A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation

Wang,Xin-Hua; Huang,Cong-Xin; Wang,Qian; Li,Ruo-Gu; Xu,Ying-Jia; Liu,Xu; Fang,Wei-Yi; Yang,Yi-Qing

doi:10.3892/ijmm.2012.1189

A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation

Authors:
- Xin-Hua Wang
- Cong-Xin Huang
- Qian Wang
- Ruo-Gu Li
- Ying-Jia Xu
- Xu Liu
- Wei-Yi Fang
- Yi-Qing Yang
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Affiliations: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China, Departments of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Medical College of Shanghai Jiaotong University, Shanghai 200030, P.R. China
Published online on: November 20, 2012 https://doi.org/10.3892/ijmm.2012.1189
Pages: 43-50

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Abstract

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with significantly increased morbidity and mortality. Cumulative evidence highlights the importance of genetic defects in the pathogenesis of AF. However, AF is of remarkable heterogeneity and the genetic determinants of AF in a vast majority of patients remain illusive. In this study, the coding exons and splice junctions of the GATA5 gene, which encodes a zinc-finger transcription factor essential for normal cardiogenesis, were sequenced in 118 unrelated patients with lone AF. The available relatives of the index patient carrying an identified mutation and 200 unrelated ethnically-matched healthy individuals used as controls were genotyped. The functional effect of the mutant GATA5 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA5 mutation, p.W200G, was identified in a family with AF inherited as an autosomal dominant trait. The mutation was absent in 200 control individuals and the altered amino acid was completely conserved evolutionarily across species. Functional analysis showed that the mutation of GATA5 was associated with a significantly decreased transcriptional activity. These findings provide novel insight into the molecular mechanism involved in AF, suggesting potential implications for the early prophylaxis and gene-specific therapy of AF.

