Hostname: page-component-77c89778f8-fv566 Total loading time: 0 Render date: 2024-07-20T07:47:48.119Z Has data issue: false hasContentIssue false
  • English
  • Français

A nonsense variation p.Arg325X in the vascular endothelial growth factor-A gene may be associated with congenital tricuspid aortic valve stenosis

Published online by Cambridge University Press:  09 November 2011

Wu Zhao ,
Jian Wang ,
Jie Shen ,
Kun Sun ,
Yiwei Chen ,
Wei Ji ,
Lijun Fu ,
Yurong Wu  and
Fen Li
Wu Zhao
Affiliation:
Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Department of Pediatrics, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, People's Republic of China
Jian Wang
Affiliation:
Research Division of Birth Defects, Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai, People's Republic of China
Jie Shen
Affiliation:
Department of Cardiology, Shanghai Children's Hospital, Shanghai, People's Republic of China
Kun Sun
Affiliation:
Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
Yiwei Chen
Affiliation:
Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
Wei Ji
Affiliation:
Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
Lijun Fu
Affiliation:
Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
Yurong Wu
Affiliation:
Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
Fen Li*
Affiliation:
Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
*
Correspondence to: Dr F. Li, Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, People's Republic of China. Tel: +86 21 38626161; Fax: +86 21 58393915; E-mail: lifen_88@yahoo.com.cn
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

In our recent study, we first reported that mutation in vascular endothelial growth factor-A is associated with bicuspid aortic valve stenosis. However, to date no groups have explored the role of vascular endothelial growth factor-A variations in the aetiology of congenital tricuspid aortic valve stenosis.

Methods

We sequenced all eight coding exons and exon–intron boundaries of the vascular endothelial growth factor-A gene in deoxyribonucleic acid samples of a cohort of 32 sporadic patients with tricuspid aortic valve stenosis, 300 normal controls, and 103 disease controls – conotruncal defects – in order to identify sequence variants.

Results

We identified a c.973C > T heterozygous nonsense variation in exon 6 of the vascular endothelial growth factor-A gene in a patient with an isolated tricuspid aortic valve stenosis. The c.973C > T variation, which was absent in all controls, changes a highly conserved arginine at amino acid position 325 to a stop codon (p.Arg325X) and is predicted to produce a truncated protein of 324 amino acid residues. The proband's parents had a normal cardiac phenotype; however, his father was a carrier of the p.Arg325X variation, which indicates that the p.Arg325X variation is inherited and incompletely penetrant.

Conclusion

We report for the first time that the p.Arg325X nonsense variation in the vascular endothelial growth factor-A gene may be associated with congenital tricuspid aortic valve stenosis.

