A novel GATA4 mutation responsible for congenital ventricular septal defects

Abstract

Abstract. Ventricular septal defect (VSD) is the most common type of cardiovascular developmental anomaly and is an important risk factor for the substantially increased morbidity and mortality in newborns. Aggregating evidence implicates genetic defects in the pathogenesis of congenital VSD. However, VSD is genetically heterogeneous and the genetic determinants for VSD in most patients remain to be identified. In this study, the whole coding region of the GATA4 gene, which encodes a zinc-finger transcription factor pivotal to cardiogenesis, was initially sequenced in 210 unrelated patients with VSD. The relatives of the index patient carrying the identified mutation and 200 unrelated ethnically-matched healthy individuals used as controls were subsequently genotyped. The functional effect of the mutant GATA4 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. A novel heterozygous GATA4 mutation, p.G296R, was identified in a family with VSD inherited as an autosomal dominant trait. Absent in 200 control individuals, the mutation co-segregated with VSD in the family with 100% penetrance and was completely conserved evolutionarily across species. Functional analysis displayed that the p.G296R mutation of GATA4 was associated with a decreased transcriptional activity. The findings expand the spectrum of mutations in GATA4 linked to VSD and provide more insight into the molecular mechanism involved in VSD. The results of the present study imply the potential implications in the genetic diagnosis and gene-specific therapy of this common malformation in infancy.

A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation

“…Similarly, congenital cardiovascular malformations were previously confirmed in AF patients carrying GATA4, GATA5 or GATA6 mutations (49)(50)(51)(52)(53)(54)(55)(56)(57). Markedly, a long list of mutations in these genes has been implicated in a wide variety of congenital cardiovascular anomalies (65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75). These observational results indicate that AF may share a common genetic origin with congenital heart disease.…”

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.…”

Genotyping of GATA4 Gene Variant (G296S) in Malaysian Congenital Heart Disease Subjects by Real-Time PCR High Resolution Melting Analysis

“…So far, the G296S variant of the GATA4 gene has been reported mainly in familial cases of CHD with the septation defect (8) (11,15). Nevertheless, several studies (Japan (16), China (17)(18)(19)(20)(21)(22), Denmark (23) and Indonesia (24)) failed to detect the G296S variant of the GATA4 gene in CHD patients despite including familial cases of CHD as well as cases with septation defects. Their reports were in agreement with the findings of our study, which included 52 cases of VSD and 16 case of ASD.…”