A novel GATA4 loss-of-function mutation responsible for familial dilated cardiomyopathy

Zhao,Lan; Xu,Jia-Hong; Xu,Wen-Jun; Yu,Hong; Wang,Qian; Zheng,Hong-Zhen; Jiang,Wei-Feng; Jiang,Jin-Fa; Yang,Yi-Qing

doi:10.3892/ijmm.2013.1600

A novel GATA4 loss-of-function mutation responsible for familial dilated cardiomyopathy

Authors:
- Lan Zhao
- Jia-Hong Xu
- Wen-Jun Xu
- Hong Yu
- Qian Wang
- Hong-Zhen Zheng
- Wei-Feng Jiang
- Jin-Fa Jiang
- Yi-Qing Yang
View Affiliations

Affiliations: Department of Cardiology, Yantaishan Hospital, Yantai, Shandong 264001, P.R. China, Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China, Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
Published online on: December 23, 2013 https://doi.org/10.3892/ijmm.2013.1600
Pages: 654-660

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disorder and is associated with substantial morbidity and mortality. Increasing evidence suggests that genetic risk factors play an important role in the pathogenesis of idiopathic DCM. However, DCM is a genetically heterogeneous disease, and the genetic defects responsible for DCM in an overwhelming majority of cases remain to be identified. In the present study, the entire coding region and the splice junction sites of the GATA4 gene, which encodes a cardiac transcription factor essential for cardiogenesis, were sequenced in 150 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped. The functional characteristics of the mutant GATA4 were delineated in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.V291L, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes, and the altered amino acid was completely conserved evolutionarily among species. Functional analysis revealed that the GATA4 mutant was associated with significantly diminished transcriptional activity. The findings expand the mutational spectrum of GATA4 linked to DCM and provide novel insight into the molecular etiology involved in DCM, suggesting the potential implications in the early prophylaxis and allele-specific treatment for this common type of cardiomyopathy.