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1	Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Huezey JY, Lowe JE, et al: American College of Cardiology Foundation/American Heart Association Task Force: 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 123:e269–e367. 2011.
2	Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV and Singer DE: Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 285:2370–2375. 2001. View Article : Google Scholar : PubMed/NCBI
3	Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D’Agostino RB, Massaro JM, Beiser A, Wolf PA and Benjamin EJ: Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 110:1042–1046. 2004. View Article : Google Scholar : PubMed/NCBI
4	Wolf PA, Abbott RD and Kannel WB: Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 22:983–988. 1991. View Article : Google Scholar : PubMed/NCBI
5	Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB and Levy D: Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 98:946–952. 1998. View Article : Google Scholar : PubMed/NCBI
6	Magnani JW, Rienstra M, Lin H, Sinner MF, Lubitz SA, McManus DD, Dupuis J, Ellinor PT and Benjamin EJ: Atrial fibrillation: current knowledge and future directions in epidemiology and genomics. Circulation. 124:1982–1993. 2011. View Article : Google Scholar : PubMed/NCBI
7	Darbar D, Herron KJ, Ballew JD, Jahangir A, Gersh BJ, Shen WK, Hammill SC, Packer DL and Olson TM: Familial atrial fibrillation is a genetically heterogeneous disorder. J Am Coll Cardiol. 41:2185–2192. 2003. View Article : Google Scholar : PubMed/NCBI
8	Ellinor PT, Yoerger DM, Ruskin JN and MacRae CA: Familial aggregation in lone atrial fibrillation. Hum Genet. 118:179–184. 2005. View Article : Google Scholar : PubMed/NCBI
9	Arnar DO, Thorvaldsson S, Manolio TA, Thorgeirsson G, Kristjansson K, Hakonarson H and Stefansson K: Familial aggregation of atrial fibrillation in Iceland. Eur Heart J. 27:708–712. 2006. View Article : Google Scholar : PubMed/NCBI
10	Junttila MJ, Raatikainen MJ, Perkiömäki JS, Hong K, Brugada R and Huikuri HV: Familial clustering of lone atrial fibrillation in patients with saddleback-type ST-segment elevation in right precordial leads. Eur Heart J. 28:463–468. 2007. View Article : Google Scholar : PubMed/NCBI
11	Christophersen IE, Ravn LS, Budtz-Joergensen E, Skytthe A, Haunsoe S, Svendsen JH and Christensen K: Familial aggregation of atrial fibrillation: a study in Danish twins. Circ Arrhythm Electrophysiol. 2:378–383. 2009. View Article : Google Scholar : PubMed/NCBI
12	Yang YQ, Zhang XL, Wang XH, Tan HW, Shi HF, Fang WY and Liu X: Familial aggregation of lone atrial fibrillation in the Chinese population. Intern Med. 49:2385–2391. 2010. View Article : Google Scholar : PubMed/NCBI
13	Lubitz SA, Yin X, Fontes JD, Magnani JW, Rienstra M, Pai M, Villalon ML, Vasan RS, Pencina MJ, Levy D, et al: Association between familial atrial fibrillation and risk of new-onset atrial fibrillation. JAMA. 304:2263–2269. 2010. View Article : Google Scholar : PubMed/NCBI
14	Fox CS, Parise H, D’Agostino RB Sr, Lloyd-Jones DM, Vasan RS, Wang TJ, Levy D, Wolf PA and Benjamin EJ: Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 291:2851–2855. 2004. View Article : Google Scholar : PubMed/NCBI
15	Brugada R, Tapscott T, Czernuszewicz GZ, Marian AJ, Iglesias A, Mont L, Brugada J, Girona J, Domingo A, Bachinski LL and Roberts R: Identification of a genetic locus for familial atrial fibrillation. N Engl J Med. 336:905–911. 1997. View Article : Google Scholar : PubMed/NCBI
16	Ellinor PT, Shin JT, Moore RK, Yoerger DM and MacRae CA: Locus for atrial fibrillation maps to chromosome 6q14–16. Circulation. 107:2880–2883. 2003.PubMed/NCBI
17	Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, Jin HW, Sun H, Su XY, Zhuang QN, et al: KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 299:251–254. 2003. View Article : Google Scholar : PubMed/NCBI
18	Oberti C, Wang L, Li L, Dong J, Rao S, Du W and Wang Q: Genome-wide linkage scan identifies a novel genetic locus on chromosome 5p13 for neonatal atrial fibrillation associated with sudden death and variable cardiomyopathy. Circulation. 110:3753–3759. 2004. View Article : Google Scholar
19	Zhang X, Chen S, Yoo S, Chakrabarti S, Zhang T, Ke T, Oberti C, Yong SL, Fang F, Li L, et al: Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death. Cell. 135:1017–1027. 2008. View Article : Google Scholar : PubMed/NCBI
20	Volders PG, Zhu Q, Timmermans C, Eurlings PM, Su X, Arens YH, Li L, Jongbloed RJ, Xia M, Rodriguez LM and Chen YH: Mapping a novel locus for familial atrial fibrillation on chromosome 10p11–q21. Heart Rhythm. 4:469–475. 2007.PubMed/NCBI
21	Darbar D, Hardy A, Haines JL and Roden DM: Prolonged signal-averaged P-wave duration as an intermediate phenotype for familial atrial fibrillation. J Am Coll Cardiol. 51:1083–1089. 2008. View Article : Google Scholar : PubMed/NCBI
22	Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y, Liang B, Lin J, Liu Y, Liu B, et al: Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Am J Hum Genet. 75:899–905. 2004. View Article : Google Scholar : PubMed/NCBI
23	Lundby A, Ravn LS, Svendsen JH, Hauns S, Olesen SP and Schmitt N: KCNE3 mutation V17M identified in a patient with lone atrial fibrillation. Cell Physiol Biochem. 21:47–54. 2008. View Article : Google Scholar : PubMed/NCBI
24	Ravn LS, Aizawa Y, Pollevick GD, Hofman-Bang J, Cordeiro JM, Dixen U, Jensen G, Wu Y, Burashnikov E, Haunso S, et al: Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation. Heart Rhythm. 5:427–435. 2008. View Article : Google Scholar : PubMed/NCBI
25	Hong K, Bjerregaard P, Gussak I and Brugada R: Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol. 16:394–396. 2005. View Article : Google Scholar : PubMed/NCBI
26	Xia M, Jin Q, Bendahhou S, He Y, Larroque MM, Chen Y, Zhou Q, Yang Y, Liu Y, Liu B, et al: A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation. Biochem Biophys Res Commun. 332:1012–1019. 2005. View Article : Google Scholar : PubMed/NCBI
27	Olson TM, Alekseev AE, Liu XK, Park S, Zingman LV, Bienengraeber M, Sattiraju S, Ballew JD, Jahangir A and Terzic A: Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet. 15:2185–2191. 2006. View Article : Google Scholar : PubMed/NCBI
28	Yang Y, Li J, Lin X, Yang Y, Hong K, Wang L, Liu J, Li L, Yan D, Liang D, et al: Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation. J Hum Genet. 54:277–283. 2009. View Article : Google Scholar : PubMed/NCBI
29	Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ and Anderson JL: Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA. 293:447–454. 2005. View Article : Google Scholar : PubMed/NCBI
30	Watanabe H, Darbar D, Kaiser DW, Jiramongkolchai K, Chopra S, Donahue BS, Kannankeril PJ and Roden DM: Mutations in sodium channel beta1- and beta2-subunits associated with atrial fibrillation. Circ Arrhythm Electrophysiol. 2:268–275. 2009. View Article : Google Scholar : PubMed/NCBI
31	Wang P, Yang Q, Wu X, Yang Y, Shi L, Wang C, Wu G, Xia Y, Yang B, Zhang R, et al: Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population. Biochem Biophys Res Commun. 398:98–104. 2010. View Article : Google Scholar : PubMed/NCBI
32	Hodgson-Zingman DM, Karst ML, Zingman LV, Heublein DM, Darbar D, Herron KJ, Ballew JD, de Andrade M, Burnett JC Jr and Olson TM: Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. N Engl J Med. 359:158–165. 2008. View Article : Google Scholar : PubMed/NCBI
33	Ren X, Xu C, Zhan C, Yang Y, Shi L, Wang F, Wang C, Xia Y, Yang B, Wu G, et al: Identification of NPPA variants associated with atrial fibrillation in a Chinese GeneID population. Clin Chim Acta. 411:481–485. 2010. View Article : Google Scholar : PubMed/NCBI
34	Thibodeau IL, Xu J, Li Q, Liu G, Lam K, Veinot JP, Birnie DH, Jones DL, Krahn AD, Lemery R, et al: Paradigm of genetic mosaicism and lone atrial fibrillation: physiological characterization of a connexin 43-deletion mutant identified from atrial tissue. Circulation. 122:236–244. 2010. View Article : Google Scholar
35	Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, Liu X, Veinot JP, Tang AS, Stewart AF, et al: Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med. 354:2677–2688. 2006. View Article : Google Scholar : PubMed/NCBI
36	Yang YQ, Zhang XL, Wang XH, Tan HW, Shi HF, Jiang WF, Fang WY and Liu X: Connexin40 nonsense mutation in familial atrial fibrillation. Int J Mol Med. 26:605–610. 2010.PubMed/NCBI
37	Yang YQ, Liu X, Zhang XL, Wang XH, Tan HW, Shi HF, Jiang WF and Fang WY: Novel connexin40 missense mutations in patients with familial atrial fibrillation. Europace. 12:1421–1427. 2010. View Article : Google Scholar : PubMed/NCBI
38	Bruneau BG: The developmental genetics of congenital heart disease. Nature. 451:943–948. 2008. View Article : Google Scholar : PubMed/NCBI
39	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
