PUBLICATION
Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation
- Authors
- Qian, Y., Xiao, D., Guo, X., Chen, H., Hao, L., Ma, X., Huang, G., Ma, D., Wang, H.
- ID
- ZDB-PUB-170405-9
- Date
- 2017
- Source
- Journal of translational medicine 15: 69 (Journal)
- Registered Authors
- Keywords
- Congenital heart disease (CHD), Functional study, Multigene disease, Next-generation sequencing, Variants
- MeSH Terms
-
- Adolescent
- Amino Acid Sequence
- Animals
- Base Sequence
- Child
- Child, Preschool
- Female
- GATA Transcription Factors/chemistry
- GATA Transcription Factors/genetics*
- Gene Expression Regulation*
- Genetic Variation*
- HEK293 Cells
- Heart Defects, Congenital/genetics*
- Humans
- Infant
- Infant, Newborn
- Male
- Tetralogy of Fallot/genetics
- Transcription, Genetic*
- Transcriptional Activation/genetics
- Zebrafish
- PubMed
- 28372585 Full text @ J Transl Med
Citation
Qian, Y., Xiao, D., Guo, X., Chen, H., Hao, L., Ma, X., Huang, G., Ma, D., Wang, H. (2017) Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation. Journal of translational medicine. 15:69.
Abstract
Background Congenital heart disease (CHD) is a common birth defect, and most cases occur sporadically. Mutations in key genes that are responsible for cardiac development could contribute to CHD. To date, the genetic causes of CHD remain largely unknown.
Methods In this study, twenty-nine candidate genes in CHD were sequenced in 106 patients with Tetralogy of Fallot (TOF) using target exome sequencing (TES). The co-immunoprecipitation (CO-IP) and luciferase reporter gene assays were performed in HEK293T cells, and wild-type and mutant mRNA of ZFPM2 were microinjected into zebrafish embryos.
Results Rare variants in key cardiac transcriptional factors and JAG1 were identified in the patients. Four patients carried multiple gene variants. The novel E1148K variant was located at the eighth Zinc-finger domain of FOG2 protein. The CO-IP assays in the HEK293T cells revealed that the variant significantly damaged the interaction between ZFPM2/FOG2 and GATA4. The luciferase reporter gene assays revealed that the E1148K mutant ZFPM2 protein displayed a significantly greater inhibition of the transcriptional activation of GATA4 than the wild-type protein. The wild-type mRNA and the E1148K mutant mRNA of ZFPM2 were injected into zebrafish embryos. At 48 hpf, in the mutant mRNA injection group, the number of embryos with an abnormal cardiac chamber structure and a loss of left-right asymmetry was increased. By 72 hpf, the defects in the chamber and left-right asymmetry became obvious.
Conclusions We performed TES in sporadic TOF patients and identified rare variants in candidate genes in CHD. We first validated the E1148 K variant in ZFPM2, which is likely involved in the pathogenesis of CHD via GATA4. Moreover, our results suggest that TES could be a useful tool for discovering sequence variants in CHD patients.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping