Identification and functional study of GATA4 gene regulatory variants in atrial septal defects
Dongchen Fan1, Shuchao Pang2,3,4, Jing Chen5
1Division of Medical Ultrasonics, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272100, Shandong, China.
Insights
New GATA4 gene regulatory variants are linked to atrial septal defects (ASD). These genetic changes may increase ASD risk by reducing GATA4 gene expression, offering insights into congenital heart disease causes.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Congenital heart disease (CHD) is a major cause of death from birth defects.
- Adults with repaired CHD may develop late-stage cardiac complications, potentially due to genetic factors.
- While GATA4 mutations are known in CHD, its regulatory variants are less understood.
Purpose of the Study:
- To investigate GATA4 gene regulatory variants in patients with atrial septal defects (ASD).
- To determine the functional impact of identified regulatory variants on GATA4 gene expression.
Main Methods:
- Studied the GATA4 gene regulatory region in 332 ASD patients and 336 controls.
- Utilized functional analysis to assess the effect of variants on promoter activity and transcription factor binding.
Main Results:
- Identified five heterozygous regulatory variants exclusively in ASD patients.
- Demonstrated that these variants significantly alter GATA4 promoter transcriptional activity.
- Observed that two variants impact transcription factor binding sites.
Conclusions:
- GATA4 gene regulatory variants may contribute to ASD susceptibility.
- These variants might confer risk by reducing GATA4 gene expression levels.
Background:
Congenital heart disease (CHD) is the leading cause of mortality from birth defects. In adult CHD patients with successful surgical repair, cardiac complications including heart failure develop at late stage, likely due to genetic causes. To date, many mutations in cardiac developmental genes have been associated with CHD. Recently, regulatory variants in genes have been linked to many human diseases. Although mutations and splicing variants in GATA4 gene have been reported in CHD patients, few regulatory variants of GATA4 gene are identified in CHD patients.
Methods:
GATA4 gene regulatory region was investigated in the patients with atrial septal defects (ASD) (n = 332) and ethnic-matched controls (n = 336).
Results:
Five heterozygous regulatory variants including four SNPs [g.31360 T>C (rs372004083), g.31436G>A, g.31437C>A (rs769262495), g.31487C>G (rs1053351749) and g.31856C>T (rs1385460518)] were only identified in ASD patients. Functional analysis indicated that the regulatory variants significantly affected the transcriptional activity of GATA4 gene promoter. Furthermore, two of the five regulatory variants have evidently effected on transcription factor binding sites.
Conclusions:
Our data suggested that GATA4 gene regulatory variants may confer ASD susceptibility by decreasing GATA4 levels.
