Abstract
Background: Dilated cardiomyopathy (DCM) is a major cause of congestive heart failure, sudden cardiac death and cardiac transplantation. Aggregating evidence highlights the genetic origin of DCM. However, DCM is a genetically heterogeneous disorder, and the genetic components underlying DCM in most cases remain unknown.
Methods: The coding regions and splicing junction sites of the TBX20 gene were sequenced in 120 unrelated patients with idiopathic DCM. The available close relatives of the index patient carrying an identified mutation and 300 unrelated ethnically matched healthy individuals used as controls were genotyped for TBX20. The functional characteristics of the mutant TBX20 were assayed in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system.
Results: A novel heterozygous TBX20 mutation, p.F256I, was identified in a family with DCM transmitted in an autosomal dominant fashion, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 600 control chromosomes and the altered amino acid was completely conserved evolutionarily among various species. Functional assays revealed that the mutant TBX20 had significantly diminished transcriptional activity. Furthermore, the mutation markedly reduced the synergistic activation of TBX20 with NKX2-5 or GATA4.
Conclusions: This study links TBX20 loss-of-function mutation to idiopathic DCM in humans for the first time, providing novel insight into the molecular mechanism underpinning DCM.
Acknowledgments
We are grateful to the subjects for their participation in the study. This work was supported by grants from the National Natural Science Fund of China (81270161), the key program for Basic Research of Shanghai, China (14JC1405500), and the Natural Science Fund of Shanghai, China (14ZR1438000).
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. McNally EM, Golbus JR, Puckelwartz MJ. Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest 2013;123:19–26.10.1172/JCI62862Search in Google Scholar
2. Lakdawala NK, Winterfield JR, Funke BH. Dilated cardiomyopathy. Circ Arrhythm Electrophysiol 2013;6:228–37.10.1161/CIRCEP.111.962050Search in Google Scholar
3. Kamisago M, Sharma SD, DePalma SR, Solomon S, Sharma P, McDonough B, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 2000;343:1688–96.10.1056/NEJM200012073432304Search in Google Scholar
4. Luo B, Wang F, Li B, Dong Z, Liu X, Zhang C, et al. Association of nucleotide-binding oligomerization domain-like receptor 3 inflammasome and adverse clinical outcomes in patients with idiopathic dilated cardiomyopathy. Clin Chem Lab Med 2013;51:1521–8.10.1515/cclm-2012-0600Search in Google Scholar
5. Liaquat A, Shauket U, Ahmad W, Javed Q. The tumor necrosis factor-α-238G/A and IL-6-572G/C gene polymorphisms and the risk of idiopathic dilated cardiomyopathy: a meta-analysis of 25 studies including 9493 cases and 13,971 controls. Clin Chem Lab Med 2015;53:307–18.10.1515/cclm-2014-0502Search in Google Scholar
6. McCulley DJ, Black BL. Transcription factor pathways and congenital heart disease. Curr Top Dev Biol 2012;100:253–77.10.1016/B978-0-12-387786-4.00008-7Search in Google Scholar
7. Oka T, Xu J, Molkentin JD. Re-employment of developmental transcription factors in adult heart disease. Semin Cell Dev Biol 2007;18:117–31.10.1016/j.semcdb.2006.11.012Search in Google Scholar
8. Stennard FA, Costa MW, Elliott DA, Rankin S, Haast SJ, Lai D, et al. Cardiac T-box factor Tbx20 directly interacts with Nkx2-5, GATA4, and GATA5 in regulation of gene expression in the developing heart. Dev Biol 2003;262:206–24.10.1016/S0012-1606(03)00385-3Search in Google Scholar
9. Qu XK, Qiu XB, Yuan F, Wang J, Zhao CM, Liu XY, et al. A novel NKX2.5 loss-of-function mutation associated with congenital bicuspid aortic valve. Am J Cardiol 2014;114:1891–5.10.1016/j.amjcard.2014.09.028Search in Google Scholar PubMed
10. Huang RT, Xue S, Xu YJ, Zhou M, Yang YQ. A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation. Int J Mol Med 2013;31:1119–26.10.3892/ijmm.2013.1316Search in Google Scholar PubMed
11. Perera JL, Johnson NM, Judge DP, Crosson JE. Novel and highly lethal NKX2.5 missense mutation in a family with sudden death and ventricular arrhythmia. Pediatr Cardiol 2014;35:1206–12.10.1007/s00246-014-0917-3Search in Google Scholar PubMed
12. Yang YQ, Gharibeh L, Li RG, Xin YF, Wang J, Liu ZM, et al. GATA4 loss-of-function mutations underlie familial tetralogy of Fallot. Hum Mutat 2013;34:1662–71.10.1002/humu.22434Search in Google Scholar PubMed
13. Xiang R, Fan LL, Huang H, Cao BB, Li XP, Peng DQ, et al. A novel mutation of GATA4 (K319E) is responsible for familial atrial septal defect and pulmonary valve stenosis. Gene 2014;534:320–3.10.1016/j.gene.2013.10.028Search in Google Scholar
14. Wang J, Sun YM, Yang YQ. Mutation spectrum of the GATA4 gene in patients with idiopathic atrial fibrillation. Mol Biol Rep 2012;39:8127–35.10.1007/s11033-012-1660-6Search in Google Scholar PubMed
15. Wei D, Bao H, Zhou N, Zheng GF, Liu XY, Yang YQ. GATA5 loss-of-function mutation responsible for the congenital ventriculoseptal defect. Pediatr Cardiol 2013;34:504–11.10.1007/s00246-012-0482-6Search in Google Scholar PubMed
16. Shi LM, Tao JW, Qiu XB, Wang J, Yuan F, Xu L, et al. GATA5 loss-of-function mutations associated with congenital bicuspid aortic valve. Int J Mol Med 2014;33:1219–26.10.3892/ijmm.2014.1700Search in Google Scholar PubMed
17. Huang RT, Xue S, Xu YJ, Zhou M, Yang YQ. Somatic GATA5 mutations in sporadic tetralogy of Fallot. Int J Mol Med 2014;33:1227–35.10.3892/ijmm.2014.1674Search in Google Scholar PubMed
18. Wang XH, Huang CX, Wang Q, Li RG, Xu YJ, Liu X, et al. A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation. Int J Mol Med 2013;31:43–50.10.3892/ijmm.2012.1189Search in Google Scholar PubMed
19. Huang RT, Xue S, Xu YJ, Yang YQ. Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot. Int J Mol Med 2013;31:51–8.10.3892/ijmm.2012.1188Search in Google Scholar PubMed
20. Li J, Liu WD, Yang ZL, Yang YQ. Novel GATA6 loss-of-function mutation responsible for familial atrial fibrillation. Int J Mol Med 2012;30:783–90.10.3892/ijmm.2012.1068Search in Google Scholar PubMed
21. Baban A, Postma AV, Marini M, Trocchio G, Santilli A, Pelegrini M, et al. Identification of TBX5 mutations in a series of 94 patients with tetralogy of Fallot. Am J Med Genet A 2014;164:3100–7.10.1002/ajmg.a.36783Search in Google Scholar PubMed
22. Postma AV, van de Meerakker JB, Mathijssen IB, Barnett P, Christoffels VM, Ilgun A, et al. A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation. Circ Res 2008;102:1433–42.10.1161/CIRCRESAHA.107.168294Search in Google Scholar PubMed
23. Pan Y, Geng R, Zhou N, Zheng GF, Zhao H, Wang J, et al. TBX20 loss-of-function mutation contributes to double outlet right ventricle. Int J Mol Med 2015;35:1058–66.10.3892/ijmm.2015.2077Search in Google Scholar PubMed
24. Andersen TA, Troelsen Kde L, Larsen LA. Of mice and men: molecular genetics of congenital heart disease. Cell Mol Life Sci 2014;71:1327–52.10.1007/s00018-013-1430-1Search in Google Scholar PubMed PubMed Central
25. Hong K, Xiong Q. Genetic basis of atrial fibrillation. Curr Opin Cardiol 2014;29:220–6.10.1097/HCO.0000000000000051Search in Google Scholar PubMed
26. Yuan F, Qiu XB, Li RG, Qu XK, Wang J, Xu YJ, et al. A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias. Int J Mol Med 2015;35:478–86.10.3892/ijmm.2014.2029Search in Google Scholar PubMed
27. Li RG, Li L, Qiu XB, Yuan F, Xu L, Li X, et al. GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy. Biochem Biophys Res Commun 2013;439:591–6.10.1016/j.bbrc.2013.09.023Search in Google Scholar PubMed
28. Li J, Liu WD, Yang ZL, Yuan F, Xu L, Li RG, et al. Prevalence and spectrum of GATA4 mutations associated with sporadic dilated cardiomyopathy. Gene 2014;548:174–81.10.1016/j.gene.2014.07.022Search in Google Scholar PubMed
