GATA4 Loss-of-Function Mutation and the Congenitally Bicuspid Aortic Valve.

Aggregating evidence suggests that genetic determinants play a pivotal role in the pathogenesis of the congenitally bicuspid aortic valve (BAV). BAV is of pronounced genetic heterogeneity, and the genetic components underlying BAV in an overwhelming majority of patients remain elusive. In the current study, the whole coding exons and adjacent introns, as well as 5' and 3' untranslated regions of the GATA4 gene, which codes for a zinc-finger transcription factor crucial for the normal development of the aortic valve, were screened by direct sequencing in 150 index patients with congenital BAV. The available family members of an identified mutation carrier and 300 unrelated, ethnically matched healthy individuals used as controls were also genotyped for GATA4. The functional effect of the mutation was characterized using a dual-luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.E147X, was identified in a family with BAV transmitted in an autosomal dominant pattern. The nonsense mutation was absent in 600 control chromosomes. Functional deciphers revealed that the mutant GATA4 protein lost transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation disrupted the synergistic transcriptional activation between GATA4 and NKX2.5, another transcription factor responsible for BAV. In conclusion, this study associates the GATA4 loss-of-function mutation with enhanced susceptibility to a BAV, thus providing novel insight into the molecular mechanism underpinning the BAV.