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In silico analysis of GATA4 variants demonstrates main contribution to congenital heart disease.

ABSTRACT: Introduction: Congenital heart disease (CHD) is the most common congenital abnormality and the main cause of infant mortality worldwide. Some of the mutations that occur in the GATA4 gene region may result in different types of CHD. Here, we report our in silico analysis of gene variants to determine the effects of the GATA4 gene on the development of CHD. Methods: Online 1000 Genomes Project, ExAC, gnomAD, GO-ESP, TOPMed, Iranome, GME, ClinVar, and HGMD databases were drawn upon to collect information on all the reported GATA4 variations.The functional importance of the genetic variants was assessed by using SIFT, MutationTaster, CADD,PolyPhen-2, PROVEAN, and GERP prediction tools. Thereafter, network analysis of the GATA4protein via STRING, normal/mutant protein structure prediction via HOPE and I-TASSER, and phylogenetic assessment of the GATA4 sequence alignment via ClustalW were performed. Results: The most frequent variant was c.874T>C (45.58%), which was reported in Germany.Ventricular septal defect was the most frequent type of CHD. Out of all the reported variants of GATA4,38 variants were pathogenic. A high level of pathogenicity was shown for p.Gly221Arg (CADD score=31), which was further analyzed. Conclusion: The GATA4 gene plays a significant role in CHD; we, therefore, suggest that it be accorded priority in CHD genetic screening.

SUBMITTER: Abbasi S

PROVIDER: S-EPMC8749364 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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In silico analysis of GATA4 variants demonstrates main contribution to congenital heart disease.

Abbasi Shiva S Mohsen-Pour Neda N Naderi Niloofar N Rahimi Shahin S Maleki Majid M Kalayinia Samira S

Journal of cardiovascular and thoracic research 20211101 4

Introduction: Congenital heart disease (CHD) is the most common congenital abnormality and the main cause of infant mortality worldwide. Some of the mutations that occur in the GATA4 gene region may result in different types of CHD. Here, we report our in silico analysis of gene variants to determine the effects of the GATA4 gene on the development of CHD. Methods: Online 1000 Genomes Project, ExAC, gnomAD, GO-ESP, TOPMed, Iranome, GME, ClinVar, a ...[more]

PMID: 35047139

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Project 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.

Project description:Recent studies indicate that mammals, including humans, maintain some capacity to renew cardiomyocytes throughout postnatal life. Yet, there is little or no significant cardiac muscle regeneration after an injury such as acute myocardial infarction. By contrast, zebrafish efficiently regenerate lost cardiac muscle, providing a model for understanding how natural heart regeneration may be blocked or enhanced. In the absence of lineage-tracing technology applicable to adult zebrafish, the cellular origins of newly regenerated cardiac muscle have remained unclear. Using new genetic fate-mapping approaches, here we identify a population of cardiomyocytes that become activated after resection of the ventricular apex and contribute prominently to cardiac muscle regeneration. Through the use of a transgenic reporter strain, we found that cardiomyocytes throughout the subepicardial ventricular layer trigger expression of the embryonic cardiogenesis gene gata4 within a week of trauma, before expression localizes to proliferating cardiomyocytes surrounding and within the injury site. Cre-recombinase-based lineage-tracing of cells expressing gata4 before evident regeneration, or of cells expressing the contractile gene cmlc2 before injury, each labelled most cardiac muscle in the ensuing regenerate. By optical voltage mapping of surface myocardium in whole ventricles, we found that electrical conduction is re-established between existing and regenerated cardiomyocytes between 2 and 4 weeks post-injury. After injury and prolonged fibroblast growth factor receptor inhibition to arrest cardiac regeneration and enable scar formation, experimental release of the signalling block led to gata4 expression and morphological improvement of the injured ventricular wall without loss of scar tissue. Our results indicate that electrically coupled cardiac muscle regenerates after resection injury, primarily through activation and expansion of cardiomyocyte populations. These findings have implications for promoting regeneration of the injured human heart.

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In silico analysis of GATA4 variants demonstrates main contribution to congenital heart disease.

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<i>In silico</i> analysis of <i>GATA4</i> variants demonstrates main contribution to congenital heart disease.

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