGoogle Scholar
  7. 7.
    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
  8. 8.
    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
  9. 9.
    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
  10. 10.
    Gioli-Pereira L, Pereira AC, Mesquita SM, Xavier-Neto J, Lopes AA, Krieger JE (2010) NKX2.5 mutations in patients with nonsyndromic congenital heart disease. Int J Cardiol 138:261–265CrossRefPubMedGoogle Scholar
  11. 11.
    Hamanoue H, Rahayuningsih SE, Hirahara Y, Itoh J, Yokoyama U, Mizuguchi T, Saitsu H, Miyake N, Hirahara F, Matsumoto N (2009) Genetic screening of 104 patients with congenitally malformed hearts revealed a fresh mutation of GATA4 in those with atrial septal defects. Cardiol Young 19:482–485CrossRefPubMedGoogle Scholar
  12. 12.
    Hentze MW, Kulozik AE (1999) A perfect message: RNA surveillance and nonsense-mediated decay. Cell 96:307–310CrossRefPubMedGoogle Scholar
  13. 13.
    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
  14. 14.
    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 134:223–225Google Scholar
  15. 15.
    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
  16. 16.
    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
  17. 17.
    Inga A, Reamon-Buettner SM, Borlak J, Resnick MA (2005) Functional dissection of sequence-specific NKX2-5 DNA binding domain mutations associated with human heart septation defects using a yeast-based system. Hum Mol Genet 14:1965–1975CrossRefPubMedGoogle Scholar
  18. 18.
    Jacobs JP, Quintessenza JA, Burke RP, Mavroudis C (2000) Congenital Heart Surgery Nomenclature and Database Project: atrial septal defect. Ann Thorac Surg 69:S18–S24CrossRefPubMedGoogle Scholar
  19. 19.
    Jenkins KJ, Correa A, Feinstein JA, Botto L, Britt AE, Daniels SR, Elixson M, Warnes CA, Webb CL, American Heart Association Council on Cardiovascular Disease in the Young (2007) Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115:2995–3014CrossRefPubMedGoogle Scholar
  20. 20.
    Kasahara H, Benson DW (2004) Biochemical analyses of eight NKX2.5 homeodomain missense mutations causing atrioventricular block and cardiac anomalies. Cardiovasc Res 64:40–51CrossRefPubMedGoogle Scholar
  21. 21.
    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
  22. 22.
    Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ, Brook JD (1997) Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet 15:21–29CrossRefPubMedGoogle Scholar
  23. 23.
    Lin X, Huo Z, Liu X, Zhang Y, Li L, Zhao H, Yan B, Liu Y, Yang Y, Chen YH (2010) A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect. J Hum Genet 55:662–667CrossRefPubMedGoogle Scholar
  24. 24.
    Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D, Nichol G, O’Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R, Steinberger J, Thom T, Wasserthiel-Smoller S, Wong N, Wylie-Rosett J, Hong Y, American Heart Association Statistics Committee and Stroke Statistics Subcommittee (2009) Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119:e21–e181CrossRefPubMedGoogle Scholar
  25. 25.
    Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L (2007) Congenital heart disease in the general population: changing prevalence and age distribution. Circulation 115:163–172CrossRefPubMedGoogle Scholar
  26. 26.
    Matsson H, Eason J, Bookwalter CS, Klar J, Gustavsson P, Sunnegårdh J, Enell H, Jonzon A, Vikkula M, Gutierrez I, Granados-Riveron J, Pope M, Bu’Lock F, Cox J, Robinson TE, Song F, Brook DJ, Marston S, Trybus KM, Dahl N (2008) Alpha-cardiac actin mutations produce atrial septal defects. Hum Mol Genet 17:256–265CrossRefPubMedGoogle Scholar
  27. 27.
    McElhinney DB, Geiger E, Blinder J, Woodrow BD, Goldmuntz E (2003) NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol 42:1650–1655CrossRefPubMedGoogle Scholar
  28. 28.
    Monzen K, Zhu W, Kasai H, Hiroi Y, Hosoda T, Akazawa H, Zou Y, Hayashi D, Yamazaki T, Nagai R, Komuro I (2002) Dual effects of the homeobox transcription factor Csx/NKX2-5 on cardiomyocytes. Biochem Biophys Res Commun 298:493–500CrossRefPubMedGoogle Scholar
  29. 29.
