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Identification of novel significant variants of ZFPM2/FOG2 in non-syndromic tetralogy of fallot and double outlet right ventricle in a Chinese Han population

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Abstract

Tetralogy of Fallot (TOF) and double outlet right ventricle (DORV) are two common subtypes of conotruncal defects. Recent reports have implicated mutations in the zinc finger protein, FOG family member 2 (ZFPM2/FOG2) as a cause of TOF/DORV, but no current literature focuses on the relationship between ZFPM2/FOG2 gene and non-syndromic TOF and DORV in Chinese Han population. The purpose of this study was to estimate the occurrence and the prevalence of ZFPM2/FOG2 genetic variants in Chinese Han population with non-syndromic TOF and DORV and to investigate genotype–phenotype correlations in individuals with ZFPM2/FOG2 mutations. The whole exons of ZFPM2/FOG2 were sequenced in 98 non-syndromic TOF/DORV patients and 200 control subjects. All the six variants (G2482A, G1552A, A2107C, C452T, C3239T, C1208G) changed the amino acid (p.Val828Met, p.Ala518Thr, p.Met703Leu, p.Thr151Ile, p.Ser1080Phe, p.Ala403Gly), in which four variants (G2482A, C452T, G1552A, C3239T) were not reported before and absent in control subjects. Further analysis revealed that only occurrences of variants G2482A and A2107C had statistical significance compared to the control group (P < 0.05). In conclusion, our results provide strong evidence regarding the susceptibility of the ZFPM2 gene to the development of non-syndromic TOF/DORV. It suggests that ZFPM2/FOG2 genetic variants may be a novel potential bio-markers and treatment targets for the non-syndromic TOF and DORV.

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References

  1. Hoffman JI, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39(12):1890–1900

    Article  PubMed  Google Scholar 

  2. Goldmuntz E (2001) The epidemiology and genetics of congenital heart disease. Clin Perinatol 28:1–10

    Article  PubMed  CAS  Google Scholar 

  3. Kuehl KS et al (2005) Genetic and environmental influences on malformations of the cardiac outflow tract. Expert Rev Cardiovasc Ther 3(6):1125–1130

    Article  PubMed  Google Scholar 

  4. Müller AM, Sarioglu N (2012) Congenital heart defects of the septa, endocardial cushions and the conotruncus. Pathologe 33(3):205–216. doi:10.1007/s00292-011-1557-5

    Article  PubMed  Google Scholar 

  5. Tevosian SG et al (2000) FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium. Cell 101(7):729–739

    Article  PubMed  CAS  Google Scholar 

  6. Griffin HR et al (2010) Systematic survey of variants in TBX1 in non-syndromic tetralogy of Fallot identifies a novel 57 base pair deletion that reduces transcriptional activity but finds no evidence for association with common variants. Heart 96(20):1651–1655. doi:10.1136/hrt.2010.200121

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. Takahashi K, Kido S et al (1995) Frequency of a 22q11 deletion in patients with conotruncal cardiac malformations: a prospective study. Eur J Pediatr 154(11):878–881

    Article  PubMed  CAS  Google Scholar 

  8. Green way SC et al (2009) De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet 41(8):931–935. doi:10.1038/ng.415

    Article  CAS  Google Scholar 

  9. Stennard FA, Costa MW et al (2003) Cardiac T-box factor Tbx20 directly interacts with NKX2-5, GATA4, and GATA5 in regulation of gene expression in the developing heart. Dev Biol 262:206–224

    Article  PubMed  CAS  Google Scholar 

  10. Nemer G, Nemer M (2003) Transcriptional activation of BMP-4 and regulation of mammalian organogenesis by GATA-4 and -6. Dev Biol 254(1):131–148

    Article  PubMed  CAS  Google Scholar 

  11. Tan ZP et al (2011) Novel ZFPM2/FOG2 variants in patients with double outlet right ventricle. Clin Genet 82(5):466–471. doi:10.1111/j.1399-0004.2011.01787.x

