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Congenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits In Vivo

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....

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Autores principales: Misra, Chaitali, Sachan, Nita, McNally, Caryn Rothrock, Koenig, Sara N., Nichols, Haley A., Guggilam, Anuradha, Lucchesi, Pamela A., Pu, William T., Srivastava, Deepak, Garg, Vidu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349729/
https://www.ncbi.nlm.nih.gov/pubmed/22589735
http://dx.doi.org/10.1371/journal.pgen.1002690
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author Misra, Chaitali
Sachan, Nita
McNally, Caryn Rothrock
Koenig, Sara N.
Nichols, Haley A.
Guggilam, Anuradha
Lucchesi, Pamela A.
Pu, William T.
Srivastava, Deepak
Garg, Vidu
author_facet Misra, Chaitali
Sachan, Nita
McNally, Caryn Rothrock
Koenig, Sara N.
Nichols, Haley A.
Guggilam, Anuradha
Lucchesi, Pamela A.
Pu, William T.
Srivastava, Deepak
Garg, Vidu
author_sort Misra, Chaitali
collection PubMed
description 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.
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spelling pubmed-33497292012-05-15 Congenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits In Vivo Misra, Chaitali Sachan, Nita McNally, Caryn Rothrock Koenig, Sara N. Nichols, Haley A. Guggilam, Anuradha Lucchesi, Pamela A. Pu, William T. Srivastava, Deepak Garg, Vidu PLoS Genet Research Article 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. Public Library of Science 2012-05-10 /pmc/articles/PMC3349729/ /pubmed/22589735 http://dx.doi.org/10.1371/journal.pgen.1002690 Text en Misra et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Misra, Chaitali
Sachan, Nita
McNally, Caryn Rothrock
Koenig, Sara N.
Nichols, Haley A.
Guggilam, Anuradha
Lucchesi, Pamela A.
Pu, William T.
Srivastava, Deepak
Garg, Vidu
Congenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits In Vivo
title Congenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits In Vivo
title_full Congenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits In Vivo
title_fullStr Congenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits In Vivo
title_full_unstemmed Congenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits In Vivo
title_short Congenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits In Vivo
title_sort congenital heart disease–causing gata4 mutation displays functional deficits in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349729/
https://www.ncbi.nlm.nih.gov/pubmed/22589735
http://dx.doi.org/10.1371/journal.pgen.1002690
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