A mutation in the Kozak sequence of GATA4 hampers translation in a family with atrial septal defects. Issue 11 (5th August 2014)

• Record Type: Journal Article
• Authors: Mohan, Rajiv A.; van Engelen, Klaartje; Stefanovic, Sonia; Barnett, Phil; Ilgun, Aho; Baars, Marieke J.H.; Bouma, Berto J.; Mulder, Barbara J.M.; Christoffels, Vincent M.; Postma, Alex V.
• Is Part Of: American journal of medical genetics. Volume 164:Issue 11(2014.)
• Page Start: 2732
• Page End: 2738
• Publication Date: 2014-08-05
• Subjects: Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.36703
• Languages: English
• ISSNs: 1552-4825

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ajmga36703-sec-0001" sec-type="section"> <p>Atrial septal defect (ASD) is the most common congenital heart defect clinically characterized by an opening in the atrial septum. Mutations in <italic>GATA4</italic>, <italic>TBX5</italic>, and <italic>NKX2‐5</italic> underlie this phenotype. Here, we report on the identification of a novel ‐6 G &gt; C mutation in the highly conserved Kozak sequence in the 5'UTR of <italic>GATA4</italic> 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 <italic>Nppa</italic> (ANF) promoter. In conclusion, we identified a mutation in the <italic>GATA4</italic> 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. © 2014 Wiley Periodicals, Inc.</p> </sec> </abstract>