Cardiovascular System ; GATA4 Transcription Factor ; metabolism ; Humans

Gata4 is an important transcription factor in heart development. Gata4 post-transcriptional protein modification regulates transcriptional activity and DNA binding, which in turn affects expression of downstream genes and transcription factors, differentiation of embryonic stem cells and cardiogenesis. This article summarizes the effect of post-transcriptional protein modification on transcriptional activity of Gata4 and the relationship between this effect and congenital heart disease. It was shown that acetylation, phosphorylation and SUMOylation upregulate transcriptional activity, DNA binding, downstream gene expression and embryonic stem cell differentiation. On the other hand, methylation and deacetylation downregulate Gata4 transcriptional activity. Post-transcriptional protein modification of Gata4 is very important in clinical research on congenital and other heart diseases.
Acetylation ; Animals ; GATA4 Transcription Factor ; chemistry ; genetics ; metabolism ; Humans ; Methylation ; Phosphorylation ; Protein Processing, Post-Translational ; Sumoylation

The GATA family proteins are a group of zinc finger transcription factors that are expressed in human and mammalian animals and play an important role in mammalian organ morphogenesis, cell proliferation and sex differentiation. GATA-4 and GATA-6 have been identified in the ovaries and testes of humans, mice, pigs and chickens. GATA-4 contributes to fetal male gonadal development by regulating the genes that mediate Müllerian duct regression and the onset of testosterone production. GATA-4 and GATA-6 are localized in and regulate the function of the ovarian and testicular somatic cells of fetal mice, especially granulosa cells, thecal cells, Sertoli cells and Leydig cells. GATA-4 is also present in the germ cells of fetal and prepubertal mice.
Animals ; Chickens ; Female ; GATA4 Transcription Factor ; metabolism ; GATA6 Transcription Factor ; metabolism ; Humans ; Male ; Mice ; Ovary ; embryology ; Reproduction ; Swine ; Testis ; embryology ; Transcription Factors ; classification

OBJECTIVETo identify the genetic defects in patients with congenital atrial septal defects (ASD).

METHODSThe clinical data and blood samples from 180 unrelated subjects with congenital ASD were collected and evaluated. Two hundred healthy individuals served as controls. The coding exons and the flanking introns of GATA4 gene were amplified by polymerase chain reaction and sequenced using the di-deoxynucleotide chain termination approach. The acquired sequences were aligned with the sequences publicized in GenBank by the aid of programme BLAST to identify the sequence variations. Clustal W software was applied for analysis of the conservation of altered amino acids.

RESULTSTwo novel heterozygous missense GATA4 mutations were identified in 2 out of 180 ASD patients. Namely, the triplet substitutions of GTC for GGC at codon 21 and TCG for CCG at codon 87 were detected, predicting the conversions of glycine into valine at amino acid residue 21 (G21V) and proline into serine at amino acid residue 87 (P87S). None of the two mutations were detected in 200 healthy controls. Across-species alignment of GATA4 encoded protein sequences displayed that the mutated amino acids were highly conserved evolutionarily. Additionally, a single nucleotide polymorphism c.99G>T was observed. However, the polymorphic frequency distribution in ASD cases was similar with that in healthy controls (for genotype GT, χ(2) = 0.7556, P = 0.3847; for allele T, χ(2) = 0.7235, P = 0.3950).

CONCLUSIONSTwo novel mutations of GATA4 gene are identified in two unrelated ASD patients. This finding provides new insight into the molecular etiology responsible for ASD.

Case-Control Studies ; Child, Preschool ; DNA Mutational Analysis ; GATA4 Transcription Factor ; genetics ; Genome ; Heart Septal Defects, Atrial ; genetics ; Humans ; Mutation

OBJECTIVE: To explore the correlation between DSG2, TTN and GATA4 genes and Brugada syndrome in Henan Province of China. METHODS: From February 2017 to February 2019, 100 patients with Brugada syndrome and 100 healthy individuals were selected as the study and the control groups, respectively. Electrocardiogram and echocardiography were carried out, and peripheral blood samples was collected. Coding regions of DSG2, TTN and GATA4 genes were amplified by PCR and sequenced. The results were compared with standard sequences from GenBank. RESULTS: Electrocardiogram showed that all patients from the study group had ventricular arrhythmia, 87 cases (87%) presented ventricular tachycardia (VT), 84 cases (84%) presented T wave inversion, and 51 cases (51%) presented Epsilon wave. Echocardiography showed that the right ventricle in the study group was enlarged with the inner diameter of the right ventricle being (40.0±13.3) mm, and the right ventricle showed various degree of abnormal systolic function. The enlargement of right atrium accounted for 64%, and the involvement of the left ventricle accounted for 27%. The right ventricular diameter and left ventricular diastolic diameter of the study group were significantly greater than those of the control group (P< 0.05). DNA sequencing showed that 60 patients carried DSG2 gene variants, among which 18 had missense variant of exon 8. Fifty patients carried TTN gene variants, including 8 in the A-band domain and 3 in the I-band domain. Twenty patients carried 3 variants of the GATA4 gene. CONCLUSION Variants of the DSG2, TTN and GATA4 genes in Henan region are correlated with the onset of Brugada syndrome.
Arrhythmogenic Right Ventricular Dysplasia ; Brugada Syndrome/genetics* ; China ; Connectin ; Desmoglein 2/genetics* ; GATA4 Transcription Factor ; Humans ; Pedigree ; Sequence Analysis, DNA

OBJECTIVETo investigate the role of GATA4 gene in the endocardial cushions development.

METHODSTarget gene eukaryote expression vectors were constructed by pcDNA3.1(-) vector plasmid, and were identified by DNA sequence analysis. Recombinant plasmids were transfected into Hela cells with lipofectamine 2000, meanwhile Hela cells transfected with empty vector or those without transfection served as transfection control group and blank control group, respectively. Real-time PCR and Western blot were performed to detect the relative expression of mRNA and protein of transcription factors GATA4, Sox9, Scleraxis and ECM proteins Aggrecan, Tenascin in each group.

RESULTSThe relative mRNA expression of GATA4 in experimental group was significantly higher than in transfection control group and blank control group. GATA4 mRNA expression in Hela(GATA4), Hela(H436Y), Hela(Null) and Hela group was 310.83 ± 2.39, 146.35 ± 1.74, 0.94 ± 0.32, 1.00 ± 0.28, respectively (F = 72.508, P < 0.05). Western blot results were consistent with the results obtained by qRT-PCR. The relative mRNA and protein expressions of Sox9, Scleraxis, Aggrecan and Tenascin in both experimental groups were significantly higher than that in transfection control group and blank control group (P < 0.05), and above gene expressions were significantly downregulated in GATA4(H436Y) group, while they were similar between transfection control group and blank control group (all P > 0.05).

CONCLUSIONSGATA4 H436Y mutation reduces it's transcriptional activation, which might serve as a theoretical framework to demonstrate the roles of GATA4 gene in endocardial cushion development.

Aggrecans ; metabolism ; Basic Helix-Loop-Helix Transcription Factors ; metabolism ; Down-Regulation ; Endocardial Cushions ; embryology ; GATA4 Transcription Factor ; genetics ; metabolism ; Gene Expression ; Genetic Vectors ; HeLa Cells ; Humans ; RNA, Messenger ; SOX9 Transcription Factor ; metabolism ; Tenascin ; metabolism ; Transfection

OBJECTIVETo explore the characteristics and distribution of GATA-4 in the testis of male mice.

METHODSParaffin sections were obtained from the testes of 24 male B6SJLF1/J mice, aged 0 day (n = 6), 2 weeks (n = 6), 4 weeks (n = 6) and 6 weeks (n = 6), and the expressions of GATA-4 in the testis were observed by the immunohistochemical ABC method and DAB visualization at different times.

RESULTSPositive expressions of GATA4 were found in the Sertoli cells and Leydig cells of all the mice, but significantly higher in the 4- and 6-week-old than in the 0-day and 2-week-old groups (P < 0.01). And they were also observed in the germ cells of the 4- and 6-week-old mice, significantly higher in the latter than in the former (P < 0.01).

CONCLUSIONGATA-4 exists in the testis of male mice, which has provided a morphological base for sex determination and differentiation and hormone regulation in the testis.

Animals ; Cell Differentiation ; GATA4 Transcription Factor ; metabolism ; Germ Cells ; metabolism ; Leydig Cells ; metabolism ; Male ; Mice ; Sertoli Cells ; metabolism ; Testis ; cytology ; metabolism

OBJECTIVETo screen the gene GATA4 for novel mutations associated with congenital atrial septal defect (ASD).

METHODSThe clinical data and peripheral venous blood specimen from 85 unrelated subjects with congenital ASD were collected and analyzed in contrast to 200 healthy individuals. The coding exons and the exon/intron boundaries of GATA4 gene were amplified by polymerase chain reaction and sequenced using the di-deoxynucleotide chain termination procedure. The obtained sequences were aligned with those publicized in GenBank with the help of programme BLAST to identify the sequence variations. The software Clustal W was applied to analysis of the conservation of altered amino acids.

RESULTSThree novel heterozygous missense GATA4 mutations were identified in 3 of 85 ASD patients, respectively. Namely, the triplet substitutions of ATG for GTG at codon 267, GCC for ACC at codon 354, and CAA for CCA at codon 407, predicting the conversions of valine into methionine at amino acid residue 267 (V267M), threonine into alanine at amino acid residue 354 (T354A), and proline into glutamine at amino acid residue 407 (P407Q), were identified. No mutation was detected in 200 healthy controls. A cross-species alignment of GATA4 encoded protein sequences showed that the valine at amino acid residue 267 and proline at amino acid residue 407 were completely conserved evolutionarily.

CONCLUSIONThree novel heterozygous missense GATA4 mutations were identified in patients with congenital ASD, which reveals new molecular etiology responsible for ASD, and contributes to the early prophylaxis and therapy for ASD.

Base Sequence ; Case-Control Studies ; DNA Mutational Analysis ; GATA4 Transcription Factor ; genetics ; Genetic Testing ; Heart Septal Defects, Atrial ; genetics ; Humans ; Mutation, Missense

Bone Morphogenetic Protein 4 ; genetics ; Cell Adhesion Molecules ; genetics ; Extracellular Matrix Proteins ; genetics ; GATA4 Transcription Factor ; genetics ; Heart Septal Defects, Atrial ; genetics ; Heart Septal Defects, Ventricular ; genetics ; Humans

Disorder of Sex Development, 46,XY/genetics* ; GATA4 Transcription Factor/genetics* ; Genetic Testing ; Heart Defects, Congenital ; Humans ; Male ; Molecular Structure ; Mutation/genetics*