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Identification of ZFPM2 mutations in sporadic conotruncal heart defect patients
1Department of Pediatric Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Conotruncal heart defects (CTDs) are a group of cardiac malformations that involve outflow tract anomalies and the arterial pole of the heart. Recent reports have identified mutations in a number of genes associated with CTDs in human and animal models. ZFPM2 plays a role in cardiac development by acting as a transcriptional cofactor that interacts with GATA4. Because ZFPM2 was found to be important for cardiac development in a knockout mouse model, we screened for ZFPM2 mutations in 528 CTD patients. We identified six rare and nonsynonymous ZFPM2 variants, and this was the first time that five of these variants (R698Q, R736L, E1005K, T32A, and I488V) were reported in East Asians. Western blots showed that there was no significant difference in the protein expression of wild-type ZFPM2, ZFPM2R698Q, or ZFPM2R736L. A dual luciferase reporter assay demonstrated that both ZFPM2 mutants R698Q and R736L reduced GATA4-mediated transcription. However, when ZFPM2R698Q was co-transfected with GATA4, BNP promoter activity increased significantly, whereas co-transfection with ZFPM2R736L and GATA4 did not significantly increase BNP promoter activity. This suggests that the R698Q mutation may affect the ability of ZFPM2 to bind GATA4.
Insights
Mutations in the ZFPM2 gene were identified in conotruncal heart defect (CTD) patients. Specific ZFPM2 variants impact GATA4-mediated transcription, potentially affecting cardiac development.
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Cardiology
Background:
- Conotruncal heart defects (CTDs) are congenital heart malformations involving outflow tract anomalies.
- Genetic mutations are increasingly implicated in the etiology of CTDs.
- ZFPM2 functions as a transcriptional cofactor crucial for cardiac development, interacting with GATA4.
Purpose of the Study:
- To investigate the role of ZFPM2 gene mutations in patients with CTDs.
- To identify and characterize novel ZFPM2 variants in a cohort of CTD patients.
Main Methods:
- Screening of ZFPM2 gene in 528 CTD patients.
- Western blot analysis to assess protein expression levels.
- Dual luciferase reporter assays to evaluate transcriptional activity.
Main Results:
- Six rare, nonsynonymous ZFPM2 variants were identified in CTD patients, with five novel in East Asians.
- ZFPM2 variants R698Q and R736L reduced GATA4-mediated transcription.
- The R698Q mutation showed a distinct effect on BNP promoter activity compared to R736L, suggesting altered GATA4 binding.
Conclusions:
- ZFPM2 mutations represent a potential genetic cause for CTDs.
- Specific ZFPM2 variants, like R698Q, may impair cardiac development by disrupting the ZFPM2-GATA4 interaction.
- Further research is warranted to elucidate the precise mechanisms by which ZFPM2 variants contribute to CTDs.