View Figures

View References

1	Garcia-Pavia P, Cobo-Marcos M, Guzzo-Merello G, Gomez-Bueno M, Bornstein B, Lara-Pezzi E, Segovia J and Alonso-Pulpon L: Genetics in dilated cardiomyopathy. Biomark Med. 7:517–533. 2013. View Article : Google Scholar
2	Lakdawala NK, Winterfield JR and Funke BH: Dilated cardiomyopathy. Circ Arrhythm Electrophysiol. 6:228–237. 2013. View Article : Google Scholar
3	McNally EM, Golbus JR and Puckelwartz MJ: Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest. 123:19–26. 2013. View Article : Google Scholar : PubMed/NCBI
4	Flack E and Kannankeril PJ: The genetics of dilated cardiomyopathy. Heart Rhythm. 9:397–398. 2012. View Article : Google Scholar
5	Pikkarainen S, Tokola H, Kerkelä R and Ruskoaho H: GATA transcription factors in the developing and adult heart. Cardiovasc Res. 63:196–207. 2004. View Article : Google Scholar : PubMed/NCBI
6	Perrino C and Rockman HA: GATA4 and the two sides of gene expression reprogramming. Circ Res. 98:715–716. 2006. View Article : Google Scholar : PubMed/NCBI
7	Brody MJ, Cho E, Mysliwiec MR, Kim TG, Carlson CD, Lee KH and Lee Y: Lrrc10 is a novel cardiac-specific target gene of Nkx2-5 and GATA4. J Mol Cell Cardiol. 62:237–246. 2013. View Article : Google Scholar : PubMed/NCBI
8	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 and Srivastava D: GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 424:443–447. 2003. View Article : Google Scholar : PubMed/NCBI
9	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 and Pu WT: Spectrum of heart disease associated with murine and human GATA4 mutation. J Mol Cell Cardiol. 43:677–685. 2007. View Article : Google Scholar : PubMed/NCBI
10	Wang J, Fang M, Liu XY, Xin YF, Liu ZM, Chen XZ, Wang XZ, Fang WY, Liu X and Yang YQ: A novel GATA4 mutation responsible for congenital ventricular septal defects. Int J Mol Med. 28:557–564. 2011.
11	Liu XY, Wang J, Zheng JH, Bai K, Liu ZM, Wang XZ, Liu X, Fang WY and Yang YQ: Involvement of a novel GATA4 mutation in atrial septal defects. Int J Mol Med. 28:17–23. 2011.PubMed/NCBI
12	McCulley DJ and Black BL: Transcription factor pathways and congenital heart disease. Curr Top Dev Biol. 100:253–277. 2012. View Article : Google Scholar : PubMed/NCBI
13	Yang YQ, Li L, Wang J, Liu XY, Chen XZ, Zhang W, Wang XZ, Jiang JQ, Liu X and Fang WY: A novel GATA4 loss-of-function mutation associated with congenital ventricular septal defect. Pediatr Cardiol. 33:539–546. 2012. View Article : Google Scholar : PubMed/NCBI
14	Yang YQ, Wang J, Liu XY, Chen XZ, Zhang W, Wang XZ, Liu X and Fang WY: Novel GATA4 mutations in patients with congenital ventricular septal defects. Med Sci Monit. 18:CR344–CR350. 2012.PubMed/NCBI
15	Wang E, Sun S, Qiao B, Duan W, Huang G, An Y, Xu S, Zheng Y, Su Z, Gu X, Jin L and Wang H: Identification of functional mutations in GATA4 in patients with congenital heart disease. PLoS One. 8:e621382013. View Article : Google Scholar : PubMed/NCBI
16	Yang YQ, Gharibeh L, Li RG, Xin YF, Wang J, Liu ZM, Qiu XB, Xu YJ, Xu L, Qu XK, Liu X, Fang WY, Huang RT, Xue S and Nemer G: GATA4 loss-of-function mutations underlie familial tetralogy of Fallot. Hum Mutat. 34:1662–1671. 2013. View Article : Google Scholar : PubMed/NCBI
17	Li RG, Li L, Qiu XB, Yuan F, Xu L, Li X, Xu YJ, Jiang WF, Jiang JQ, Liu X, Fang WY, Zhang M, Peng LY, Qu XK and Yang YQ: GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy. Biochem Biophys Res Commun. 439:591–596. 2013. View Article : Google Scholar : PubMed/NCBI
18	Molkentin JD, Lin Q, Duncan SA and Olson EN: Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev. 11:1061–1072. 1997. View Article : Google Scholar : PubMed/NCBI
19	Kuo CT, Morrisey EE, Anandappa R, Sigrist K, Lu MM, Parmacek MS, Soudais C and Leiden JM: GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev. 11:1048–1060. 1997. View Article : Google Scholar : PubMed/NCBI
20	Pu WT, Ishiwata T, Juraszek AL, Ma Q and Izumo S: GATA4 is a dosage-sensitive regulator of cardiac morphogenesis. Dev Biol. 275:235–244. 2004. View Article : Google Scholar : PubMed/NCBI
