Transcription Factor GATA-4 Expression In The Human Developing Hearts And Its Mutation In Fetuses With Congenital Heart Disease

ObjectivesCongenital heart disease(CHD) is one of the most common diseases of all human birth defects. Mutations in heart developmental regulatory genes have been found to be responsible for some cases of congenital heart disease,so searching for the related genes in congenital heart disease has been one of the focuses in the field of prenatal diagnosis and current study of heart and blood, vessel disease. GATA-4, a zinc finger transcription factor,is one of the earliest markers for heart precursor cells,and is a very important transcription factor during heart development.GATA-4 gene mutations will reduce its transcriptional activity,and affect other heart development related genes play their roles,so that they will affect normal heart development,and result in congenital heart disease. By detecting GATA-4 which is expressed in cardiac development of human embryo,we comprehend the express law of this factor in cardiac development so as to recognize its function in cardiac development. It was also studied the mutations in gene of zinc transcription factor GATA-4 in fetuses with CHD, thus hoped to offer evidence in exploring the molecular mechanism of CHD, and provide the theoretical evidence for genetic counseling and prenatal diagnosis.Methods1,45 normal human embryonic or fetal hearts in 6～23 gestational weeks were included in this study. Immunohistochemistry was used to detect the GATA-4 expression. 2,The products of PCR were directly sequenced to screen for mutations in exon 3,4,5,6 of GATA-4 in 20 fetuses with a variety of CHD. 25 fetuses and 25 children who had no CHD were randomly selected as controls.Results1,In early stage of development of human fetal heart ,no GATA-4 expression was detected in ventricular and weak expression in artrial,relatively high expression in trabecular nets. With the heart development GATA-4 expression was enhanced in artial,ventricular,trabecular nets and artial-ventricular valves. GATA-4 expression was also observed in muscular and membranous interventricular septum,which expression is the highest in each part of heart.2,A missense mutation 799G→A in exon 4 of GATA-4 gene, which resulted in a subtitution of valine by methionine at 267, was detected in a fetus with ASD and VSD.3,A polymorphism 723C/T in exon 3 was observed in 3 fetuses with CHD and 1 control. No significantly difference in the frequency of GATA-4 723C/T genotype and alleles was observed between CHD group and control group(P>0.05).Conclusion1,Transcription factor GATA-4 plays an important role in the human heart development. GATA-4 is one regulatory factor of proliferation of cardiomyocytes.2,Mutations of GATA-4 may be associated with fetal CHD. Because of the somatic nature of GATA-4 mutations, we proposed that the same mutation occurred in different developmental stages or different parts of heart may result in different phenotypes. The mechanism through which the mutation (V267M) associated with CHD remains to be investigated. 3,Our statistics results showed that there existed no significant difference in the frequency of GATA-4 723C/T genotype and alleles between the CHD and control groups. However, given the important role of the cysteine encoded by the cSNP, we still think that the correlation between the polymorphism of GATA-4 723C/T genotype and fetal CHD deserves further investigation.