Abstract
Congenital heart defects (CHDs) are the most common developmental anomaly and are the leading non-infectious cause of mortality in newborns1. Only one causative gene, NKX2-5, has been identified through genetic linkage analysis of pedigrees with non-syndromic CHDs2,3. Here, we show that isolated cardiac septal defects in a large pedigree were linked to chromosome 8p22-23. A heterozygous G296S missense mutation of GATA4, a transcription factor essential for heart formation4,5,6,7, was found in all available affected family members but not in any control individuals. This mutation resulted in diminished DNA-binding affinity and transcriptional activity of Gata4. Furthermore, the Gata4 mutation abrogated a physical interaction between Gata4 and TBX5, a T-box protein responsible for a subset of syndromic cardiac septal defects8,9. Conversely, interaction of Gata4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects. In a second family, we identified a frame-shift mutation of GATA4 (E359del) that was transcriptionally inactive and segregated with cardiac septal defects. These results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5.
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References
Hoffman, J. I. E. Incidence of congenital heart disease: I. Postnatal incidence. Pediatr. Cardiol. 16, 103–113 (1995)
Schott, J. J. et al. Congenital heart disease caused by mutations in the transcription factor NKX2–5. Science 281, 108–111 (1998)
Srivastava, D. & Olson, E. N. A genetic blueprint for cardiac development. Nature 407, 221–226 (2000)
Molkentin, J. D., Lin, Q., Duncan, S. A. & Olson, E. N. Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev. 11, 1061–1072 (1997)
Kuo, C. T. et al. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev. 11, 1048–1060 (1997)
Gajewski, K., Fossett, N., Molkentin, J. D. & Schulz, R. A. The zinc finger proteins Pannier and GATA4 function as cardiogenic factors in Drosophila. Development 126, 5679–5688 (1999)
Reiter, J. F. et al. Gata5 is required for the development of the heart and endoderm in zebrafish. Genes Dev. 13, 2983–2995 (1999)
Basson, C. T. et al. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nature Genet. 15, 30–35 (1997)
Li, Q. Y. et al. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nature Genet. 15, 21–29 (1997)
Frischmeyer, P. A. et al. An mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science 295, 2258–2261 (2002)
Pehlivan, T. et al. GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. Am. J. Med. Genet. 83, 201–206 (1999)
Evans, T. & Felsenfeld, G. The erythroid-specific transcription factor Eryf1: a new finger protein. Cell 58, 877–885 (1989)
Tsai, S. F. et al. Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells. Nature 339, 446–451 (1989)
Arceci, R. J., King, A. A., Simon, M. C., Orkin, S. H. & Wilson, D. B. Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart. Mol. Cell. Biol. 13, 2235–2246 (1993)
Nichols, K. E. et al. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nature Genet. 24, 266–270 (2000)
Van Esch, H. et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature 406, 419–422 (2000)
Molkentin, J. D. The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J. Biol. Chem. 275, 38949–38952 (2000)
Molkentin, J. D., Kalvakolanu, D. V. & Markham, B. E. Transcription factor GATA-4 regulates cardiac muscle-specific expression of the alpha-myosin heavy-chain gene. Mol. Cell. Biol. 14, 4947–4957 (1994)
Sprenkle, A. B., Murray, S. F. & Glembotski, C. C. 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)
Morrisey, E. E., Ip, H. S., Tang, Z. & Parmacek, M. S. GATA-4 activates transcription via two novel domains that are conserved within the GATA-4/5/6 subfamily. J. Biol. Chem. 272, 8515–8524 (1997)
McFadden, D. G. et al. A GATA-dependent right ventricular enhancer controls dHAND transcription in the developing heart. Development 127, 5331–5341 (2000)
Durocher, D., Charron, F., Warren, R., Schwartz, R. J. & Nemer, M. The cardiac transcription factors Nkx2–5 and GATA-4 are mutual cofactors. EMBO J. 16, 5687–5696 (1997)
Hiroi, Y. et al. Tbx5 associates with Nkx2–5 and synergistically promotes cardiomyocyte differentiation. Nature Genet. 28, 276–280 (2001)
Bruneau, B. G. et al. A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell 106, 709–721 (2001)
Basson, C. T. et al. Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc. Natl Acad. Sci. USA 96, 2919–2924 (1999)
Cross, S. J. et al. The mutation spectrum in Holt-Oram syndrome. J. Med. Genet. 37, 785–787 (2000)
Yang, J. et al. Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome. Am. J. Med. Genet. 92, 237–240 (2000)
Garcia, C. K. et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 292, 1394–1398 (2001)
Kruglyak, L., Daly, M. J., Reeve-Daly, M. P. & Lander, E. S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347–1363 (1996)
Yamagishi, H. et al. Tbx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer. Genes Dev. 17, 269–281 (2003)
Acknowledgements
The authors thank both families for their participation; McDermott Center for Human Growth and Development for assistance with linkage analysis and sequencing; the Divisions of Pediatric Cardiology and Pediatric Cardiothoracic Surgery at Children's Medical Center of Dallas for assistance with clinical information and management; E. N. Olson and H. H. Hobbs for discussions and critical review of this manuscript; S. Johnson for graphic assistance; A. Garg for blood collection assistance; I. Komuro, R. J. Schwartz, S. R. Grant and E. N. Olson for plasmids; and S. Izumo for sharing unpublished data. This work was supported by a grant from NICHD/NIH to V.G.; grants from the NHLBI/NIH, March of Dimes Birth Defects Foundation, Smile Train Inc. and the Donald W. Reynolds Cardiovascular Clinical Research Center to D.S.; the NHLBI/NIH Programs for Genomic Applications to J.C.; and the Grant for the Promotion of the Advancement of Education and Research in Graduate Schools in Japan to R.M. I.N.K. is an NICHD/NIH fellow of the Pediatric Scientist Development Program. I.S.K. is a fellow of the NIH Medical Scientist Training Program.
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Garg, V., Kathiriya, I., Barnes, R. et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424, 443–447 (2003). https://doi.org/10.1038/nature01827
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DOI: https://doi.org/10.1038/nature01827
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