Novel Loss-of-Function Variant in HNF1a Induces β-Cell Dysfunction through Endoplasmic Reticulum Stress

Chen, Yinling; Jia, Jianxin; Zhao, Qing; Zhang, Yuxian; Huang, Bingkun; Wang, Likun; Tian, Juanjuan; Huang, Caoxin; Li, Mingyu; Li, Xuejun

doi:10.3390/ijms232113022

Open AccessArticle

Novel Loss-of-Function Variant in HNF1a Induces β-Cell Dysfunction through Endoplasmic Reticulum Stress

by

Yinling Chen

^1,2,†

,

Jianxin Jia

^2,†,

Qing Zhao

¹,

Yuxian Zhang

^1,3,

Bingkun Huang

^1,3,

Likun Wang

^1,2,

Juanjuan Tian

²,

Caoxin Huang

³,

Mingyu Li

^2,*

and

Xuejun Li

^1,3,*

¹

Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361005, China

²

Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences and School of Life Sciences, Xiamen University, Xiamen 361102, China

³

Fujian Province Key Laboratory of Diabetes Translational Medicine, Xiamen Diabetes Institute, Xiamen 361003, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2022, 23(21), 13022; https://doi.org/10.3390/ijms232113022

Submission received: 13 September 2022 / Revised: 21 October 2022 / Accepted: 21 October 2022 / Published: 27 October 2022

(This article belongs to the Section Biochemistry)

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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.

Keywords: HNF1a; β cell; insulin secretion; ER stress; variant

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MDPI and ACS Style

Chen, Y.; Jia, J.; Zhao, Q.; Zhang, Y.; Huang, B.; Wang, L.; Tian, J.; Huang, C.; Li, M.; Li, X. Novel Loss-of-Function Variant in HNF1a Induces β-Cell Dysfunction through Endoplasmic Reticulum Stress. Int. J. Mol. Sci. 2022, 23, 13022. https://doi.org/10.3390/ijms232113022

AMA Style

Chen Y, Jia J, Zhao Q, Zhang Y, Huang B, Wang L, Tian J, Huang C, Li M, Li X. Novel Loss-of-Function Variant in HNF1a Induces β-Cell Dysfunction through Endoplasmic Reticulum Stress. International Journal of Molecular Sciences. 2022; 23(21):13022. https://doi.org/10.3390/ijms232113022

Chicago/Turabian Style

Chen, Yinling, Jianxin Jia, Qing Zhao, Yuxian Zhang, Bingkun Huang, Likun Wang, Juanjuan Tian, Caoxin Huang, Mingyu Li, and Xuejun Li. 2022. "Novel Loss-of-Function Variant in HNF1a Induces β-Cell Dysfunction through Endoplasmic Reticulum Stress" International Journal of Molecular Sciences 23, no. 21: 13022. https://doi.org/10.3390/ijms232113022

APA Style

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), 13022. https://doi.org/10.3390/ijms232113022

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Novel Loss-of-Function Variant in HNF1a Induces β-Cell Dysfunction through Endoplasmic Reticulum Stress

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