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Am J Med Genet A. 2014 Nov;164A(11):2732-8. doi: 10.1002/ajmg.a.36703. Epub 2014 Aug 5.

A mutation in the Kozak sequence of GATA4 hampers translation in a family with atrial septal defects.

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Department of Anatomy, Embryology & Physiology, Academic Medical Center, Amsterdam, the Netherlands.


Atrial septal defect (ASD) is the most common congenital heart defect clinically characterized by an opening in the atrial septum. Mutations in GATA4, TBX5, and NKX2-5 underlie this phenotype. Here, we report on the identification of a novel -6 G>C mutation in the highly conserved Kozak sequence in the 5'UTR of GATA4 in a small family presenting with two different forms of ASD. This is the first time a mutation in the Kozak sequence has been linked to heart disease. Functional assays demonstrate reduced GATA4 translation, though the GATA4 transcript levels remain normal. This leads to a reduction of GATA4 protein level, consequently diminishing the ability of GATA4 to transactivate target genes, as demonstrated by using the GATA4-driven Nppa (ANF) promoter. In conclusion, we identified a mutation in the GATA4 Kozak sequence that likely contributes to the pathogenesis of ASD. In general, it points to the importance of accurate protein level regulation during heart development and emphasizes the need to analyze the entire transcribed region when screening for mutations.


GATA4 protein; Kozak sequence; atrial septal defects; congenital heart defects

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