Genetic mutations in GATA4, a transcriptional factor, have been found to cause congenital heart
diseases. The underlying mechanism, however, remains largely unknown. We previously reported 7
heterozygous variants in patients with ventricular septal defects (VSD). Here we functionally characterized a de
novo mutation p.S335X and demonstrated that this mutation led to the pre-termination of its translation,
producing a truncated GATA4 lacking a conservative region at C-terminus. Truncated GATA4 did not disturb
its subcellular localization; however, it delayed the cardiomyocyte differentiation in P19cl6 model and
prohibited Bcl2 expression that led to apoptosis proved by fragmented genomic DNA and positive TUNEL
staining in H9C2 cells. By ChIP assay, we showed that GATA4 without C-terminus reduced its DNA binding
affinity and suppressed the expressions of its target genes. These findings suggest that C-terminus of GATA4
is critical to maintain DNA binding, and genetic mutations in this region may affect genes important for myocyte
apoptosis and differentiation associated with congenital heart defects.
Keywords: Apoptosis, DNA-binding, differentiation, GATA4, ventricular septal defect.
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