Rare GATA5 Sequence Variants Identified in Individuals with Bicuspid Aortic Valve

Overview

Journal Pediatr Res

Specialties Biology
Pediatrics

Date 2014 May 7

PMID 24796370

Citations 44

Authors

Elizabeth M Bonachea

Sheng-Wei Chang

Gloria Zender

Stephanie LaHaye

Sara Fitzgerald-Butt

Kim L McBride

Vidu Garg

Affiliations

Soon will be listed here.

Abstract

Background: Bicuspid aortic valve (BAV) is the most common type of congenital heart disease (CHD) and has a proposed genetic etiology. BAV is categorized by cusp fusion, with right-left (R-L) cusp fusion being associated with additional CHD, and right-noncoronary cusp (R-NC) fusion being associated with aortic valve dysfunction. Loss of murine Gata5, which encodes a cardiac transcription factor, results in a partially penetrant R-NC BAV, and we hypothesize that mutations in GATA5 are associated with R-NC BAV in humans.

Methods: A cohort of 78 BAV patients (50 with isolated BAV and 28 with associated aortic coarctation) was analyzed using Sanger sequencing to identify GATA5 sequence variants. Biochemical assays were performed to identify functional deficits of identified sequence variants.

Results: We identified two rare heterozygous nonsynonymous variants, p.Gln3Arg and p.Leu233Pro, for a frequency of 2.6% (2/78). Both individuals with nonsynonymous variants had BAV and aortic coarctation, one R-L and one R-NC subtype. Of the nonsynonymous variants, only p.Gln3Arg demonstrated decreased transcriptional activity in vitro.

Conclusion: Rare sequence variants in GATA5 are associated with human BAV. Our findings suggest a genotype-phenotype correlation in regards to associated CHD but not cusp fusion.

Citing Articles

Whole-Exome Sequencing Identifies Novel GATA5/6 Variants in Right-Sided Congenital Heart Defects.

Zodanu G, Hwang J, Mudery J, Sisniega C, Kang X, Wang L Int J Mol Sci. 2025; 26(5).

PMID: 40076735 PMC: 11901071. DOI: 10.3390/ijms26052115.

Chromosomal Location and Identification of as a New Gene Responsible for Familial Bicuspid Aortic Valve.

Li Y, Zou S, Bian Y, Liu X, Yang C, Li L Diagnostics (Basel). 2025; 15(5).

PMID: 40075846 PMC: 11898536. DOI: 10.3390/diagnostics15050600.

Human Genetics of Semilunar Valve and Aortic Arch Anomalies.

Prapa M, Ho S Adv Exp Med Biol. 2024; 1441:761-775.

PMID: 38884747 DOI: 10.1007/978-3-031-44087-8_45.

Identification of congenital aortic valve malformations in juvenile natriuretic peptide receptor 2-deficient mice using high-frequency ultrasound.

Guruji V, Zhou Y, Tang M, Mirzaei Z, Ding Y, Elbatarny M Am J Physiol Heart Circ Physiol. 2024; 327(1):H56-H66.

PMID: 38758128 PMC: 11381018. DOI: 10.1152/ajpheart.00769.2023.

In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease.

Nappi F Int J Mol Sci. 2024; 25(3).

PMID: 38339013 PMC: 10855915. DOI: 10.3390/ijms25031734.

References

Wei D, Bao H, Zhou N, Zheng G, Liu X, Yang Y . GATA5 loss-of-function mutation responsible for the congenital ventriculoseptal defect. Pediatr Cardiol. 2012; 34(3):504-11. DOI: 10.1007/s00246-012-0482-6. View

Laforest B, Andelfinger G, Nemer M . Loss of Gata5 in mice leads to bicuspid aortic valve. J Clin Invest. 2011; 121(7):2876-87. PMC: 3223824. DOI: 10.1172/JCI44555. View

Mohamed S, Aherrahrou Z, Liptau H, Erasmi A, Hagemann C, Wrobel S . Novel missense mutations (p.T596M and p.P1797H) in NOTCH1 in patients with bicuspid aortic valve. Biochem Biophys Res Commun. 2006; 345(4):1460-5. DOI: 10.1016/j.bbrc.2006.05.046. View

