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An HNF1α truncation associated with maturity-onset diabetes of the young impairs pancreatic progenitor differentiation by antagonizing HNF1β function

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Ana Maria Cujba, Mario E. Alvarez-Fallas, Sergio Pedraza-Arevalo, Anna Laddach, Maggie H. Shepherd, Andrew T. Hattersley, Fiona M. Watt, Rocio Sancho

Original languageEnglish
Article number110425
JournalCell Reports
Issue number9
Published1 Mar 2022

Bibliographical note

Funding Information: We thank Francesca Spagnoli and Anne Grapin-Botton for critical reading of the manuscript and Franca Fraternali for sharing discussions about the genomic analysis. We thank Davide Danovi for access to HipSci lines. A.-M.C. is supported by a Wellcome Trust PhD fellowship (108874/Z/15/Z). M.H.S. is supported by the NIHR Exeter Clinical Research Facility and is an NIHR Senior Nurse and Midwife Research Leader. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. This work was supported by a Wellcome Seed Award in Science (207529/Z/17/Z), MRC grant ( MR/S000011/1 ) and MRC/JDRF grant ( MR/T015470/1 ) to R.S. Publisher Copyright: © 2022 The Authors

King's Authors


The HNF1αp291fsinsC truncation is the most common mutation associated with maturity-onset diabetes of the young 3 (MODY3). Although shown to impair HNF1α signaling, the mechanism by which HNF1αp291fsinsC causes MODY3 is not fully understood. Here we use MODY3 patient and CRISPR/Cas9-engineered human induced pluripotent stem cells (hiPSCs) grown as 3D organoids to investigate how HNF1αp291fsinsC affects hiPSC differentiation during pancreatic development. HNF1αp291fsinsC hiPSCs shows reduced pancreatic progenitor and β cell differentiation. Mechanistically, HNF1αp291fsinsC interacts with HNF1β and inhibits its function, and disrupting this interaction partially rescues HNF1β-dependent transcription. HNF1β overexpression in the HNF1αp291fsinsC patient organoid line increases PDX1+ progenitors, while HNF1β overexpression in the HNF1αp291fsinsC patient iPSC line partially rescues β cell differentiation. Our study highlights the capability of pancreas progenitor-derived organoids to model disease in vitro. Additionally, it uncovers an HNF1β-mediated mechanism linked to HNF1α truncation that affects progenitor differentiation and could explain the clinical heterogeneity observed in MODY3 patients.

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