GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease

Abstract

Previous studies have shown that patients with deletion of distal human chromosome arm 8p may have congenital heart disease and other physical anomalies. The gene encoding GATA-4, a zinc finger transcription factor implicated in cardiac gene expression and development, localizes to chromosome region 8p23.1. To examine whether GATA-4 deficiency is present in patients with monosomy of 8p23.1 with congenital heart disease, we performed fluorescence in situ hybridization (FISH) with a GATA4 probe on cells from a series of patients with interstitial deletion of 8p23.1. Four individuals with del(8)(p23.1) and congenital heart disease were found to be haploinsufficient at the GATA4 locus by FISH. The GATA4 gene was not deleted in a fifth patient with del(8)(p23.1) who lacked cardiac anomalies. FISH analysis on cells from 48 individuals with congenital heart disease and normal karyotypes failed to detect any submicroscopic deletions at the GATA4 locus. We conclude that haploinsufficiency at the GATA4 locus is often seen in patients with del(8)(p23.1) and congenital heart disease. Based on these findings and recent studies showing that haploinsufficiency for other cardiac transcription factor genes (e.g., TBX5, NKX2-5) causes congenital heart disease, we postulate that GATA-4 deficiency may contribute to the phenotype of patients with monosomy of 8p23.1.

A novel GATA4 mutation completely segregated with atrial septal defect in a large Japanese family

“…It is likely that the c.1074delC is unable to activate transcription of downstream genes, being similar to the c.1075delG as reported by Garg et al 10 In summary, the GATA4 c.1074delC likely results in haploinsufficiency, and causes a cardiac phenotype similar to that described in 8p deletion syndrome. 16 In addition, a syndromic PS associated with Noonan/LEOPARD syndrome and Alagille syndrome has been shown to be caused by mutations of PTPN11 at 12q22 17 18 and JAG1 at 20p12, 19 20 respectively. JAG1 mutation can also result in isolated PS.…”

Spectrum of atrial septal defects associated with mutations of NKX2.5 and GATA4 transcription factors

“…Distal 8p deletions in humans are characterised by a wide spectrum of CHDs, microcephaly, other physical anomalies, and mental retardation. 26 The contribution of GATA4 to the 8p cardiac phenotype has been postulated, 27 although other evidence has mapped GATA4 outside the critical region for this condition. 28 Heterozygous GATA4 mutations cause distinct cardiac defects, such as ASD, PVS, AVCD, and dextrocardia, which are also features of 8p syndrome.…”

The KLF Family of Transcriptional Regulators in Cardiomyocyte Proliferation and Differentiation

“…11 Disruption in the onset or dosage of these regulators is associated with defective heart development in experimental models and, for several, with congenital heart disease in humans. 12 This is the case for GATA4 [13][14][15] and Nkx2.5 16 for which mutations correlate with atrial septal defects and tetralogy of fallot, and Tbx5 17,18 the gene mutated in Holt-Oram syndrome. Although much remains to be learned concerning their mechanisms of action, the finding that these regulators act cooperatively within multiprotein transcription complexes to regulate common targets has provided a molecular framework for understanding how mutations in different genes can cause similar phenotypes.…”