40	Hu DL, Chen FK, Liu YQ, Sheng YH, Yang R, Kong XQ, Cao KJ, Gu HT and Qian LM: GATA-4 promotes the differentiation of P19 cells into cardiac myocytes. Int J Mol Med. 26:365–372. 2010.PubMed/NCBI
41	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
42	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
43	Liu XY, Wang J, Yang YQ, Zhang YY, Chen XZ, Zhang W, Wang XZ, Zheng JH and Chen YH: Novel NKX2-5 mutations in patients with familial atrial septal defects. Pediatr Cardiol. 32:193–201. 2011. View Article : Google Scholar : PubMed/NCBI
44	Wang J, Liu XY and Yang YQ: Novel NKX2-5 mutations responsible for congenital heart disease. Genet Mol Res. 10:2905–2915. 2011. View Article : Google Scholar : PubMed/NCBI
45	Gutierrez-Roelens I, De Roy L, Ovaert C, Sluysmans T, Devriendt K, Brunner HG and Vikkula M: A novel CSX/NKX2-5 mutation causes autosomal-dominant AV block: are atrial fibrillation and syncopes part of the phenotype? Eur J Hum Genet. 14:1313–1316. 2006. View Article : Google Scholar : PubMed/NCBI
46	Boldt LH, Posch MG, Perrot A, Polotzki M, Rolf S, Parwani AS, Huemer M, Wutzler A, Ozcelik C and Haverkamp W: Mutational analysis of the PITX2 and NKX2-5 genes in patients with idiopathic atrial fibrillation. Int J Cardiol. 145:316–317. 2010. View Article : Google Scholar : PubMed/NCBI
47	Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, et al: GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 424:443–447. 2003. View Article : Google Scholar : PubMed/NCBI
48	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.PubMed/NCBI
49	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.
50	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
51	Posch MG, Boldt LH, Polotzki M, Richter S, Rolf S, Perrot A, Dietz R, Ozcelik C and Haverkamp W: Mutations in the cardiac transcription factor GATA4 in patients with lone atrial fibrillation. Eur J Med Genet. 53:201–203. 2010. View Article : Google Scholar : PubMed/NCBI
52	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
53	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
54	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
55	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.
56	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
57	Zhang Y, Rath N, Hannenhalli S, Wang Z, Cappola T, Kimura S, Atochina-Vasserman E, Lu MM, Beers MF and Morrisey EE: GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo. Development. 134:189–198. 2007. View Article : Google Scholar : PubMed/NCBI
58	Nemer G, Qureshi ST, Malo D and Nemer M: Functional analysis and chromosomal mapping of Gata5, a gene encoding a zinc finger DNA-binding protein. Mamm Genome. 10:993–999. 1999. View Article : Google Scholar : PubMed/NCBI
59	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
60	Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P and Clémenty J: Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 339:659–666. 1998.PubMed/NCBI
61	Mommersteeg MT, Brown NA, Prall OW, de Gier-de Vries C, Harvey RP, Moorman AF and Christoffels VM: Pitx2c and Nkx2-5 are required for the formation and identity of the pulmonary myocardium. Circ Res. 101:902–909. 2007. View Article : Google Scholar : PubMed/NCBI
62	Mommersteeg MT, Christoffels VM, Anderson RH and Moorman AF: Atrial fibrillation: a developmental point of view. Heart Rhythm. 6:1818–1824. 2009. View Article : Google Scholar : PubMed/NCBI
63	Mommersteeg MT, Hoogaars WM, Prall OW, de Gier-de Vries C, Wiese C, Clout DE, Papaioannou VE, Brown NA, Harvey RP, Moorman AF and Christoffels VM: Molecular pathway for the localized formation of the sinoatrial node. Circ Res. 100:354–362. 2007. View Article : Google Scholar : PubMed/NCBI
64	Watanabe Y, Benson DW, Yano S, Akagi T, Yoshino M and Murray JC: Two novel frameshift mutations in NKX2.5 result in novel features including visceral inversus and sinus venosus type ASD. J Med Genet. 39:807–811. 2002. View Article : Google Scholar : PubMed/NCBI
65	Pabst S, Wollnik B, Rohmann E, Hintz Y, Glänzer K, Vetter H, Nickenig G and Grohé C: A novel stop mutation truncating critical regions of the cardiac transcription factor NKX2-5 in a large family with autosomal-dominant inherited congenital heart disease. Clin Res Cardiol. 97:39–42. 2008. View Article : Google Scholar
66	Gruver EJ, Fatkin D, Dodds GA, Kisslo J, Maron BJ, Seidman JG and Seidman CE: Familial hypertrophic cardiomyopathy and atrial fibrillation caused by Arg663His beta-cardiac myosin heavy chain mutation. Am J Cardiol. 83:H13–H18. 1999. View Article : Google Scholar : PubMed/NCBI