21	Oka T, Maillet M, Watt AJ, Schwartz RJ, Aronow BJ, Duncan SA and Molkentin JD: Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy, compensation, and myocyte viability. Circ Res. 98:837–845. 2006. View Article : Google Scholar : PubMed/NCBI
22	Suzuki YJ and Evans TL: Regulation of cardiac myocyte apoptosis by the GATA-4 transcription factor. Life Sci. 74:1829–1838. 2004. View Article : Google Scholar : PubMed/NCBI
23	Xu X, Zhang L and Liang J: Rosuvastatin prevents pressure overload-induced myocardial hypertrophy via inactivation of the Akt, ERK1/2 and GATA4 signaling pathways in rats. Mol Med Rep. 8:385–392. 2013.PubMed/NCBI
24	Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, Evans T, Macrae CA, Stainier DY and Poss KD: Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature. 464:601–605. 2010.PubMed/NCBI
25	Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L, Conway SJ, Fu JD and Srivastava D: In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 485:593–598. 2012. View Article : Google Scholar : PubMed/NCBI
26	Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN, Acharya A, Smith CL, Tallquist MD, Neilson EG, Hill JA, Bassel-Duby R and Olson EN: Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 485:599–604. 2012. View Article : Google Scholar : PubMed/NCBI
27	Lyons I, Parsons LM, Hartley L, Li R, Andrews JE, Robb L and Harvey RP: Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev. 9:1654–1666. 1995. View Article : Google Scholar : PubMed/NCBI
28	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 and Harvey RP: An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Cell. 128:947–959. 2007. View Article : Google Scholar : PubMed/NCBI
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 and Chien KR: Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Cell. 117:373–386. 2004.
30	Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE and Seidman JG: Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science. 281:108–111. 1998. View Article : Google Scholar : PubMed/NCBI
31	Reamon-Buettner SM and Borlak J: NKX2-5: an update on this hypermutable homeodomain protein and its role in human congenital heart disease (CHD). Hum Mutat. 31:1185–1194. 2010. View Article : Google Scholar : PubMed/NCBI
32	Wang J, Xin YF, Liu XY, Liu ZM, Wang XZ and Yang YQ: A novel NKX2-5 mutation in familial ventricular septal defect. Int J Mol Med. 27:369–375. 2011.PubMed/NCBI
33	Costa MW, Guo G, Wolstein O, Vale M, Castro ML, Wang L, Otway R, Riek P, Cochrane N, Furtado M, Semsarian C, Weintraub RG, Yeoh T, Hayward C, Keogh A, Macdonald P, Feneley M, Graham RM, Seidman JG, Seidman CE, Rosenthal N, Fatkin D and Harvey RP: Functional characterization of a novel mutation in NKX2-5 associated with congenital heart disease and adult-onset cardiomyopathy. Circ Cardiovasc Genet. 6:238–247. 2013. View Article : Google Scholar : PubMed/NCBI
34	Elliott P, O’Mahony C, Syrris P, Evans A, Rivera Sorensen C, Sheppard MN, Carr-White G, Pantazis A and McKenna WJ: Prevalence of desmosomal protein gene mutations in patients with dilated cardiomyopathy. Circ Cardiovasc Genet. 3:314–322. 2010. View Article : Google Scholar : PubMed/NCBI
35	Schlesinger J, Schueler M, Grunert M, Fischer JJ, Zhang Q, Krueger T, Lange M, Tönjes M, Dunkel I and Sperling SR: The cardiac transcription network modulated by Gata4, Mef2a, Nkx2.5, Srf, histone modifications, and microRNAs. PLoS Genet. 7:e10013132011. View Article : Google Scholar : PubMed/NCBI
36	Liang Q, De Windt LJ, Witt SA, Kimball TR, Markham BE and Molkentin JD: The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo. J Biol Chem. 276:30245–30253. 2001. View Article : Google Scholar : PubMed/NCBI
37	Kirk EP, Sunde M, Costa MW, Rankin SA, Wolstein O, Castro ML, Butler TL, Hyun C, Guo G, Otway R, Mackay JP, Waddell LB, Cole AD, Hayward C, Keogh A, Macdonald P, Griffiths L, Fatkin D, Sholler GF, Zorn AM, Feneley MP, Winlaw DS and Harvey RP: 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. 81:280–291. 2007. View Article : Google Scholar : PubMed/NCBI