    Article  PubMed  CAS  Google Scholar 

  12. Zhou P et al (2012) Regulation of GATA4 transcriptional activity in cardiovascular development and disease. Curr Top Dev Biol 100:143–169. doi:10.1016/B978-0-12-387786-4.00005-1

    Article  PubMed  CAS  Google Scholar 

  13. Svensson EC, Tufts RL et al (1999) Molecular cloning of FOG-2: a modulator of transcription factor GATA-4 in cardiomyocytes. Proc Natl Acad Sci USA 96(3):956–961

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Pincelli AI, Finelli P (2007) Disruption of friend of GATA 2 gene (FOG-2) by a de novo t(8;10) chromosomal translocation is associated with heart defects and gonadal dysgenesis. Clin Genet 71(3):195–204

    Article  PubMed  Google Scholar 

  15. De Luca A et al (2011) New mutations in ZFPM2/FOG2 gene in tetralogy of Fallot double outlet right ventricle. Clin Genet 80(2):184–190. doi:10.1111/j.1399-0004.2010.01523.x

    Article  PubMed  CAS  Google Scholar 

  16. Zhou B, Ma Q, Kong SW et al (2009) FOG2 is critical for cardiac function and maintenance of coronary vasculature in the adult mouse heart. J Clin Invest 119(6):1462–1476. doi:10.1172/JCI38723

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Tevosian SG et al (2000) FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium. Cell 101(7):729–739

    Article  PubMed  CAS  Google Scholar 

  18. Anttonen M, Ketola I et al (2003) FOG-2 and GATA-4 Are coexpressed in the mouse ovary and can modulate mullerian-inhibiting substance expression. Biol Reprod 68(4):1333–1340

    Article  PubMed  CAS  Google Scholar 

  19. Pizzuti A, Sarkozy A et al (2003) Mutations of ZFPM2/FOG2 gene in sporadic cases of tetralogy of fallot. Hum Mutat 22(5):372–377

    Article  PubMed  CAS  Google Scholar 

  20. Wilkinson JL, Anderson RH et al (1974) Morphogenesis of bulboventricular malformations. II. Observations on malformed hearts. Br Heart J 36(10):948–970

    Article  PubMed Central  PubMed  Google Scholar 

  21. Wilkinson JL, Anderson RH et al (1974) Morphogenesis of bulboventricular malformations. I. Consideration of embryogenesis in the normal heart. Br Heart J 36(3):242–255

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This project was supported by Shanghai Municipal of Health Bureau (2007149). We thank all patients for participating in this study. We thank professor Jian-Qing Ding for critical suggestions. We thank the lab of Neurodegenerative Diseases in the Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine for the technical support.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The authors declared that the experiments comply with the current laws of the country.

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Authors and Affiliations

  1. Heart Center, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road 1678, Shanghai, 200127, China

    Xiaomin Huang, Chunxia Zhou, Zhiwei Xu, Jinfen Liu, Zhaokang Su, Wenxiang Ding & Haibo Zhang

  2. State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Wenquan Niu

  3. Shanghai Pediatric Congenital Heart Disease Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Zhen Zhang

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  1. Xiaomin Huang
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  2. Wenquan Niu
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  3. Zhen Zhang
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  4. Chunxia Zhou
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  5. Zhiwei Xu
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  6. Jinfen Liu
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  7. Zhaokang Su
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  8. Wenxiang Ding
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  9. Haibo Zhang
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Corresponding author

Correspondence to Haibo Zhang.

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Huang, X., Niu, W., Zhang, Z. et al. Identification of novel significant variants of ZFPM2/FOG2 in non-syndromic tetralogy of fallot and double outlet right ventricle in a Chinese Han population. Mol Biol Rep 41, 2671–2677 (2014). https://doi.org/10.1007/s11033-014-3126-5

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  • DOI: https://doi.org/10.1007/s11033-014-3126-5

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