PUBLICATION
Functional characterization of GATA6 genetic variants associated with mild congenital heart defects
- Authors
- Wu, H., Wu, H., He, Y., Sun, W., Meng, Y., Wen, B., Chu, M.
- ID
- ZDB-PUB-221218-1
- Date
- 2022
- Source
- Biochemical and Biophysical Research Communications 641: 778377-83 (Journal)
- Registered Authors
- Keywords
- Congenital heart defects, GATA6 transcription factor, Genetic variants, Genotype-phenotype correlation, Zebrafish
- MeSH Terms
-
- Animals
- GATA6 Transcription Factor/genetics
- GATA6 Transcription Factor/metabolism
- Genetic Association Studies
- Heart
- Heart Defects, Congenital*/genetics
- Heart Defects, Congenital*/metabolism
- Phenotype
- Zebrafish*/genetics
- Zebrafish*/metabolism
- PubMed
- 36525927 Full text @ Biochem. Biophys. Res. Commun.
Citation
Wu, H., Wu, H., He, Y., Sun, W., Meng, Y., Wen, B., Chu, M. (2022) Functional characterization of GATA6 genetic variants associated with mild congenital heart defects. Biochemical and Biophysical Research Communications. 641:778377-83.
Abstract
Damaging GATA6 variants can cause moderate congenital heart defects. With the application of next-generation sequencing approaches, various novel GATA6 variants with unknown significance have been identified from a broad spectrum of congenital heart defects. However, functional assessment for distinct GATA6 variants from different severity of congenital heart defects, especially from mild defects, is lacking, which hinders our understanding of the genotype-phenotype correlations and underlying mechanisms. Here, we assessed the functional consequences of nine rare GATA6 variants, which had been implicated as the most significant variants associated with mild congenital heart defects using the largest case and control cohort. We examined the effects of these variants on subcellular localization, transcriptional activity, and protein interactions in 293T or AC16 cells and their ability to rescue heart malformation in gata6 zebrafish mutant. We found that two of these nine variants, Q120X and S424I, significantly decreased transcriptional activity. Additionally, Q120X altered subcellular localization. Consistent with the in vitro results, the in vivo results showed that Q120X and S424I lost their potency to rescue ventricular malformation in gata6 -/- embryos. The results indicated that Q120X and S424I are pathogenic in mild congenital heart defects. Further, the inconsistence of severely impaired Q120X function and mild CHDs phenotype suggested the complexity of the genotype-phenotype correlation between the GATA6 variant and heart phenotype, which may help to inform prenatal genetic counseling and pre-implantation genotyping for congenital heart defects.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping