Congenital heart disease-causing Gata4 mutation displays functional deficits in vivo

Misra, C and Sachan, N and McNally, C R and Koenig, S N and Nichols, H and Guggilam, A and Lucchesi, P A and Pu, W T and Srivastava, D and Garg, V (2012) Congenital heart disease-causing Gata4 mutation displays functional deficits in vivo. PLoS Genetics, 8 (5).

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Abstract

Defects of atrial and ventricular septation are the most frequent form of congenital heart disease, accounting for almost 50 of all cases. We previously reported that a heterozygous G296S missense mutation of GATA4 caused atrial and ventricular septal defects and pulmonary valve stenosis in humans. GATA4 encodes a cardiac transcription factor, and when deleted in mice it results in cardiac bifida and lethality by embryonic day (E)9.5. In vitro, the mutant GATA4 protein has a reduced DNA binding affinity and transcriptional activity and abolishes a physical interaction with TBX5, a transcription factor critical for normal heart formation. To characterize the mutation in vivo, we generated mice harboring the same mutation, Gata4 G295S. Mice homozygous for the Gata4 G295S mutant allele have normal ventral body patterning and heart looping, but have a thin ventricular myocardium, single ventricular chamber, and lethality by E11.5. While heterozygous Gata4 G295S mutant mice are viable, a subset of these mice have semilunar valve stenosis and small defects of the atrial septum. Gene expression studies of homozygous mutant mice suggest the G295S protein can sufficiently activate downstream targets of Gata4 in the endoderm but not in the developing heart. Cardiomyocyte proliferation deficits and decreased cardiac expression of CCND2, a member of the cyclin family and a direct target of Gata4, were found in embryos both homozygous and heterozygous for the Gata4 G295S allele. To further define functions of the Gata4 G295S mutation in vivo, compound mutant mice were generated in which specific cell lineages harbored both the Gata4 G295S mutant and Gata4 null alleles. Examination of these mice demonstrated that the Gata4 G295S protein has functional deficits in early myocardial development. In summary, the Gata4 G295S mutation functions as a hypomorph in vivo and leads to defects in cardiomyocyte proliferation during embryogenesis, which may contribute to the development of congenital heart defects in humans. © 2012 Misra et al.

ISB Creators:
ISB CreatorsORCiD
Sachan, NUNSPECIFIED
Item Type: Article
Uncontrolled Keywords: cyclin D2; transcription factor GATA 4; Ccnd2 protein, mouse; cyclin D2; Gata4 protein, mouse; T box transcription factor; T-box transcription factor 5; transcription factor GATA 4; transcription factor TBX5
Subjects: Business and Management
Depositing User: Users 13 not found.
Date Deposited: 27 Nov 2014 16:51
Last Modified: 27 Nov 2014 16:51
URI: http://eprints.exchange.isb.edu/id/eprint/338
Publisher URL: http://dx.doi.org/10.1371/journal.pgen.1002690
Publisher OA policy: http://www.sherpa.ac.uk/romeo/issn/1553-7390/
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