Research on the Mutation and Expression of Nkx2.5 in Right Ventricular Outflow Tract Myocardial of Congenital Heart Disease Patients with Diminutive Pulmonary Blood_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

1. Department of Cardiothoracic Surgery, the Frist Affiliated Hospital of Bengbu Medical College, Bengbu 233004 Anhui, P. R. China;
2. Department of Cardiac surgery, Provincial Children's Hospital, Hefei 230000, P. R. China;

Corresponding author：

Keywords：

Nkx2.5; Congenital heart disease; Diminutive pulmonary blood; Gene mutation

DOI：

10.7507/1007-4848.20160011

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Objective To observe the mutation and expression of Nkx2.5 in congenital heart disease patients with diminutive pulmonary blood. We preliminarily explored the association between Nkx2.5 gene and pathogenesis of congenital heart disease patients with diminutive pulmonary blood. Methods Fifty six patients of congenital heart disease with diminutive pulmonary blood in the first affiliated hospital of Bengbu medical college and Anhui province children, s hospital between May 2012 and May 2014 were as an experimental group. Sixty three patients of ventricular septal defect were as a control group. In the trial group, there were 30 males and 26 females averagely aged 5.82± 4.23 years ranking from 6 months to 14 years. In the control group, there were 36 males and 27 females averagely aged 6.93± 4.56 years ranking from 6 months to 14 years. Before operation, peripheral venous blood of all the patients were collected. We used polymerase chain reaction combined with DNA sequencing technology to detect Nkx2.5 gene exon sequence and to analyze the association between Nkx2.5 gene mutation and congenital heart disease with diminutive pulmonary blood. And we got some hypertrophic myocardial tissue from right ventricular outflow tract in the operation, whose size was 0.5× 0.5× 0.5 cubic centimeter. And we extracted myocardial tissue RNA. The expression changes of Nkx2.5 gene mRNA were detected by real-time fluorescence quantitative polymerase chain reaction technique. Results There was no mutations tested out in the peripheral venous blood in both two groups. The expression of mRNA in Nkx2.5 gene of the trial group was lower than that in the control group with a statistical difference. Conclusion Nkx2.5 gene mutation may be associated with multiple factors. The occurrence of congenital heart disease with diminutive pulmonary blood may be related with a decline of Nkx2.5 gene expression in the myocardial tissue.

Citation： WANGKang-wu, LIUXue-gang, WANGZu-yi, YINCheng-guo, DINGLi, DIAOWen-jie. Research on the Mutation and Expression of Nkx2.5 in Right Ventricular Outflow Tract Myocardial of Congenital Heart Disease Patients with Diminutive Pulmonary Blood. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2016, 23(1): 44-49. doi: 10.7507/1007-4848.20160011 Copy

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5.	Schott JJ, Benson DW, Basson CT, et al. Congenital heart disease caused by mutations in the transcription factor Nkx2.5. Science, 1998, 281(5): 108.
6.	丁建东, 方翔, 李开如, 等.转录因子Nkx2.5和GATA4的相互作用.中国组织工程研究, 2012, 16(11): 1933-1936.
7.	Ermis PR, Morales DL. The adult Fontan patient: update for 2011. Methodist Debakey Cardiovasc J, 2011, 7(2): 3-8.
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10.	Takeuchi JK, Lou X, Alexander JM, et al. Chromatin remodelling complex dosage modulates transcription factor function in heart development. Nat Commun, 2011, 2(4): 187.
11.	Martin LK, Mezentseva NV, Bratoeva M, et al. Canonical WNT signaling enhances stem cell expression in the developing heart without a corresponding inhibition of cardiogenic differentiation. Stem Cells Dev, 2011, 20(11): 1973-1983.
12.	Peng T, Wang L, Zhou SF, et al. Mutations of the GATA4 and Nkx2.5 genes in Chinese pediatric patients with non-familial congenital heart disease. Genetica, 2010, 138(11): 1231-1240.
13.	Butler TL, Esposito G, Blue GM, et al. GATA4 mutations in 357 unrelated patients with congenital heart malformation. Genet Test Mol Biomarkers, 2010, 14(6): 797-802.
14.	Lyons I, Parsons LM, Hartley L, et al. Myogenic and morpho genetic defects in the heart tubes of murlne embryos lacking the homeobox gene Nkx2.5. Gene Dev, 1995, 9(13): 1654-1666.
15.	Akazawa H, Komuro I. Cardiac transcription factor CSx/Nkx2.5: its role in cardiac development and diseases. Pharmacol Ther, 2005, 107(2): 252-268.
16.	Groot AG, Bartelings M, Deruiter M, et al. Basics of cardiac develo-pment for the understanding of congenital heart malformations. Pediatr Res, 2005, 57(2): 169-176.
17.	Meysen S, Marger L, Hewett KW, et al. Nkx2.5 cell-autonomous gene function is required for the postnatal formation of the peripheral ventricular conduction system. Dev Biol, 2007, 303(2): 740-753.
18.	Moskowitz IP, Wang J, Peterson MA, et al. Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve develo-pment. Proc Natl Acad Sci USA, 2011, 108(10): 4006-4011.
19.	Pashmforoush M, Lu JT, Chen H, et al. Nkx2.5 pathways and congenital heart disease:loss of ventricular myocyte lineage specifica-tion leads to progressive cardiomyopathy and complete heart block. Cell, 2004, 117(3): 373-386.
20.	Kiewitz R, Lyons GE, Schafer BW, et al. Transcriptional regulation of S100A1 and expression during mouse heart development. BBA, 2000, 1498(2-3): 207-219.
21.	Willingham-Rocky LA, Golding MC, Wright JM, et al. Cloning of GJA1(connexin43) and its expression in canine ovarian follicles throughout the estrous cycle. Gene ExPr Patterns, 2007, 7(1-2): 66-71.

1. Terada R, Warren S, Lu JT, et al. Ablation of Nkx2.5 at mid-embr-yonic stage results in premature lethality and cardiac malformation. Cardiovasc Res, 2011, 91(2): 289-299.
2. Sizarov A, Devalla HD, Anderson RH, et al. Molecular analysis of patterning of conduction tissues in the developing human heart. Circ Arrhythm Electrophysiol, 2013, 4(4): 532-542.
3. 陈轶维, 赵武, 李奋等.动脉导管未闭患儿TFAP-2B基因突变的研究.中华儿科杂志, 2010, 48(12): 900-904.
4. Vianna CB, Miura N, Pereira AC, et al. Holt-Oram syndrome:novel TBX5 mutation and associated anomalous right coronary artery. Cardiol Young, 2011, 28(10): 1-3.
5. Schott JJ, Benson DW, Basson CT, et al. Congenital heart disease caused by mutations in the transcription factor Nkx2.5. Science, 1998, 281(5): 108.
6. 丁建东, 方翔, 李开如, 等.转录因子Nkx2.5和GATA4的相互作用.中国组织工程研究, 2012, 16(11): 1933-1936.
7. Ermis PR, Morales DL. The adult Fontan patient: update for 2011. Methodist Debakey Cardiovasc J, 2011, 7(2): 3-8.
8. Gong LG, Qiu GR, Jiang H, et al. Analysis of single nucleotide polymorphisms and haplotypes in HOXC gene cluster within susceptible region 12q13 of simple congenital heart disease. Chin J Med Genet, 2005, 22(50): 297-501.
9. Vianna CB, Miura N, Pereira AC, et al. Holt-Oram syndrome: novel TBX5 mutation and associated anomalous right coronary artery. Cardiol Young, 2011, 28(8): 1-3.
10. Takeuchi JK, Lou X, Alexander JM, et al. Chromatin remodelling complex dosage modulates transcription factor function in heart development. Nat Commun, 2011, 2(4): 187.
11. Martin LK, Mezentseva NV, Bratoeva M, et al. Canonical WNT signaling enhances stem cell expression in the developing heart without a corresponding inhibition of cardiogenic differentiation. Stem Cells Dev, 2011, 20(11): 1973-1983.
12. Peng T, Wang L, Zhou SF, et al. Mutations of the GATA4 and Nkx2.5 genes in Chinese pediatric patients with non-familial congenital heart disease. Genetica, 2010, 138(11): 1231-1240.
13. Butler TL, Esposito G, Blue GM, et al. GATA4 mutations in 357 unrelated patients with congenital heart malformation. Genet Test Mol Biomarkers, 2010, 14(6): 797-802.
14. Lyons I, Parsons LM, Hartley L, et al. Myogenic and morpho genetic defects in the heart tubes of murlne embryos lacking the homeobox gene Nkx2.5. Gene Dev, 1995, 9(13): 1654-1666.
15. Akazawa H, Komuro I. Cardiac transcription factor CSx/Nkx2.5: its role in cardiac development and diseases. Pharmacol Ther, 2005, 107(2): 252-268.
16. Groot AG, Bartelings M, Deruiter M, et al. Basics of cardiac develo-pment for the understanding of congenital heart malformations. Pediatr Res, 2005, 57(2): 169-176.
17. Meysen S, Marger L, Hewett KW, et al. Nkx2.5 cell-autonomous gene function is required for the postnatal formation of the peripheral ventricular conduction system. Dev Biol, 2007, 303(2): 740-753.
18. Moskowitz IP, Wang J, Peterson MA, et al. Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve develo-pment. Proc Natl Acad Sci USA, 2011, 108(10): 4006-4011.
19. Pashmforoush M, Lu JT, Chen H, et al. Nkx2.5 pathways and congenital heart disease:loss of ventricular myocyte lineage specifica-tion leads to progressive cardiomyopathy and complete heart block. Cell, 2004, 117(3): 373-386.
20. Kiewitz R, Lyons GE, Schafer BW, et al. Transcriptional regulation of S100A1 and expression during mouse heart development. BBA, 2000, 1498(2-3): 207-219.
21. Willingham-Rocky LA, Golding MC, Wright JM, et al. Cloning of GJA1(connexin43) and its expression in canine ovarian follicles throughout the estrous cycle. Gene ExPr Patterns, 2007, 7(1-2): 66-71.

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