Genetic analysis of the promoter region of the GATA4 gene in patients with ventricular septal defects

Wu, Guanghua; Shan, Jiping; Pang, Shuchao; Wei, Xiaodan; Zhang, Hao; Yan, Bo

doi:10.1016/j.trsl.2011.10.012

Cited by 19 publications

(12 citation statements)

References 53 publications

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“…Similar diversity of lesions was found in other studies done by Butler et al and Tomita-Mitchell et al (9,12). The study was limited to VSD cases only in the study by Wu et al (16) and septal defects as in the study done by Chen et al (14).…”

Section: Discussionsupporting

confidence: 75%

A novel mutation in exon 1 of GATA4 in Egyptian patients with congenital heart disease

et al. 2017

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Background/aim: Congenital heart disease (CHD) is a common birth defect. Many studies have reported GATA4 mutations in patients with CHD, mainly septal defects. This study aimed to investigate the GATA4 exon 1 mutation in Egyptian patients with isolated congenital heart defects as a possible causative mutation. Materials and methods:Screening for mutations or any sequence variations in exon 1 of the GATA4 gene was carried out by PCR amplification followed by direct sequencings in 165 Egyptian patients with different nonsyndromic congenital heart diseases and 93 controls who were matched in terms of age and sex. Thorough clinical assessments were done for all subjects, along with X-ray, 2D echocardiography, and Doppler examinations. Results:The most common CHD among our cases was isolated ventricular septal defect (VSD) in 47.3% (78/165), followed by isolated atrial septal defect. A novel nonsynonymous sequence variation in fragment 2 (P193H) of exon 1 of GATA4 was detected in 15 (9.1%) of the subjects with septal defects. This mutation was not seen in any of the control group subjects. Conclusion:There is a high prevalence of exon 1 GATA4 mutation (9.1%) in our study compared to other studies in different populations, which may correlate with different ethnic populations.

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Section: Discussionsupporting

confidence: 75%

A novel mutation in exon 1 of GATA4 in Egyptian patients with congenital heart disease

et al. 2017

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“…Interestingly though, the findings of published studies that used targeted gene panels or exome sequencing implicate that approximately 90% of sporadic CHD patients do not carry mutations in exon regions ( Blue et al, 2017 ), indicating that other causes including unknown pathogenic genes and variations in regulatory regions, should not be ignored. Indeed, mutations in the regulatory regions of cardiac genes can also cause several heart defects ( Pang et al, 2012 ; Smemo et al, 2012 ; Wu et al, 2012 ; Gu et al, 2017 ), such as the mutation rs118026695 within the promoter of NKX2.5 and the homozygous mutation in an enhancer, which is located approximately 90 kb downstream of TBX5. In this study, we found that an enhancer located 84 kb upstream of tnni1b was capable of mediating specific GFP expression in zebrafish hearts.…”