38	Jiang JQ, Shen FF, Fang WY, Liu X and Yang YQ: Novel GATA4 mutations in lone atrial fibrillation. Int J Mol Med. 28:1025–1032. 2011.PubMed/NCBI
39	Yang YQ, Wang MY, Zhang XL, Tan HW, Shi HF, Jiang WF, Wang XH, Fang WY and Liu X: GATA4 loss-of-function mutations in familial atrial fibrillation. Clin Chim Acta. 412:1825–1830. 2011. View Article : Google Scholar : PubMed/NCBI
40	Wang J, Sun YM and Yang YQ: Mutation spectrum of the GATA4 gene in patients with idiopathic atrial fibrillation. Mol Biol Rep. 39:8127–8135. 2012. View Article : Google Scholar : PubMed/NCBI
41	Jiang JQ, Li RG, Wang J, Liu XY, Xu YJ, Fang WY, Chen XZ, Zhang W, Wang XZ and Yang YQ: Prevalence and spectrum of GATA5 mutations associated with congenital heart disease. Int J Cardiol. 165:570–573. 2013. View Article : Google Scholar : PubMed/NCBI
42	Wei D, Bao H, Liu XY, Zhou N, Wang Q, Li RG, Xu YJ and Yang YQ: GATA5 loss-of-function mutations underlie tetralogy of Fallot. Int J Med Sci. 10:34–42. 2013. View Article : Google Scholar : PubMed/NCBI
43	Wei D, Bao H, Zhou N, Zheng GF, Liu XY and Yang YQ: GATA5 loss-of-function mutation responsible for the congenital ventriculoseptal defect. Pediatr Cardiol. 34:504–511. 2013. View Article : Google Scholar : PubMed/NCBI
44	Yang YQ, Wang J, Wang XH, Wang Q, Tan HW, Zhang M, Shen FF, Jiang JQ, Fang WY and Liu X: Mutational spectrum of the GATA5 gene associated with familial atrial fibrillation. Int J Cardiol. 157:305–307. 2012. View Article : Google Scholar : PubMed/NCBI
45	Gu JY, Xu JH, Yu H and Yang YQ: Novel GATA5 loss-of-function mutations underlie familial atrial fibrillation. Clinics (Sao Paulo). 67:1393–1399. 2012. View Article : Google Scholar : PubMed/NCBI
46	Wang XH, Huang CX, Wang Q, Li RG, Xu YJ, Liu X, Fang WY and Yang YQ: A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation. Int J Mol Med. 31:43–50. 2013.PubMed/NCBI
47	Kodo K, Nishizawa T, Furutani M, Arai S, Yamamura E, Joo K, Takahashi T, Matsuoka R and Yamagishi H: GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling. Proc Natl Acad Sci USA. 106:13933–13938. 2009. View Article : Google Scholar : PubMed/NCBI
48	Maitra M, Koenig SN, Srivastava D and Garg V: Identification of GATA6 sequence variants in patients with congenital heart defects. Pediatr Res. 68:281–285. 2010. View Article : Google Scholar : PubMed/NCBI
49	Lin X, Huo Z, Liu X, Zhang Y, Li L, Zhao H, Yan B, Liu Y, Yang Y and Chen YH: A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect. J Hum Genet. 55:662–667. 2010. View Article : Google Scholar
50	Wang J, Luo XJ, Xin YF, Liu Y, Liu ZM, Wang Q, Li RG, Fang WY, Wang XZ and Yang YQ: Novel GATA6 mutations associated with congenital ventricular septal defect or tetralogy of Fallot. DNA Cell Biol. 31:1610–1617. 2012. View Article : Google Scholar : PubMed/NCBI
51	Zheng GF, Wei D, Zhao H, Zhou N, Yang YQ and Liu XY: A novel GATA6 mutation associated with congenital ventricular septal defect. Int J Mol Med. 29:1065–1071. 2012.PubMed/NCBI
52	Huang RT, Xue S, Xu YJ and Yang YQ: Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot. Int J Mol Med. 31:51–58. 2013.
53	Bui PH, Dorrani N, Wong D, Perens G, Dipple KM and Quintero-Rivera F: First report of a de novo 18q11.2 microdeletion including GATA6 associated with complex congenital heart disease and renal abnormalities. Am J Med Genet A. 161A:1773–1778. 2013.PubMed/NCBI
54	Yang YQ, Wang XH, Tan HW, Jiang WF, Fang WY and Liu X: Prevalence and spectrum of GATA6 mutations associated with familial atrial fibrillation. Int J Cardiol. 155:494–496. 2012. View Article : Google Scholar : PubMed/NCBI
55	Yang YQ, Li L, Wang J, Zhang XL, Li RG, Xu YJ, Tan HW, Wang XH, Jiang JQ, Fang WY and Liu X: GATA6 loss-of-function mutation in atrial fibrillation. Eur J Med Genet. 55:520–526. 2012. View Article : Google Scholar : PubMed/NCBI
56	Li J, Liu WD, Yang ZL and Yang YQ: Novel GATA6 loss-of-function mutation responsible for familial atrial fibrillation. Int J Mol Med. 30:783–790. 2012.PubMed/NCBI