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Novel Point Mutations in 3′-Untranslated Region of GATA4 Gene Are Associated with Sporadic Non-syndromic Atrial and Ventricular Septal Defects

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Abstract

Objective

Transcription factor GATA4 has significant roles in embryonic heart development. Mutations of GATA4 appear to be responsible for a wide variety of congenital heart defects (CHD). Despite the high prevalence of GATA4 mutations in CHD phenotypes, extensive studies have not been performed. The 3′-untranslated region (3′-UTR) of the GATA4 gene comprises regulatory motifs and microRNA binding sites that are critical for the appropriate gene expression, nuclear transportation, and regulation of translation, and stability of mRNA. This study aimed to evaluate the association between mutations in the 3′-UTR of the GATA4 gene and CHD risk among Iranian patients.

Methods

We analyzed the coding region of exon 6 and the whole 3′-UTR of GATA4 in DNA isolated from 175 blood samples of CHD patients and 115 unrelated healthy individuals. The functional importance of the observed GATA4 mutations was evaluated using a variety of bioinformatics algorithms for assessment of nonsynonymous mutations and those observed in miRNA binding sites of 3′-UTR.

Results

Twenty-one point mutations including one missense mutation (c.511A>G: p.Ser377Gly) in exon 6 and 20 nucleotide variations in 3′-UTR of GATA4 gene were identified in 65 of the 175 CHD patients. In our patients, we identified 12 novel sequence alterations and 8 single nucleotide polymorphisms in the 3′-UTR of GATA4. Most of them had statistically significant differences between CHD patients and controls.

Conclusion

Our results suggest that 3′-UTR variations of the GATA4 gene probably change microRNA binding sites and present an additional molecular risk factor for the susceptibility of CHD.

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References

  1. Best KE, Rankin J. Long-Term Survival of Individuals Born With Congenital Heart Disease: A Systematic Review and Meta-Analysis. J Am Heart Assoc, 2016,5(6):e002846

    Article  PubMed  PubMed Central  Google Scholar 

  2. Triedman JK, Newburger JW. Trends in Congenital Heart Disease: The Next Decade. Circulation, 2016,133(25):2716–2733

    Article  PubMed  Google Scholar 

  3. Akhirome E, Walton NA, Nogee JM, et al. The Complex Genetic Basis of Congenital Heart Defects. Circ J, 2017,81(5):629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pierpont ME, Basson CT, Benson DW, Jr., et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation, 2007,115(23):3015–3038

    Article  PubMed  Google Scholar 

  5. Nashat H, Montanaro C, Li W, et al. Atrial septal defects and pulmonary arterial hypertension. J Thorac Dis, 2018,10(Suppl 24):S2953–S2965

    Article  PubMed  PubMed Central  Google Scholar 

  6. Vecoli C, Pulignani S, Foffa I, et al. Congenital heart disease: the crossroads of genetics, epigenetics and environment. Curr Genomics, 2014,15(5):390–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bruneau BG. Signaling and transcriptional networks in heart development and regeneration. Cold Spring Harb Perspect Biol, 2013,5(3):a008292

    Article  PubMed  PubMed Central  Google Scholar 

  8. Paige SL, Plonowska K, Xu A, et al. Molecular regulation of cardiomyocyte differentiation. Circ Res, 2015,116(2):341–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ma L, Wang J, Li L, et al. ISL1 loss-of-function mutation contributes to congenital heart defects. Heart Vessels, 2019,34(4):658–668

    Article  PubMed  Google Scholar 

  10. Wang Z, Song HM, Wang F, et al. A New ISL1 Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle. Int Heart J, 2019,60(5):1113–1122

    Article  CAS  PubMed  Google Scholar 

  11. Brand T. Heart development: molecular insights into cardiac specification and early morphogenesis. Dev Biol, 2003,258(1):1–19

    Article  CAS  PubMed  Google Scholar 

  12. Granados-Riveron JT, Pope M, Bu’lock FA, et al. Combined mutation screening of NKX2-5, GATA4, and TBX5 in congenital heart disease: multiple heterozygosity and novel mutations. Congenit Heart Dis, 2012,7(2):151–159