Chen B, Yates E, Huang Y, Kogut P, Ma L, Turner J . Alternative promoter and GATA5 transcripts in mouse. Am J Physiol Gastrointest Liver Physiol. 2009; 297(6):G1214-22. PMC: 2850090. DOI: 10.1152/ajpgi.00165.2009. View

Garg V, Muth A, Ransom J, Schluterman M, Barnes R, King I . Mutations in NOTCH1 cause aortic valve disease. Nature. 2005; 437(7056):270-4. DOI: 10.1038/nature03940. View

Foffa I, Ait Ali L, Panesi P, Mariani M, Festa P, Botto N . Sequencing of NOTCH1, GATA5, TGFBR1 and TGFBR2 genes in familial cases of bicuspid aortic valve. BMC Med Genet. 2013; 14:44. PMC: 3637327. DOI: 10.1186/1471-2350-14-44. View

Martin L, Ramachandran V, Cripe L, Hinton R, Andelfinger G, Tabangin M . Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations. Hum Genet. 2007; 121(2):275-84. DOI: 10.1007/s00439-006-0316-9. View

Padang R, Bagnall R, Richmond D, Bannon P, Semsarian C . Rare non-synonymous variations in the transcriptional activation domains of GATA5 in bicuspid aortic valve disease. J Mol Cell Cardiol. 2012; 53(2):277-81. DOI: 10.1016/j.yjmcc.2012.05.009. View

Nemer G, Nemer M . Cooperative interaction between GATA5 and NF-ATc regulates endothelial-endocardial differentiation of cardiogenic cells. Development. 2002; 129(17):4045-55. DOI: 10.1242/dev.129.17.4045. View

10.

Andelfinger G, Tapper A, Welch R, Vanoye C, George Jr A, Benson D . KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet. 2002; 71(3):663-8. PMC: 379203. DOI: 10.1086/342360. View

11.

Molkentin J . The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem. 2000; 275(50):38949-52. DOI: 10.1074/jbc.R000029200. View

12.

Biben C, Weber R, Kesteven S, Stanley E, McDonald L, Elliott D . Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5. Circ Res. 2000; 87(10):888-95. DOI: 10.1161/01.res.87.10.888. View

13.

Maitra M, Koenig S, Srivastava D, Garg V . Identification of GATA6 sequence variants in patients with congenital heart defects. Pediatr Res. 2010; 68(4):281-5. PMC: 2940936. DOI: 10.1203/PDR.0b013e3181ed17e4. View

14.

Majumdar R, Yagubyan M, Sarkar G, Bolander M, Sundt 3rd T . Bicuspid aortic valve and ascending aortic aneurysm are not associated with germline or somatic homeobox NKX2-5 gene polymorphism in 19 patients. J Thorac Cardiovasc Surg. 2006; 131(6):1301-5. DOI: 10.1016/j.jtcvs.2006.01.039. View

15.

Emanuel R, Withers R, OBrien K, Ross P, Feizi O . Congenitally bicuspid aortic valves. Clinicogenetic study of 41 families. Br Heart J. 1978; 40(12):1402-7. PMC: 483586. DOI: 10.1136/hrt.40.12.1402. View

16.

Fernandes S, Sanders S, Khairy P, Jenkins K, Gauvreau K, Lang P . Morphology of bicuspid aortic valve in children and adolescents. J Am Coll Cardiol. 2004; 44(8):1648-51. DOI: 10.1016/j.jacc.2004.05.063. View

17.

Huntington K, Hunter A, Chan K . A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve. J Am Coll Cardiol. 1997; 30(7):1809-12. DOI: 10.1016/s0735-1097(97)00372-0. View

18.

Schluterman M, Krysiak A, Kathiriya I, Abate N, Chandalia M, Srivastava D . Screening and biochemical analysis of GATA4 sequence variations identified in patients with congenital heart disease. Am J Med Genet A. 2007; 143A(8):817-23. DOI: 10.1002/ajmg.a.31652. View

19.

Morrisey E, Ip H, Tang Z, Lu M, Parmacek M . GATA-5: a transcriptional activator expressed in a novel temporally and spatially-restricted pattern during embryonic development. Dev Biol. 1997; 183(1):21-36. DOI: 10.1006/dbio.1996.8485. View

20.

Abecasis G, Auton A, Brooks L, DePristo M, Durbin R, Handsaker R . An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422):56-65. PMC: 3498066. DOI: 10.1038/nature11632. View