Section: Discussionmentioning

confidence: 99%

Tnni1b-ECR183-d2, an 87 bp cardiac enhancer of zebrafish

Zhang

Wang

et al. 2020

PeerJ

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Background Several heart malformations are associated with mutations in the regulatory regions of cardiac genes. Troponin I type 1b (tnni1b) is important for the formation of the atrioventricular canal in zebrafish hearts; however, the regulation of tnni1b is poorly understand. We aimed to identify a small but functional enhancer that is distal to tnni1b. Methods Evolutionary Conserved Region (ECR) Browser was used to analyze the 219 kb zebrafish and human genomes covering the tnni1b gene as well as the 100 kb regions upstream and downstream of tnni1b. Putative transcription factor binding sites (TFBSs) were analyzed using JASPAR and PROMO, and the enhancer activity was identified using zebrafish embryos and the luciferase reporter assay. A correlation analysis between the enhancer and transcription factors (TFs) was performed via TF overexpression and TFBS mutation experiments and the electrophoretic mobility shift assay (EMSA). To analyze the conservation between zebrafish and human enhancers, human DNA fragments were functionally verified. Images were captured and analyzed by fluorescence microscopy or confocal microscopy. Results Combined with comparative analysis and functional validation, we identified a 183 bp ECR (termed tnni1b-ECR183) that was located approximately 84 kb upstream of tnni1b that had the heart-specific enhancer activity in zebrafish. TFBS analysis and the enhancer activity detection assay data showed that the 87 bp core region (termed tnni1b-ECR183-d2) was capable of driving specific GFP expression near the atrioventricular junction and increased luciferase expression in HEK293 and HL1 cell lines. The GFP pattern in zebrafish embryos was similar to the expression profiles of tnni1b. A correlation analysis showed that the enhancer activity of tnni1b-ECR183-d2 was increased when NKX2.5 (p = 0.0006) or JUN (p < 0.0001) was overexpressed and was decreased when the TFBSs of NKX2.5 (p < 0.0001) or JUN (p = 0.0018) were mutated. In addition, DNA-protein interactions were not observed between these TFs and tnni1b-ECR183-d2 in the EMSA experiment. The conservation analysis showed that tnni1b-ECR183-h179 (aligned from tnni1b-ECR183) drove GFP expression in the heart and skeletal muscles and increased the luciferase expression after NKX2.5 (p < 0.0001), JUN (p < 0.0001) or ETS1 (p < 0.0001) was overexpressed. Interestingly, the truncated fragment tnni1b-ECR183-h84 mainly drove GFP expression in the skeletal muscles of zebrafish and the enhancer activity decreased when NKX2.5 (p = 0.0028), ETS1 (p = 0.0001) or GATA4 (p < 0.0001) was overexpressed. Conclusions An 87 bp cardiac-specific enhancer located 84 kb upstream of tnni1b in zebrafish was positively correlated with NKX2.5 or JUN. The zebrafish and human enhancers in this study target different tissues. The GFP expression mediated by tnni1b-ECR183-d2 is a valuable tool for marking the domain around the atrioventricular junction.

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“…This is, however, also a common limitation of other available programs. It is known that single base exchanges or small InDels in promoter regions may lead to altered gene expression and ultimately to disease (44,45). However, to our knowledge, there is so far no systematic study, which investigated where, within the promoter, disease mutations preferentially reside.…”

Section: Discussionmentioning

confidence: 99%

RegulationSpotter: annotation and interpretation of extratranscriptic DNA variants

Schwarz

Hombach

Köhler

et al. 2019

Nucleic Acids Research

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RegulationSpotter is a web-based tool for the user-friendly annotation and interpretation of DNA variants located outside of protein-coding transcripts (extratranscriptic variants). It is designed for clinicians and researchers who wish to assess the potential impact of the considerable number of non-coding variants found in Whole Genome Sequencing runs. It annotates individual variants with underlying regulatory features in an intuitive way by assessing over 100 genome-wide annotations. Additionally, it calculates a score, which reflects the regulatory potential of the variant region. Its dichotomous classifications, ‘functional’ or ‘non-functional’, and a human-readable presentation of the underlying evidence allow a biologically meaningful interpretation of the score. The output shows key aspects of every variant and allows rapid access to more detailed information about its possible role in gene regulation. RegulationSpotter can either analyse single variants or complete VCF files. Variants located within protein-coding transcripts are automatically assessed by MutationTaster as well as by RegulationSpotter to account for possible intragenic regulatory effects. RegulationSpotter offers the possibility of using phenotypic data to focus on known disease genes or genomic elements interacting with them. RegulationSpotter is freely available at https://www.regulationspotter.org.

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Genetic analysis of the promoter region of the GATA4 gene in patients with ventricular septal defects

Cited by 19 publications

References 53 publications

A novel mutation in exon 1 of GATA4 in Egyptian patients with congenital heart disease

A novel mutation in exon 1 of GATA4 in Egyptian patients with congenital heart disease

Tnni1b-ECR183-d2, an 87 bp cardiac enhancer of zebrafish

RegulationSpotter: annotation and interpretation of extratranscriptic DNA variants

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