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

Abstract

C ongenital heart defects (CHDs) occur in nearly 1% of all live births and are the major cause of infant mortality and morbidity. In addition, about 3 per every 1000 live births will require some intervention during the first year of life. 1 Despite its clinical importance, the underlying genetic etiology of most CHD remains unknown. Previous studies succeeded in revealing genetic causes of some syndromic or familial CHD, however, there are limited numbers of such cases, and it is still difficult to approach the etiology of the majority of CHD, that manifest non-syndromic and non-familial phenotype, because of their multi-factorial nature.In this issue, Lin et al. report on a novel mutation of a gene encoding a transcription factor, GATA6, as a possible cause of CHD. 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. And their subsequent biological analysis revealed the decreased transcriptional activity of GATA6 with the S184N mutation for the gene regulation of several important cardiac factors, suggesting that the GATA6 S184N mutation may have an important role in the pathogenesis of CHD.The first identification of disease-associated mutations of GATA6 in CHD was originally reported by us. 3 We screened mutations of cardiac transcription factors in patients with selected non-syndromic CHD, namely persistent truncus arteriosus, representing the most severe cardiac outflow tract (OFT) defects. Two different GATA6 mutations were identified in two probands, but not in 182 unrelated controls with no CHD. Our subsequent biological analyses revealed that genes encoding the neurovascular guiding molecule semaphorin 3C and its receptor plexin A2 were directly regulated by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. Transgenic analysis further suggested that the expression of semaphorin 3C and plexin A2 in the OFT was dependent on GATA transcription factors during the heart development. Together, our data implicate mutations in GATA6 as novel genetic causes of CHD involving the OFT development, as a result of the disruption of the direct regulation of semaphorin-plexin signaling. Another recent study by Maitra et al. showed two novel sequence variations in GATA6 (A178V and L198V) from the screening of 310 individuals with CHD. 4 These variants were identified in two individuals, one with tetralogy of Fallot and another with atrioventricular septal defect, but not in 288 ethnically matched healthy controls. 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...

First report of a de novo 18q11.2 microdeletion including GATA6 associated with complex congenital heart disease and renal abnormalities

“…GATA6 , a zinc finger transcription factor plays an important role in the regulation of cellular differentiation and organogenesis. Heterozygous point missense mutations in this gene are associated with several congenital defects including TOF, VSDs and ASDs [Kodo and Yamagishi, ; Lin et al, ; Maitra et al, ; OMIM 601656]. Homozygous mutations of RBBP8 have been associated with Jawad syndrome and Seckel syndrome 2 (OMIM 604124).…”

“…In contrast, heterozygous mutations in GATA6 have been recently shown to cause several congenital heart defects including TOF, ASDs, and VSDs in humans [Kodo and Yamagishi, ; Lin et al, ; Maitra et al, ; Padang et al, ]. GATA6 belongs to a family of transcription factors that bind to a GATA consensus motif (A/TGATAA/G).…”

“…It has also been shown that in mice, Gata6 is expressed in myocytes, in cardiac neural crest, as well as endocardial and vascular smooth muscle cells [Nemer and Nemer, ]. Inactivation of Gata6 in neural crest cells led to PDA and lethality in E18.5 embryos, suggesting an important role in the patterning of the outflow tract (OFT) and aortic arch [Lepore et al, ], and in endodermal differentiation [Kodo and Yamagishi, ]. Mice with compound heterozygous mutations for Gata4 and Gata6 die in utero and exhibit a spectrum of congenital heart defect, including septal and OFT defects.…”

“…Here we describe a 14‐month‐old female with multiple congenital anomalies and with a submicroscopic deletion of 18q11.2 that was identified by SNP oligonucleotide CMA. The deletion includes several RefSeq genes, including GATA6 , mutation of which has been associated with atrial and ventricular septal defect (ASD, VSD), and tetralogy of Fallot (TOF) [Kodo and Yamagishi, ; Lin et al, ; Maitra et al, ]. This is the first published occurrence of GATA6 deletion, and also the most proximal and smallest 18q11.2 deletion.…”

Utilization of Whole Exome Sequencing to Identify Causative Mutations in Familial Congenital Heart Disease

“…34, 35 The Gly115Trp (G115W) mutation occurs near one of the transactivation domains of GATA4, a region in which prior mutations have been identified in patients with ASD. 36 In addition, in vitro transactivation studies demonstrate similar loss of function deficits as those identified with other disease-causing mutations. 18, 20 This mutation highlights the ability of our WES methodology to identify likely pathogenic mutations in familial CHD cases when there is limited availability of affected family members for analysis.…”