Keywords

Congenital cardiac diseasegeneticssequence analysis
Type
Original Article
Information
Cardiology in the Young , Volume 22 , Issue 3 , June 2012 , pp. 316 - 322
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.St Louis, JD, Jaggers, J. Left ventricular outflow tract obstruction. In: Nichols DG, Ungerleider RM, Spevak PJ (eds.). Critical Heart Disease in Infants and Children, 2nd edn. Mosby, Philadelphia, 2006, pp 609–623.CrossRefGoogle Scholar
2.Mack, G, Silberbach, M. Aortic and pulmonary stenosis. Pediatr Rev 2000; 21: 79–85.CrossRefGoogle ScholarPubMed
3.Reich, O. Aortic valve, congenital stenosis. In: Sievert H, Qureshi SA, Wilson N, Hijazi ZM (eds.). Percutaneous Interventions for Congenital Heart disease. Informa Healthcare, London, 2007, pp 153–162.Google Scholar
4.Roberts, WC, Ko, JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation 2005; 111: 920–925.CrossRefGoogle ScholarPubMed
5.Godden, DJ, Sandhu, PS, Kerr, F. Stenosed bicuspid aortic valves in twins. Eur Heart J 1987; 8: 316–318.CrossRefGoogle ScholarPubMed
6.McDonald, K, Maurer, BJ. Familial aortic valve disease: evidence for a genetic influence? Eur Heart J 1989; 10: 676–677.CrossRefGoogle ScholarPubMed
7.McBride, KL, Riley, MF, Zender, GA, et al. NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. Hum Mol Genet 2008; 17: 2886–2893.CrossRefGoogle ScholarPubMed
8.Zhao, W, Wang, J, Shen, J, et al. Mutations in VEGFA are associated with congenital left ventricular outflow tract obstruction. Biochem Biophys Res Commun 2010; 396: 483–488.CrossRefGoogle ScholarPubMed
9.Armstrong, EJ, Bischoff, J. Heart valve development: endothelial cell signaling and differentiation. Circ Res 2004; 95: 459–470.CrossRefGoogle ScholarPubMed
10.Wagner, M, Siddiqui, MA. Signal transduction in early heart development (II): ventricular chamber specification, trabeculation, and heart valve formation. Exp Biol Med (Maywood) 2007; 232: 866–880.Google ScholarPubMed
11.Nguyen, KH. Congenital heart surgery nomenclature and database project: aortic valve disease. Ann Thorac Surg 2000; 69: S118–S131.CrossRefGoogle ScholarPubMed
12.Griffin, HR, Hall, DH, Topf, A, et al. Genetic variation in VEGF does not contribute significantly to the risk of congenital cardiovascular malformation. PLoS One 2009; 4: e4978.CrossRefGoogle ScholarPubMed
13.Huez, I, Bornes, S, Bresson, D, Créancier, L, Prats, H. New vascular endothelial growth factor isoform generated by internal ribosome entry site-driven CUG translation initiation. Mol Endocrinol 2001; 15: 2197–2210.CrossRefGoogle ScholarPubMed
14.Meiron, M, Anunu, R, Scheinman, EJ, Hashmueli, S, Levi, BZ. New isoforms of VEGF are translated from alternative initiation CUG codons located in its 5′UTR. Biochem Biophys Res Commun 2001; 282: 1053–1060.CrossRefGoogle ScholarPubMed
15.Tee, MK, Jaffe, RB. A precursor form of vascular endothelial growth factor arises by initiation from an upstream in-frame CUG codon. Biochem J 2001; 359: 219–226.CrossRefGoogle ScholarPubMed
16.Dowlati, A. Hunting and trapping the vascular endothelial growth factor. J Clin Oncol 2010; 28: 185–187.CrossRefGoogle ScholarPubMed
17.Ribeiro, LA, Bacci, ML, Seren, E, Tamanini, C, Forni, M. Characterization and differential expression of vascular endothelial growth factor isoforms and receptors in swine corpus luteum throughout estrous cycle. Mol Reprod Dev 2007; 74: 163–171.CrossRefGoogle ScholarPubMed
18.Tischer, E, Mitchell, R, Hartman, T, et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 1991; 266: 11947–11954.CrossRefGoogle ScholarPubMed
19.Poltorak, Z, Cohen, T, Sivan, R, et al. VEGF145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J Biol Chem 1997; 272: 7151–7158.CrossRefGoogle ScholarPubMed
20.Whittle, C, Gillespie, K, Harrison, R, Mathieson, PW, Harper, SJ. Heterogeneous vascular endothelial growth factor (VEGF) isoform mRNA and receptor mRNA expression in human glomeruli, and the identification of VEGF148 mRNA, a novel truncated splice variant. Clin Sci (Lond) 1999; 97: 303–312.CrossRefGoogle ScholarPubMed
21.Bates, DO, Cui, TG, Doughty, JM, et al. VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res 2002; 62: 4123–4131.Google ScholarPubMed
22.Lei, J, Jiang, A, Pei, D. Identification and characterization of a new splicing variant of vascular endothelial growth factor: VEGF183. Biochim Biophys Acta 1998; 1443: 400–406.CrossRefGoogle ScholarPubMed
23.Houck, KA, Ferrara, N, Winer, J, Cachianes, G, Li, B, Leung, DW. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 1991; 5: 1806–1814.CrossRefGoogle ScholarPubMed
24.Nicholson, P, Yepiskoposyan, H, Metze, S, Zamudio Orozco, R, Kleinschmidt, N, Mühlemann, O. Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors. Cell Mol Life Sci 2010; 67: 677–700.CrossRefGoogle ScholarPubMed