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dc.contributor.authorMisra, Chaitali
dc.contributor.authorSachan, Nita
dc.contributor.authorMcNally, Caryn Rothrock
dc.contributor.authorKoenig, Sara N.
dc.contributor.authorNichols, Haley A.
dc.contributor.authorGuggilam, Anuradha
dc.contributor.authorLucchesi, Pamela A.
dc.contributor.authorPu, William T.
dc.contributor.authorSrivastava, Deepak
dc.contributor.authorGarg, Vidu
dc.date.accessioned2013-03-08T17:24:15Z
dc.date.issued2012
dc.identifier.citationMisra, Chaitali, Nita Sachan, Caryn Rothrock McNally, Sara N. Koenig, Haley A. Nichols, Anuradha Guggilam, Pamela A. Lucchesi, William T. Pu, Deepak Srivastava, and Vidu Garg. 2012. Congenital heart disease–causing Gata4 mutation displays functional deficits in vivo. PLoS Genetics 8(5): e1002690.en_US
dc.identifier.issn1553-7390en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10381369
dc.description.abstractDefects 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.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pgen.1002690en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349729/pdf/en_US
dash.licenseLAA
dc.subjectBiologyen_US
dc.subjectDevelopmental Biologyen_US
dc.subjectGeneticsen_US
dc.subjectModel Organismsen_US
dc.subjectMedicineen_US
dc.subjectPediatricsen_US
dc.subjectPediatric Cardiologyen_US
dc.titleCongenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits In Vivoen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Geneticsen_US
dash.depositing.authorPu, William T.
dc.date.available2013-03-08T17:24:15Z
dc.identifier.doi10.1371/journal.pgen.1002690*
dash.contributor.affiliatedPu, William


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