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhang Y, Sun YM, Xu YJ, et al. A New TBX5 Loss-of-Function Mutation Contributes to Congenital Heart Defect and Atrioventricular Block. Int Heart J, 2020,61(4):761–768

    Article  PubMed  Google Scholar 

  14. Schaan CW, Macedo ACP, Sbruzzi G, et al. Functional Capacity in Congenital Heart Disease: A Systematic Review and Meta-Analysis. Arq Bras Cardiol, 2017,109(4):357–367

    PubMed  PubMed Central  Google Scholar 

  15. Misra C, Sachan N, McNally CR, et al. Congenital heart disease-causing Gata4 mutation displays functional deficits in vivo. PLoS Genet, 2012,8(5):e1002690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang E, Sun S, Qiao B, et al. Identification of functional mutations in GATA4 in patients with congenital heart disease. PLoS One, 2013,8(4):e62138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yang YQ, Wang J, Liu XY, et al. Novel GATA4 mutations in patients with congenital ventricular septal defects. Med Sci Monit, 2012,18(6):CR344–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tomita-Mitchell A, Maslen CL, Morris CD, et al. GATA4 sequence variants in patients with congenital heart disease. J Med Genet, 2007,44(12):779–783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Khatami M, Mazidi M, Taher S, et al. Novel Point Mutations in the NKX2.5 Gene in Pediatric Patients with Non-Familial Congenital Heart Disease. Medicina (Kaunas), 2018,54(3):46

    Article  Google Scholar 

  20. Khatami M, Heidari MM, Kazeminasab F, et al. Identification of a novel non-sense mutation in TBX5 gene in pediatric patients with congenital heart defects. J Cardiovasc Thorac Res, 2018,10(1):41–45

    Article  PubMed  PubMed Central  Google Scholar 

  21. Dianatpour S, Khatami M, Heidari MM, et al. Novel Point Mutations of CITED2 Gene Are Associated with Non-familial Congenital Heart Disease (CHD) in Sporadic Pediatric Patients. Appl Biochem Biotechnol, 2019,190(3):896–906

    Article  PubMed  Google Scholar 

  22. Reamon-Buettner SM, Cho SH, Borlak J. Mutations in the 3′-untranslated region of GATA4 as molecular hotspots for congenital heart disease (CHD). BMC Med Genet, 2007,8:38

    Article  PubMed  PubMed Central  Google Scholar 

  23. Schwerk J, Savan R. Translating the Untranslated Region. J Immunol, 2015,195(7):2963–2971

    Article  CAS  PubMed  Google Scholar 

  24. Pulignani S, Vecoli C, Sabina S, et al. 3′UTR SNPs and Haplotypes in the GATA4 Gene Contribute to the Genetic Risk of Congenital Heart Disease. Rev Esp Cardiol (Engl Ed), 2016,69(8):760–765

    Article  Google Scholar 

  25. Qu L, Li X, Wu G, et al. Efficient and sensitive method of DNA silver staining in polyacrylamide gels. Electrophoresis, 2005,26(1):99–101

    Article  CAS  PubMed  Google Scholar 

  26. Lentjes MH, Niessen HE, Akiyama Y, et al. The emerging role of GATA transcription factors in development and disease. Expert Rev Mol Med, 2016,18:e3

    Article  PubMed  PubMed Central  Google Scholar 

  27. Valimaki MJ, Ruskoaho HJ. Targeting GATA4 for cardiac repair. IUBMB Life, 2020,72(1):68–79

    Article  PubMed  Google Scholar 

  28. Patient RK, McGhee JD. The GATA family (vertebrates and invertebrates). Curr Opin Genet Dev, 2002,12(4):416–422

    Article  CAS  PubMed  Google Scholar 

  29. Peterkin T, Gibson A, Loose M, et al. The roles of GATA-4, -5 and -6 in vertebrate heart development. Semin Cell Dev Biol, 2005,16(1):83–94

