These results indicated that this GATA4 mutation may not influence cellular localization in transfected cells, but may affect the affinity of the GATA‑binding site on HAND2 and decrease transcriptional activity, thus suggesting that the GATA4 mutation may be associated with the pathogenesis of CHD.
These findings indicate that the two rare variants of GATA4 might disturb its interaction with ZFPM2 and influence corresponding downstream gene activity, suggesting that the GATA4 variants may be associated with the pathogenesis of CHD.
Furthermore, the mutation abrogated the synergistic transcriptional activation between NR2F2 and GATA4, another core cardiac transcription factor associated with CHD.
To estimate the prevalence and pathogenic potential of GATA4 variants in our CHD cohort, we have screened 285 CHD cases along with 200 controls by Sanger sequencing and identified 9 genetic variants (c.23C>A; p.Ala8Asp, c.25G>A; p.Ala9Thr, c.223G>T; p.Ala75Ser, c.383A>T; p.Glu128Val, c.397A>T; p.Ser133Cys, c.682T>A; p.Trp228Arg, c.1064C>G; p.Thr355Ser, c.1073G>C; p.Ser358Thr, and c.1220C>A; p.Pro407Gln) in 22 unrelated CHD probands (frequency:7.72%).
The mutations in GATA4 gene induce inherited atrial and ventricular septation defects, which is the most frequent forms of congenital heart defects (CHDs) constituting about half of all cases.
Furthermore, the mutation reduced the synergistic activation between TBX20 and NKX2.5 as well as GATA4, two other transcriptional factors previously associated with various CHD, encompassing TOF.
These results suggested that the early high expression of BRG1 in fetal hearts maintained normal cardiac development and that the abnormal hypomethylation and decreased expression of BRG1 in human hearts probably affect the expression of GATA4, which affects the pathogenesis of CHD.
Furthermore, the mutation significantly diminished the synergistic activation between MEF2C and GATA4, another cardiac core transcription factor that has been causally linked to CHD.
This study attempts to correlate the pattern of intronic variants of GATA4 gene which might provide new insights to unravel the possible molecular etiology of CHD.
However, subgroup analysis by types of CHD indicated that there was no significant association between GATA4 354 A>C mutation and the risk of ventricular septal defects.
Furthermore, the mutation markedly reduced the synergistic activation between HAND2 and GATA4 or NKX2.5, other two cardiac key transcription factors involved in the pathogenesis of CHD.
Variants in the GATA4 gene have been implicated in several congenital heart diseases (CHD), such as the tetralogy of Fallot (ToF), atrial septal defect (ASD), ventricular septal defect (VSD), atrioventricular septal defect (AVSD), and dilated cardiomyopathy (DCM).
In centromeric 8p23.1, microduplications including GATA4 can give rise to non-syndromic CHD but the clinical significance of two smaller centromeric microduplications without GATA4 was uncertain due to severe neurological profiles not usually found in 8p23.1 DS.
CNVs were studied using two multiplex ligation-dependent probe amplification (MLPA) kits, SALSA P250-B1® (DiGeorge gene region) and SALSA MLPA P311-A1® CHD-related gene regions (GATA4, NKX2-5, TBX5, BMP4, and CRELD1).
GATA4 plays an important role in embryonic heart development, hence the aim of this study was to find the association of GATA4 mutations with CHD among the south Indian CHD patients.
We confirmed the contribution to CHD of copy number changes in genes such as GATA4 and NODAL and identified several genes in novel recurrent CNVs that may point to novel CHD candidate loci.