Kind, L., Raasakka, A., Molnes, J., Aukrust, I., Bjørkhaug, L., Njølstad, P. R., Kursula, P., & Arnesen, T. (2022). Structural and biophysical characterization of transcription factor HNF-1A as a tool to study MODY3 diabetes variants. Journal of Biological Chemistry, 298(4), 101803. https://doi.org/10.1016/j.jbc.2022.101803
Structural and biophysical characterization of transcription factor HNF-1A as a tool to study MODY3 diabetes variants
|Author:||Kind, Laura1; Raasakka, Arne1; Molnes, Janne2,3;|
1Department of Biomedicine, University of Bergen, Bergen, Norway
2Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway
3Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
4Department of Safety, Chemistry, and Biomedical Laboratory Sciences, Western Norway University of Applied Sciences, Bergen, Norway
5Section of Endocrinology and Metabolism, Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway
6Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland
7Department of Biological Sciences, University of Bergen, Bergen, Norway
8Department of Surgery, Haukeland University Hospital, Bergen, Norway
|Online Access:||PDF Full Text (PDF, 3.1 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022091258401
American Society for Biochemistry and Molecular Biology,
|Publish Date:|| 2022-09-12
Hepatocyte nuclear factor 1A (HNF-1A) is a transcription factor expressed in several embryonic and adult tissues, modulating the expression of numerous target genes. Pathogenic variants in the HNF1A gene are known to cause maturity-onset diabetes of the young 3 (MODY3 or HNF1A MODY), a disease characterized by dominant inheritance, age of onset before 25 to 35 years of age, and pancreatic β-cell dysfunction. A precise diagnosis can alter management of this disease, as insulin can be exchanged with sulfonylurea tablets and genetic counseling differs from polygenic forms of diabetes. Therefore, more knowledge on the mechanisms of HNF-1A function and the level of pathogenicity of the numerous HNF1A variants is required for precise diagnostics. Here, we structurally and biophysically characterized an HNF-1A protein containing both the DNA-binding domain and the dimerization domain, and determined the folding and DNA-binding capacity of two established MODY3 HNF-1A variant proteins (P112L, R263C) and one variant of unknown significance (N266S). All three variants showed reduced functionality compared to the WT protein. Furthermore, while the R263C and N266S variants displayed reduced binding to an HNF-1A target promoter, we found the P112L variant was unstable in vitro and in cells. Our results support and mechanistically explain disease causality for these investigated variants and present a novel approach for the dissection of structurally unstable and DNA-binding defective variants. This study indicates that structural and biochemical investigation of HNF-1A is a valuable tool in reliable variant classification needed for precision diabetes diagnostics and management.
Journal of biological chemistry
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This work was funded with a PhD fellowship by the Medical Faculty, University of Bergen, UiB, Norway (to L. K.) and by a UiB Meltzer foundation project grant (to L. K.). L. K. received a research visit grant from the Norwegian Graduate School in Biocatalysis. T. A. was supported by the Norwegian Cancer Society (Project 171752—PR-2009-0222). P. R. N. received funding from the European Research Council (AdG SELECTionPREDISPOSED #293574), the Research Council of Norway (FRIPRO grant #240413), the Western Norway Regional Health Authority (Strategic Fund “Personalized Medicine for Children and Adults”), the Novo Nordisk Foundation (grant #54741), and the Norwegian Diabetes Association. This work has been supported by the project CALIPSOplus under the Grant Agreement 730872 from the EU Framework Programme for Research and Innovation HORIZON 2020 (to P. K.).
© 2022 THE AUTHORS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).