GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: GATA4 mutations segregate with familial cardiac septal defects.
Figure 2: Functional deficits associated with Gata4 mutations.
Figure 3: The Gata4 interaction with TBX5 is specifically disrupted by the Gata4 mG295S mutation.
Figure 4: Disrupted interaction of human TBX5 mutant proteins with Gata4 and Nkx2-5.

References

  1. 1

    Hoffman, J. I. E. Incidence of congenital heart disease: I. Postnatal incidence. Pediatr. Cardiol. 16, 103–113 (1995)

    CAS  Article  Google Scholar 

  2. 2

    Schott, J. J. et al. Congenital heart disease caused by mutations in the transcription factor NKX2–5. Science 281, 108–111 (1998)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Srivastava, D. & Olson, E. N. A genetic blueprint for cardiac development. Nature 407, 221–226 (2000)

    CAS  Article  Google Scholar 

  4. 4

    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)

    CAS  Article  Google Scholar 

  5. 5

    Kuo, C. T. et al. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev. 11, 1048–1060 (1997)

    CAS  Article  Google Scholar 

  6. 6

    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)

    CAS  PubMed  Google Scholar 

  7. 7

    Reiter, J. F. et al. Gata5 is required for the development of the heart and endoderm in zebrafish. Genes Dev. 13, 2983–2995 (1999)

    CAS  Article  PubMed Central  Google Scholar 

  8. 8

    Basson, C. T. et al. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nature Genet. 15, 30–35 (1997)

    CAS  Article  Google Scholar 

  9. 9

    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)

    Article  Google Scholar 

  10. 10

    Frischmeyer, P. A. et al. An mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science 295, 2258–2261 (2002)

    ADS  CAS  Article  PubMed Central  Google Scholar 

  11. 11

    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)

    CAS  Article  Google Scholar 

  12. 12

    Evans, T. & Felsenfeld, G. The erythroid-specific transcription factor Eryf1: a new finger protein. Cell 58, 877–885 (1989)

    CAS  Article  Google Scholar 

  13. 13

    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)

    ADS  CAS  Article  PubMed Central  Google Scholar 

  14. 14

    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)

    CAS  Article  PubMed Central  Google Scholar 

  15. 15

    Nichols, K. E. et al. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nature Genet. 24, 266–270 (2000)

    CAS  Article  Google Scholar 

  16. 16

    Van Esch, H. et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature 406, 419–422 (2000)

    ADS  CAS  Article  Google Scholar 

  17. 17

    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)

    CAS  Article  Google Scholar 

  18. 18

    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)

    CAS  Article  PubMed Central  Google Scholar 

  19. 19

    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)

    CAS  Article  Google Scholar 

  20. 20

    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)

    CAS  Article  Google Scholar 

  21. 21

    McFadden, D. G. et al. A GATA-dependent right ventricular enhancer controls dHAND transcription in the developing heart. Development 127, 5331–5341 (2000)

    CAS  PubMed  Google Scholar 

  22. 22

    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)

    CAS  Article  PubMed Central  Google Scholar 

  23. 23

    Hiroi, Y. et al. Tbx5 associates with Nkx2–5 and synergistically promotes cardiomyocyte differentiation. Nature Genet. 28, 276–280 (2001)

    CAS  Article  Google Scholar 

  24. 24

    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)

    CAS  Article  Google Scholar 

  25. 25

    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)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Cross, S. J. et al. The mutation spectrum in Holt-Oram syndrome. J. Med. Genet. 37, 785–787 (2000)

    CAS  Article  PubMed Central  Google Scholar 

  27. 27

    Yang, J. et al. Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome. Am. J. Med. Genet. 92, 237–240 (2000)

    CAS  Article  Google Scholar 

  28. 28

    Garcia, C. K. et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 292, 1394–1398 (2001)

    ADS  CAS  Article  Google Scholar 

  29. 29

    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)

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    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)

    CAS  Article  PubMed Central  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Vidu Garg or Deepak Srivastava.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing