Identification of two novel GATA6 mutations in patients with nonsyndromic conotruncal heart defects

Wang,Xike; Ji,Wei; Wang,Jian; Zhao,Pengjun; Guo,Ying; Xu,Rang; Chen,Sun; Sun,Kun

doi:10.3892/mmr.2014.2247

Identification of two novel GATA6 mutations in patients with nonsyndromic conotruncal heart defects

Authors:
- Xike Wang
- Wei Ji
- Jian Wang
- Pengjun Zhao
- Ying Guo
- Rang Xu
- Sun Chen
- Kun Sun
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Affiliations: Children's Heart Center, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China, Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, P.R. China
Published online on: May 16, 2014 https://doi.org/10.3892/mmr.2014.2247
Pages: 743-748

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Abstract

GATA binding protein 6 (GATA6) encodes a zinc‑ﬁnger transcription factor that is essential for normal heart development. Mutations in this gene lead to conotruncal heart defects associated with cyanotic congenital heart disease; however, it remains unclear whether the mutations in GATA6 are also responsible for the development of the nonsyndromic conotruncal heart defects. The coding region exons and ﬂanking intron sequences of GATA6 were screened in 157 patients with nonsyndromic conotruncal heart defects and 300 control subjects. Three heterozygous missense mutations, c.151G>A (E51K), c.551G>A (S184N) and c.733G>C (G245R), were identified in patients with tetralogy of Fallot or persistent truncus arteriosus. The two novel mutations (E51K and G245R) identified in the current study are located in evolutionarily conserved residues of the GATA6 protein. It was demonstrated that these two mutations lead to a significant reduction in the transactivation capacity of downstream genes. The current study presents two novel GATA6 mutations in patients with nonsyndromic conotruncal heart defects and provides novel insights into the pathogenesis of this disease.

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1	Hoffman JI and Kaplan S: The incidence of congenital heart disease. J Am Coll Cardiol. 39:1890–1900. 2002. View Article : Google Scholar : PubMed/NCBI
2	Debrus S, Berger G, de Meeus A, et al: Familial non-syndromic conotruncal defects are not associated with a 22q11 microdeletion. Hum Genet. 97:138–144. 1996. View Article : Google Scholar : PubMed/NCBI
3	Jenkins KJ, Correa A, Feinstein JA, et al: The American Heart Association Council on Cardiovascular Disease in the Young: Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 115:2995–3014. 2007.
4	Cooper WO, Hernandez-Diaz S, Arbogast PG, et al: Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 354:2443–2451. 2006. View Article : Google Scholar : PubMed/NCBI
5	Goldmuntz E, Clark BJ, Mitchell LE, et al: Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol. 32:492–498. 1998. View Article : Google Scholar : PubMed/NCBI
6	Xu YJ, Wang J, Xu R, et al: Detecting 22q11.2 deletion in Chinese children with conotruncal heart defects and single nucleotide polymorphisms in the haploid TBX1 locus. BMC Med Genet. 12:1692011. View Article : Google Scholar : PubMed/NCBI
7	Morrisey EE, Tang Z, Sigrist K, et al: GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev. 12:3579–3590. 1998. View Article : Google Scholar : PubMed/NCBI
8	Zhao R, Watt AJ, Battle MA, Li J, Bondow BJ and Duncan SA: Loss of both GATA4 and GATA6 blocks cardiac myocyte differentiation and results in acardia in mice. Dev Biol. 317:614–619. 2008. View Article : Google Scholar : PubMed/NCBI
9	Lepore JJ, Mericko PA, Cheng L, Lu MM, Morrisey EE and Parmacek MS: GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis. J Clin Invest. 116:929–939. 2006. View Article : Google Scholar : PubMed/NCBI
10	Kodo K, Nishizawa T, Furutani M, et al: 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
11	Sprenkle AB, Murray SF and Glembotski CC: Involvement of multiple cis elements in basal- and alpha-adrenergic agonist-inducible atrial natriuretic factor transcription. Roles for serum response elements and an SP-1-like element. Circ Res. 77:1060–1069. 1995. View Article : Google Scholar
12	Bamforth SD, Bragança J, Eloranta JJ, et al: Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. Nat Genet. 29:469–474. 2001. View Article : Google Scholar : PubMed/NCBI
13	Lin X, Huo Z, Liu X, et al: 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
14	Burch JB: Regulation of GATA gene expression during vertebrate development. Semin Cell Dev Biol. 16:71–81. 2005. View Article : Google Scholar : PubMed/NCBI
15	Brewer A and Pizzey J: GATA factors in vertebrate heart development and disease. Expert Rev Mol Med. 8:1–20. 2006. View Article : Google Scholar
16	Barillot W, Tréguer K, Faucheux C, Fédou S, Thézé N and Thiébaud P: Induction and modulation of smooth muscle differentiation in Xenopus embryonic cells. Dev Dyn. 237:3373–3386. 2008. View Article : Google Scholar : PubMed/NCBI
17	Stoller JZ and Epstein JA: Cardiac neural crest. Semin Cell Dev Biol. 16:704–715. 2005. View Article : Google Scholar : PubMed/NCBI
18	Brown CB, Feiner L, Lu MM, et al: PlexinA2 and semaphorin signaling during cardiac neural crest development. Development. 128:3071–3080. 2001.PubMed/NCBI
19	Yang H, Lu MM, Zhang L, Whitsett JA and Morrisey EE: GATA6 regulates differentiation of distal lung epithelium. Development. 129:2233–2246. 2002.PubMed/NCBI
20	Fischer A, Klattig J, Kneitz B, et al: Hey basic helix-loop-helix transcription factors are repressors of GATA4 and GATA6 and restrict expression of the GATA target gene ANF in fetal hearts. Mol Cell Biol. 25:8960–8970. 2005. View Article : Google Scholar : PubMed/NCBI
21	Suzuki E, Evans T, Lowry J, Truong L, Bell DW, Testa JR and Walsh K: The human GATA-6 gene: structure, chromosomal location, and regulation of expression by tissue-specific and mitogen-responsive signals. Genomics. 38:283–290. 1996. View Article : Google Scholar : PubMed/NCBI
22	Mano T, Luo Z, Malendowicz SL, Evans T and Walsh K: Reversal of GATA-6 downregulation promotes smooth muscle differentiation and inhibits intimal hyperplasia in balloon-injured rat carotid artery. Circ Res. 84:647–654. 1999. View Article : Google Scholar : PubMed/NCBI
23	Morrisey EE: GATA-6: the proliferation stops here: cell proliferation in glomerular mesangial and vascular smooth muscle cells. Circ Res. 87:638–640. 2000. View Article : Google Scholar : PubMed/NCBI
24	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
25	Loffredo CA, Hirata J, Wilson PD, Ferencz C and Lurie IW: Atrioventricular septal defects: possible etiologic differences between complete and partial defects. Teratology. 63:87–93. 2001. View Article : Google Scholar : PubMed/NCBI
26	Li H, Cherry S, Klinedinst D, et al: Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population. Circ Cardiovasc Genet. 5:301–308. 2012. View Article : Google Scholar : PubMed/NCBI
27	Guo Y, Shen J, Yuan L, Li F, Wang J and Sun K: Novel CRELD1 gene mutations in patients with atrioventricular septal defect. World J Pediatr. 6:348–352. 2010. View Article : Google Scholar : PubMed/NCBI
28	Joziasse IC, Smith KA, Chocron S, et al: ALK2 mutation in a patient with Down’s syndrome and a congenital heart defect. Eur J Hum Genet. 19:389–393. 2011.PubMed/NCBI