Point mutations in the PDX1 transactivation domain impair human beta-cell development and function
| dc.contributor.author | Wright, Christopher V. E. | |
| dc.date.accessioned | 2020-06-04T15:00:56Z | |
| dc.date.available | 2020-06-04T15:00:56Z | |
| dc.date.issued | 2019-06 | |
| dc.description | Only Vanderbilt University affiliated authors are listed on VUIR. For a full list of authors, access the version of record at https://pubmed.ncbi.nlm.nih.gov/30930126/ | en_US |
| dc.description.abstract | Objective: Hundreds of missense mutations in the coding region of PDX1 exist; however, if these mutations predispose to diabetes mellitus is unknown. Methods: In this study, we screened a large cohort of subjects with increased risk for diabetes and identified two subjects with impaired glucose tolerance carrying common, heterozygous, missense mutations in the PDX1 coding region leading to single amino acid exchanges (P33T, C18R) in its transactivation domain. We generated iPSCs from patients with heterozygous PDX1(P33T/)(+), PDX1(C18R/+) mutations and engineered isogenic cell lines carrying homozygous PDX1(P33T/P33T), PDX1(C18R/C18R) mutations and a heterozygous PDX1 loss-of-function mutation (PDX1(+/-)). Results: Using an in vitro beta-cell differentiation protocol, we demonstrated that both, heterozygous PDXP33T/+, PDX1(C18R/+)and homozygous PDX1(P33T/P33T), PDX1(C18R/C18R) mutations impair beta-cell differentiation and function. Furthermore, PDX1(+/-) and PDX1(P33T/P33T )mutations reduced differentiation efficiency of pancreatic progenitors (PPs), due to downregulation of PDX1 -bound genes, including transcription factors MNX1 and PDX1 as well as insulin resistance gene CES1. Additionally, both PDX1(P33T/+ )and PDX1(P33T/P33T) mutations in PPs reduced the expression of PDX1-bound genes including the long-noncoding RNA, MEG3 and the imprinted gene NNAT, both involved in insulin synthesis and secretion. Conclusions: Our results reveal mechanistic details of how common coding mutations in PDX1 impair human pancreatic endocrine lineage formation and beta-cell function and contribute to the predisposition for diabetes. (C) 2019 The Authors. Published by Elsevier GmbH. | en_US |
| dc.description.sponsorship | We thank A. Malinowski and K. Y for comments and discussions and A. Theis, B. Vogel, A. Bastidas-Ponce, M. Bamberger and K. Diemer for their technical support. We also thank Stefan Krebs and the sequencing unit of the Laboratory of Functional Genome Analysis (LAFUGA) at the Gene Center of the LMU. This work was funded in part by the German Center for Diabetes Research (DZD e.V.), by the European Union's Seventh Framework Programme for Research, Technological Development and Demonstration under grant agreement No. 602587 (http://www.hum-en.eu/), and by funds of the Helmholtz Association for the future topic "Aging and Metabolic programming" (AMPro). | en_US |
| dc.identifier.citation | Wang, X., Sterr, M., Ansarullah, Burtscher, I., Böttcher, A., Beckenbauer, J., Siehler, J., Meitinger, T., Häring, H. U., Staiger, H., Cernilogar, F. M., Schotta, G., Irmler, M., Beckers, J., Wright, C., Bakhti, M., & Lickert, H. (2019). Point mutations in the PDX1 transactivation domain impair human β-cell development and function. Molecular metabolism, 24, 80–97. https://doi.org/10.1016/j.molmet.2019.03.006 | en_US |
| dc.identifier.doi | 10.1016/j.molmet.2019.03.006 | |
| dc.identifier.issn | 2212-8778 | |
| dc.identifier.uri | http://hdl.handle.net/1803/10033 | |
| dc.language.iso | en_US | en_US |
| dc.publisher | Molecular Metabolism | en_US |
| dc.rights | Copyright © 2019 The Authors This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). | |
| dc.source.uri | https://pubmed.ncbi.nlm.nih.gov/30930126/ | |
| dc.subject | PDX1 | en_US |
| dc.subject | Transactivation domain | en_US |
| dc.subject | beta-Cell differentiation | en_US |
| dc.subject | Insulin secretion | en_US |
| dc.subject | PDX1-Bound genes | en_US |
| dc.title | Point mutations in the PDX1 transactivation domain impair human beta-cell development and function | en_US |
| dc.type | Article | en_US |
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