A Novel GATA4 Loss-of-Function Mutation Associated With Congenital Ventricular Septal Defect

Abstract

Ventricular septal defect (VSD) is the most prevalent type of congenital heart disease and a major cause for the significantly increased morbidity and mortality among infants. Aggregating evidence indicates that genetic defects are involved in the pathogenesis of congenital VSD. Nevertheless, VSD is genetically heterogeneous, and the genetic determinants for VSD in the majority of patients remain to be identified. In this study, the entire coding region of GATA4, a gene encoding a zinc finger transcription factor essential for normal cardiac morphogenesis, was sequenced in 160 unrelated patients with VSD. The available relatives of the index patient harboring the identified mutation and 200 unrelated control individuals were subsequently genotyped. The disease-causing potential of a sequence alteration was evaluated by MutationTaster, and the functional effect of the mutation was characterized using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 variation, p.R43W, was identified in a proband with VSD, that was absent in control subjects. Genetic analysis of the family members of the variation carrier showed that the substitution co-segregated with VSD. The p.R43W variant was predicted to be a pathogenic mutation, and the functional analysis demonstrated that the GATA4 R43W mutant protein resulted in significantly decreased transcriptional activity compared with its wild-type counterpart. The findings expand the mutational spectrum of GATA4 linked to VSD and provide more insight into the molecular mechanism of VSD.

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.…”

Serum microRNA 125b as a diagnostic or prognostic biomarker for advanced NSCLC patients receiving cisplatin-based chemotherapy

“…The mechanism of how miR-125b affects chemotherapy resistance/response has not been fully elucidated. Current evidence suggests that miR-125b affects cell apoptosis and proliferation, because upregulation of miR-125b causes marked inhibition of cisplatin-induced apoptosis and subsequently increases the resistance to cisplatin [19,24,25] . Ectopic miR-34a expression has also been shown to result in cell cycle arrest, growth inhibition and attenuated chemoresistance to the anticancer drug camptothecin by inducing apoptosis, suggesting that miR-34a has a potential role in the treatment of p53-defective prostate cancer [26] .…”

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.…”