{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Chen Y"],"funding":["the Natural Science Foundation of Fujian Province","National Natural Science Foundation of China"],"pagination":["13022"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9656704"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["23(21)"],"pubmed_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 (<i>hnf1a<sup>+/-</sup></i>) was generated by CRISPR/Cas9. We further crossed <i>hnf1a<sup>+/-</sup></i> 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. <i>hnf1a<sup>+/-</sup></i> zebrafish significantly decreased the β-cell number, insulin expression, and secretion. Moreover, β cells in <i>hnf1a<sup>+/-</sup></i> 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."],"journal":["International journal of molecular sciences"],"pubmed_title":["Novel Loss-of-Function Variant in HNF1a Induces β-Cell Dysfunction through Endoplasmic Reticulum Stress."],"pmcid":["PMC9656704"],"funding_grant_id":["8207033519","2021J011363"],"pubmed_authors":["Tian J","Li X","Huang C","Zhao Q","Zhang Y","Chen Y","Huang B","Li M","Jia J","Wang L"],"additional_accession":[]},"is_claimable":false,"name":"Novel Loss-of-Function Variant in HNF1a Induces β-Cell Dysfunction through Endoplasmic Reticulum Stress.","description":"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 (<i>hnf1a<sup>+/-</sup></i>) was generated by CRISPR/Cas9. We further crossed <i>hnf1a<sup>+/-</sup></i> 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. <i>hnf1a<sup>+/-</sup></i> zebrafish significantly decreased the β-cell number, insulin expression, and secretion. Moreover, β cells in <i>hnf1a<sup>+/-</sup></i> 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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Oct","modification":"2025-04-25T23:35:23.022Z","creation":"2025-04-06T09:23:29.497Z"},"accession":"S-EPMC9656704","cross_references":{"pubmed":["36361808"],"doi":["10.3390/ijms232113022"]}}