    Article  CAS  PubMed  Google Scholar 

  30. Mattapally S, Nizamuddin S, Murthy KS, et al. c.620C>T mutation in GATA4 is associated with congenital heart disease in South India. BMC Med Genet, 2015,16:7

    Article  PubMed  PubMed Central  Google Scholar 

  31. Okubo A, Miyoshi O, Baba K, et al. A novel GATA4 mutation completely segregated with atrial septal defect in a large Japanese family. J Med Genet, 2004,41(7):e97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rajagopal SK, Ma Q, Obler D, et al. Spectrum of heart disease associated with murine and human GATA4 mutation. J Mol Cell Cardiol, 2007,43(6):677–685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang J, Fang M, Liu XY, et al. A novel GATA4 mutation responsible for congenital ventricular septal defects. Int J Mol Med, 2011,28(4):557–564

    CAS  PubMed  Google Scholar 

  34. Garg V, Kathiriya IS, Barnes R, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature, 2003,424(6947):443–447

    Article  CAS  PubMed  Google Scholar 

  35. Al-Azzouny MA, El Ruby MO, Issa HA, et al. Detection and putative effect of GATA4 gene variants in patients with congenital cardiac septal defects. Cell Mol Biol (Noisy-le-grand), 2016,62(3):10–14

    CAS  Google Scholar 

  36. Bose D, D V, Shetty M, et al. Identification of intronic-splice site mutations in GATA4 gene in Indian patients with congenital heart disease. Mutat Res, 2017,803–805:26–34

    Article  PubMed  Google Scholar 

  37. Ciccacci C, Rufini S, Politi C, et al. Could MicroRNA polymorphisms influence warfarin dosing? A pharmacogenetics study on mir133 genes. Thromb Res, 2015,136(2):367–370

    Article  CAS  PubMed  Google Scholar 

  38. Chatterjee S, Pal JK. Role of 5′- and 3′-untranslated regions of mRNAs in human diseases. Biol Cell, 2009,101(5):251–262

    Article  CAS  PubMed  Google Scholar 

  39. Felekkis K, Touvana E, Stefanou C, et al. microRNAs: a newly described class of encoded molecules that play a role in health and disease. Hippokratia, 2010,14(4):236–240

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Moszynska A, Gebert M, Collawn JF, et al. SNPs in microRNA target sites and their potential role in human disease. Open Biol, 2017,7(4):170019

    Article  PubMed  PubMed Central  Google Scholar 

  41. Nury D, Chabanon H, Levadoux-Martin M, et al. An eleven nucleotide section of the 3′-untranslated region is required for perinuclear localization of rat metallothionein-1 mRNA. Biochem J, 2005,387(Pt 2):419–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sabina S, Pulignani S, Rizzo M, et al. Germline hereditary, somatic mutations and microRNAs targeting-SNPs in congenital heart defects. J Mol Cell Cardiol, 2013,60:84–89

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biology, Faculty of Science, Yazd University, Yazd, 8915818411, Iran

    Mehri Khatami, Sajedeh Ghorbani, Mojgan Rezaii Adriani, Sahar Bahaloo, Mehri Azami Naeini & Mohammad Mehdi Heidari

  2. Department of Cardiac Surgery, Afshar Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, 8915887856, Iran

    Mehdi Hadadzadeh

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  1. Mehri Khatami
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  2. Sajedeh Ghorbani
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  3. Mojgan Rezaii Adriani
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  7. Mehdi Hadadzadeh
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Correspondence to Mehri Khatami.

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Khatami, M., Ghorbani, S., Adriani, M.R. et al. Novel Point Mutations in 3′-Untranslated Region of GATA4 Gene Are Associated with Sporadic Non-syndromic Atrial and Ventricular Septal Defects. CURR MED SCI 42, 129–143 (2022). https://doi.org/10.1007/s11596-021-2428-9

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  • DOI: https://doi.org/10.1007/s11596-021-2428-9

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