Conotruncal heart defect is a complex form of congenital heart disease and usually has a poor prognosis. Although previous studies have identified several missense variants in GATA4 gene that may cause CTD, it remains unclear whether they are involved in CTD pathogenesis because the study population was limited. The aim of the study was to investigate the mutations of GATA4 gene in isolated CTD Chinese Han patients and identify the pathomechanism of the missense mutations. In this report, the coding exons and exon-intron boundaries of the GATA4 gene were sequenced in 600 CTD patients and 300 controls. Functional significance of the novel GATA4 gene mutation (p.A167D) was analyzed using PolyPhen 2 and SIFT. And, the functional characteristics of the mutant GATA4 gene were assayed in contrast to its wild-type counterpart using a luciferase reporter assay system as well as Western blot. Eight heterozygous nonsynonymous variants (V380M, G64E, A167D, V267M, S377G, P163S, P407Q, A66T) were found in 22 patients, of which one (A167D) was reported here for the first time and five (G64E, A167D, S377G, P163S, A66T) were only found in CTD patients when compared with 300 controls. The PolyPhen 2 and SIFT programs predicted that the A167D substitution was expected to influence protein function. Subsequent functional analyses revealed that the transcriptional activity and Western blot of A167D mutant GATA4 protein were not altered. These variants may be involved in other mechanisms underlying CTD or may be unrelated to CTD occurrence.
Keywords: Chinese Han population; Conotruncal heart defect; GATA4; Mutation.