PUBLICATION
Novel Loss-of-Function Variant in HNF1a Induces β-Cell Dysfunction through Endoplasmic Reticulum Stress
- Authors
- Chen, Y., Jia, J., Zhao, Q., Zhang, Y., Huang, B., Wang, L., Tian, J., Huang, C., Li, M., Li, X.
- ID
- ZDB-PUB-221115-32
- Date
- 2022
- Source
- International Journal of Molecular Sciences 23(21): (Journal)
- Registered Authors
- Li, Mingyu
- Keywords
- ER stress, HNF1a, insulin secretion, variant, β cell
- MeSH Terms
-
- Animals
- Diabetes Mellitus, Type 2*/metabolism
- Endoplasmic Reticulum Stress/genetics
- Insulin/metabolism
- Insulin-Secreting Cells*/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 36361808 Full text @ Int. J. Mol. Sci.
Citation
Chen, Y., Jia, J., Zhao, Q., Zhang, Y., Huang, B., Wang, L., Tian, J., Huang, C., Li, M., Li, X. (2022) Novel Loss-of-Function Variant in HNF1a Induces β-Cell Dysfunction through Endoplasmic Reticulum Stress. International Journal of Molecular Sciences. 23(21):.
Abstract
Heterozygous variants in the hepatocyte nuclear factor 1a (HNF1a) cause MODY3 (maturity-onset diabetes of the young, type 3). In this study, we found a case of novel HNF1a p.Gln125* (HNF1a-Q125ter) variant clinically. However, the molecular mechanism linking the new HNF1a variant to impaired islet β-cell function remains unclear. Firstly, a similar HNF1a-Q125ter variant in zebrafish (hnf1a+/-) was generated by CRISPR/Cas9. We further crossed hnf1a+/- with several zebrafish reporter lines to investigate pancreatic β-cell function. Next, we introduced HNF1a-Q125ter and HNF1a shRNA plasmids into the Ins-1 cell line and elucidated the molecular mechanism. hnf1a+/- zebrafish significantly decreased the β-cell number, insulin expression, and secretion. Moreover, β cells in hnf1a+/- dilated ER lumen and increased the levels of ER stress markers. Similar ER-stress phenomena were observed in an HNF1a-Q125ter-transfected Ins-1 cell. Follow-up investigations demonstrated that HNF1a-Q125ter induced ER stress through activating the PERK/eIF2a/ATF4 signaling pathway. Our study found a novel loss-of-function HNF1a-Q125ter variant which induced β-cell dysfunction by activating ER stress via the PERK/eIF2a/ATF4 signaling pathway.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping