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. 2010 Oct;68(4):281-5.
doi: 10.1203/PDR.0b013e3181ed17e4.

Identification of GATA6 sequence variants in patients with congenital heart defects

Meenakshi Maitra  1 , Sara N Koenig, Deepak Srivastava, Vidu Garg
Affiliations

"V体育2025版" Identification of GATA6 sequence variants in patients with congenital heart defects

Meenakshi Maitra et al. Pediatr Res. 2010 Oct.

Abstract

Although the etiology for the majority of congenital heart disease (CHD) remains poorly understood, the known genetic causes are often the result of mutations in cardiac developmental genes. GATA6 encodes for a cardiac transcription factor, which is broadly expressed in the developing heart and is critical for normal cardiac morphogenesis, making it a candidate gene for congenital heart defects in humans. The objective of this study was to determine the frequency of GATA6 sequence variants in a population of individuals with a spectrum of cardiac malformations. The coding regions of GATA6 were sequenced in 310 individuals with CHD. We identified two novel sequence variations in GATA6 that altered highly conserved amino acid residues (A178V and L198V) and were not found in a control population VSports手机版. These variants were identified in two individuals (one with tetralogy of Fallot and the other with an atrioventricular septal defect in the setting of complex CHD). Biochemical studies demonstrate that the GATA6 A178V mutant protein results in increased transactivation ability when compared with wild-type GATA6. These data suggest that nonsynonymous GATA6 sequence variants are infrequently found in individuals with CHD. .

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Figures

Figure 1
Figure 1. Expression of Gata6 in embryonic heart by radioactive section in situ hybridization
(a–f) Coronal sections of E13.5 mouse hearts. (b) Gata6 transcripts are highly expressed in the developing atrioventricular valve leaflets (arrowhead) along with lower levels of expression in the atrial and ventricular myocardium. (d and f) Sections through the cardiac outflow tract demonstrate the strongest expression in the smooth muscle surrounding the aorta and pulmonary artery (arrows) in addition to expression in the chamber myocardium. Corresponding bright field images for (b, d and f) are shown in (a, c, e). right atrium (ra); right ventricle (rv); left atrium (la); left ventricle (lv); aorta (ao); pulmonary artery (pa); and right ventricle.
Figure 2
Figure 2. Novel GATA6 sequence variations alter highly conserved amino acids
(a) Sequence chromatogram showing heterozygous C to T transition in affected subject as compared to control individual. The nucleotide variation predicts a non-synonymous amino acid substitution at codon 178 (A178V). (b) Sequence chromatogram showing heterozygous C to G transversion that predicts a valine at codon 198 in affected subject as compared to control. (c) Alignment of human GATA6 protein sequence with orthologues from multiple species. The alanine and leucine at codons 178 and 198, respectively, are highly conserved. Location of A178V and L198V is indicated by (*) and (§), respectively.
Figure 3
Figure 3. In vitro functional analysis of Gata6 sequence variations
Transactivation assays in HeLa cells transfected with 300 ng of GATA6 A178V or GATA6 L198V along with co-transfection of either αMHC-luciferase (□) or ANF-luciferase reporter (■). Over two-fold increased luciferase activation was found with the GATA6 A178V mutant on both luciferase reporters. No significant difference was demonstrated with transfection of the GATA6 L198V mutant plasmid. Experiments were performed in triplicate and mean and standard deviations are shown. *, p value < 0.05.
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References

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