A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

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.

GATA transcription factors in congenital heart defects: A Commentary on a novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

“…Biochemical analysis demonstrated that the GATA6 A178V mutant protein resulted in increased transactivation ability for cardiac genes compared with the wildtype. Our first report and subsequent reports by Maitra et al 4 and Lin et al 2 in this issue provide an approach for the etiology of nonsyndromic or 'multi-factorial' CHD in the post-genomic era, and together indicate that mutations in GATA6 cause CHD implicated in the cardiac OFT and septal development.…”

“…2 The same mutation was also observed in their parents, two fathers with no CHD and a mother with bicuspid aortic valve. In previous reports, GATA4 missense mutations identified in patients with cardiac septal defects were also found in some of their non-affected parents or family members, indicating the reduced penetrance of the phenotype.…”

“…2 The authors screened 270 individuals with non-syndromic CHD for the GATA6 gene by direct sequencing, and identified a missense mutation (S184N) in three individuals, one with tetralogy of Fallot and the others with atrial septal defect. Although the incomplete penetrance of the phenotype by this mutation was observed, the mutation was not found in 500 ethnically matched healthy controls.…”

A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation

“…Emerging evidence underscores the crucial role for several transcription factors, including NKX2-5, GATA4 and GATA6, in the proper cardiogenesis (38)(39)(40) and mutations in these genes have been causally linked to congenital cardiovascular anomalies and AF (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56). GATA5 is another member of the GATA family and its expression and function overlap with those of GATA4 and GATA6 during cardiac development, particularly in the regulation of target gene expression synergistically with NKX2-5 (57,58), suggesting the potential association of functionally compromised GATA5 with AF.…”

Novel and functional DNA sequence variants within the GATA5 gene promoter in ventricular septal defects

“…GATA6 gene mutations have been reported in familial and isolated CHD patients in different ethnic populations, including atrial septal defect, atrioventricular septal defect, persistent truncus arteriosus, tetralogy of Fallot and ventricular septal defect (VSD) [16][17][18][19][20][21][22][23][24][25]. Mutations in GATA6 gene include missense mutations, deletions and copy number variants.…”