29. Zhao L, Xu JH, Xu WJ, Yu H, Wang Q, Zheng HZ, et al. A novel GATA4 loss-of-function mutation responsible for familial dilated cardiomyopathy. Int J Mol Med 2014;33:654–60.10.3892/ijmm.2013.1600Search in Google Scholar PubMed
30. Zhang XL, Dai N, Tang K, Chen YQ, Chen W, Wang J, et al. GATA5 loss-of-function mutation in familial dilated cardiomyopathy. Int J Mol Med 2015;35:763–70.10.3892/ijmm.2014.2050Search in Google Scholar PubMed
31. Xu L, Zhao L, Yuan F, Jiang WF, Liu H, Li RG, et al. GATA6 loss-of-function mutations contribute to familial dilated cardiomyopathy. Int J Mol Med 2014;34:1315–22.10.3892/ijmm.2014.1896Search in Google Scholar PubMed
32. Zhang XL, Qiu XB, Yuan F, Wang J, Zhao CM, Li RG, et al. TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy. Biochem Biophys Res Commun 2015;459:166–71.10.1016/j.bbrc.2015.02.094Search in Google Scholar PubMed
33. Akazawa H, Komuro I. Cardiac transcription factor Csx/Nkx2-5: its role in cardiac development and diseases. Pharmacol Ther 2005;107:252–68.10.1016/j.pharmthera.2005.03.005Search in Google Scholar PubMed
34. Pikkarainen S, Tokola H, Kerkelä R, Ruskoaho H. GATA transcription factors in the developing and adult heart. Cardiovasc Res 2004;63:196–207.10.1016/j.cardiores.2004.03.025Search in Google Scholar PubMed
35. Greulich F, Rudat C, Kispert A. Mechanisms of T-box gene function in the developing heart. Cardiovasc Res 2011;91:212–22.10.1093/cvr/cvr112Search in Google Scholar PubMed
36. Elliott P, O’Mahony C, Syrris P, Evans A, Rivera Sorensen C, Sheppard MN, et al. Prevalence of desmosomal protein gene mutations in patients with dilated cardiomyopathy. Circ Cardiovasc Genet 2010;3:314–22.10.1161/CIRCGENETICS.110.937805Search in Google Scholar PubMed
37. Mestroni L, Maisch B, McKenna WJ, Schwartz K, Charron P, Rocco C, et al. Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy. Eur Heart J 1999;20:93–102.10.1053/euhj.1998.1145Search in Google Scholar PubMed
38. Kirk EP, Sunde M, Costa MW, Rankin SA, Wolstein O, Castro ML, et al. Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. Am J Hum Genet 2007;81:280–91.10.1086/519530Search in Google Scholar PubMed PubMed Central
39. Qian L, Mohapatra B, Akasaka T, Liu J, Ocorr K, Towbin JA, et al. Transcription factor neuromancer/TBX20 is required for cardiac function in Drosophila with implications for human heart disease. Proc Natl Acad Sci USA 2008;105:19833–8.10.1073/pnas.0808705105Search in Google Scholar PubMed PubMed Central
40. Shen T, Aneas I, Sakabe N, Dirschinger RJ, Wang G, Smemo S, et al. Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function. J Clin Invest 2011; 121:4640–54.10.1172/JCI59472Search in Google Scholar PubMed PubMed Central
41. Liu C, Shen A, Li X, Jiao W, Zhang X, Li Z. T-box transcription factor TBX20 mutations in Chinese patients with congenital heart disease. Eur J Med Genet 2008;51:580–7.10.1016/j.ejmg.2008.09.001Search in Google Scholar PubMed
42. Chen J, Sun F, Fu J, Zhang H. Association of TBX20 gene polymorphism with congenital heart disease in Han Chinese neonates. Pediatr Cardiol 2015;36:737–42.10.1007/s00246-014-1073-5Search in Google Scholar PubMed
43. Posch MG, Gramlich M, Sunde M, Schmitt KR, Lee SH, Richter S, et al. A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects. J Med Genet 2010;47:230–5.10.1136/jmg.2009.069997Search in Google Scholar PubMed PubMed Central
44. Liu JJ, Fan LL, Chen JL, Tan ZP, Yang YF. A novel variant in TBX20 (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect. J Zhejiang Univ Sci B 2014;15:830–7.10.1631/jzus.B1400062Search in Google Scholar PubMed PubMed Central
45. Monroy-Muñoz IE, Pérez-Hernández N, Rodríguez-Pérez JM, Muñoz-Medina JE, Angeles-Martínez J, García-Trejo JJ, et al. Novel mutations in the transcriptional activator domain of the human TBX20 in patients with atrial septal defect. Biomed Res Int 2015;2015:718786.10.1155/2015/718786Search in Google Scholar PubMed PubMed Central
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