Abstract
Heterozygous mutations in the NKX2-5 gene of patients with various congenital heart defects have been reported. Most of the congenital heart defects associated with the mutations in the NKX2-5 gene are conotruncal heart anomalies, primarily the tetralogy of Fallot. In this study, the authors screened 72 Turkish children with conotruncal heart anomalies and 185 healthy control subjects to find the NKX2-5 alterations. They found one previously documented NKX2-5 missense alteration, heterozygous c.73C>T (p.Arg25Cys), in a 10-year-old boy with tetralogy of Fallot. The same heterozygous alteration was found also in the patient’s healthy father and in two unrelated persons in the healthy control group. The current study shows for the first time the presence of p.Arg25Cys in healthy control subjects other than African Americans. These results show that no genetic support exists for the pathogenecity of this alteration, although a previous in vitro study and theoretical predictions suggest a structural/functional difference in the altered protein region.
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Benson W, Silberbach M, McHugh A, Cottrill C, Zhang Y, Riggs S, Smalls O, Johnson MC, Watson M, Seidman JG, Seidman CE, Plowden J, Kugler JD (1999) Mutations in the cardiac transcription factor NKX2-5 affect diverse cardiac development pathways. J Clin Invest 104:1567–1573
Buettner-Reamon M, Borlak J (2004) Somatic NKX2-5 mutations as a novel mechanism of disease in complex congenital heart disease. J Med Genet 41:684–690
Elliott D, Kirk E, Yeoh T, Chandar S, McKenzie F, Taylor P, Grossfeld P, Fatkin D, Jones O, Hayes P, Feneley M, Harvey R (2003) Cardiac homeobox gene NKX2-5 mutations and congenital heart disease. J Am Coll Cardiol 41:2072–2076
Goldmuntz E, Geiger E, Benson W (2001) NKX2-5 mutations in patients with tetralogy of Fallot. Circulation 104:2565–2568
Grow MW, Krieg PA (1998) Tinman function is essential for vertebrate heart development: Elimination of cardiac differentiation by dominant inhibitory mutants of the tinman- related genes, XNkx2-3 and XNkx2-5. Dev Biol 204:187–196
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 Gen 135A:47–52
Hosoda T, Komuro I, Shiojima I, Hiroi Y, Harada M, Murakawa 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 63:425–426
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 66:561–563
Kasahara H, Benson W (2004) Biochemical analyses of eight NKX2.5 homeodomain missense mutations causing atrioventricular block and cardiac anomalies. Cardiovasc Res 64:40–51
Komuro I, Izumo S (1993) Csx: A murine homeobox-containing gene specifically expressed in the developing heart. Proc Natl Acad Sci USA 90:8145–8149
Lyons I, Parsons LM, Hartley L, Li R Andrews JE, Robb L, Harvey JN (1995) Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeobox gene NKX2-5. Genes Dev 9:1654–1666
McElhinney D, Geiger E, Blinder J, Benson WD, Goldmuntz E (2003) NKX2-5 mutations in patients with congenital heart disease. J Am Coll Cardiol 42:1650–1655
Schott J, Benson W, Basson C, Pease W, Silberbach M, Moak J, Maron B, Seidman CE, Seidman JG (1998) Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281:108–111
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This study was supported by a grant from Ankara University Biotechnology Institute.
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M. İ. Akçaboy and F. B. Cengiz have contributed equally to this work.
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Akçaboy, M.İ., Cengiz, F.B., İnceoğlu, B. et al. The Effect of p.Arg25Cys Alteration in NKX2-5 on Conotruncal Heart Anomalies: Mutation or Polymorphism?. Pediatr Cardiol 29, 126–129 (2008). https://doi.org/10.1007/s00246-007-9058-2
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DOI: https://doi.org/10.1007/s00246-007-9058-2