A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect
Open Access
- 15 July 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Human Genetics
- Vol. 55 (10), 662-667
- https://doi.org/10.1038/jhg.2010.84
Abstract
GATA6 is a member of the GATA family of transcription factors, and its expression and functions overlap with those of GATA4 during heart development. Mutations in GATA4 have been related to human congenital heart diseases (CHDs) in several studies, whereas mutations in GATA6 have only recently been reported in patients with persistent truncus arteriosus. Animal experiments have revealed critical roles for GATA6 in the development of the myocardium and cardiac morphogenesis, thereby highlighting the potential involvement of GATA6 defects in the pathogenesis of CHDs. Here, we screened the GATA6 in 270 individuals with sporadic CHDs by direct sequencing. After identification of the mutation, a luciferase reporter assay and real-time quantitative polymerase chain reaction were performed to detect functional changes in the mutant transcription factor. The same heterozygous missense mutation (Ser184Asn) was identified in three patients, including one with tetralogy of Fallot and two with atrial septal defects. This mutation was not found in 500 unrelated ethnically matched healthy subjects. Direct sequencing of this region in the parents of these three patients revealed the same mutation in one of the parents for each patient, and one of the parent carriers presented with a bicuspid aortic valve. Biological analysis revealed clearly decreased transcriptional activity of GATA6 Ser184Asn in vitro. All these data suggest that GATA6 Ser184Asn is a novel mutation associated with CHDs and has an important role in disease pathogenesis.Keywords
This publication has 31 references indexed in Scilit:
- GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signalingProceedings of the National Academy of Sciences of the United States of America, 2009
- Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac developmentDevelopmental Biology, 2009
- Loss of both GATA4 and GATA6 blocks cardiac myocyte differentiation and results in acardia in miceDevelopmental Biology, 2008
- GATA4 sequence variants in patients with congenital heart diseaseJournal of Medical Genetics, 2007
- A threshold of GATA4 and GATA6 expression is required for cardiovascular developmentProceedings of the National Academy of Sciences of the United States of America, 2006
- Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defectAmerican Journal of Medical Genetics Part A, 2005
- Spectrum of atrial septal defects associated with mutations of NKX2.5 and GATA4 transcription factorsJournal of Medical Genetics, 2005
- GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5Nature, 2003
- Mutations in human cause limb and cardiac malformation in Holt-Oram syndromeNature Genetics, 1997
- Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene familyNature Genetics, 1997