    Pashmforoush M, Lu JT, Chen H, Amand TS, Kondo R, Pradervand S, Evans SM, Clark B, Feramisco JR, Giles W, Ho SY, Benson DW, Silberbach M, Shou W, Chien KR (2004) NKX2-5 pathways and congenital heart disease: loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Cell 117:373–386CrossRefPubMedGoogle Scholar
  30. 30.
    Pierpont ME, Basson CT, Benson DW Jr, Gelb BD, Giglia TM, Goldmuntz E, McGee G, Sable CA, Srivastava D, Webb CL, American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young (2007) Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115:3015–3038CrossRefPubMedGoogle Scholar
  31. 31.
    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 146:251–253Google Scholar
  32. 32.
    Prall OW, Menon MK, Solloway MJ, Watanabe Y, Zaffran S, Bajolle F, Biben C, McBride JJ, Robertson BR, Chaulet H, Stennard FA, Wise N, Schaft D, Wolstein O, Furtado MB, Shiratori H, Chien KR, Hamada H, Black BL, Saga Y, Robertson EJ, Buckingham ME, Harvey RP (2007) An NKX2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Cell 128:947–959CrossRefPubMedGoogle Scholar
  33. 33.
    Reamon-Buettner SM, Borlak J (2004) Somatic NKX2-5 mutations as a novel mechanism of disease in complex congenital heart disease. J Med Genet 41:684–690CrossRefPubMedGoogle Scholar
  34. 34.
    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 Mutat 31:1185–1194CrossRefPubMedGoogle Scholar
  35. 35.
    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
  36. 36.
    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
  37. 37.
    Sommer RJ, Hijazi ZM, Rhodes JF Jr (2008) Pathophysiology of congenital heart disease in the adult: part I: shunt lesions. Circulation 117:1090–1099CrossRefPubMedGoogle Scholar
  38. 38.
    Stallmeyer B, Fenge H, Nowak-Göttl U, Schulze-Bahr E (2010) Mutational spectrum in the cardiac transcription factor gene NKX2.5 (CSX) associated with congenital heart disease. Clin Genet 78:533–540CrossRefPubMedGoogle Scholar
  39. 39.
    Zhang W, Li X, Shen A, Jiao W, Guan X, Li Z (2009) Screening NXK2.5 mutation in a sample of 230 Han Chinese children with congenital heart diseases. Genet Test Mol Biomarkers 13:159–162CrossRefPubMedGoogle Scholar
  40. 40.
    Zhang WM, Li XF, Ma ZY, Zhang J, Zhou SH, Li T, Shi L, Li ZZ (2009) GATA4 and NKX2.5 gene analysis in Chinese Uygur patients with congenital heart disease. Chin Med J Engl 122:416–419PubMedGoogle Scholar
  41. 41.
    Zhu W, Shiojima I, Hiroi Y, Zou Y, Akazawa H, Mizukami M, Toko H, Yazaki Y, Nagai R, Komuro I (2000) Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease. J Biol Chem 275:35291–35296CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Xing-Yuan Liu
    • 1
  • Juan Wang
    • 2
  • Yi-Qing Yang
    • 3
  • Yang-Yang Zhang
    • 4
  • Xiao-Zhong Chen
    • 5
  • Wei Zhang
    • 5
  • Xiao-Zhou Wang
    • 5
  • Jing-Hao Zheng
    • 6
  • Yi-Han Chen
    • 2
  1. 1.Department of PediatricsTongji Hospital, Tongji University School of MedicineShanghaiChina
  2. 2.Department of CardiologyEast Hospital, Tongji University School of MedicineShanghaiChina
  3. 3.Department of Cardiovascular ResearchShanghai Chest Hospital, Medical College of Shanghai Jiaotong UniversityShanghaiChina
  4. 4.Department of CardiologyFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  5. 5.Department of Cardiac SurgeryShanghai Chest Hospital, Medical College of Shanghai Jiaotong UniversityShanghaiChina
  6. 6.Department of Pediatric Thoracic and Cardiovascular SurgeryShanghai Children’s Medical Center, Medical College of Shanghai Jiaotong UniversityShanghaiChina

Personalised recommendations