An HNF1α truncation associated with maturity-onset diabetes of the young impairs pancreatic progenitor differentiation by antagonizing HNF1β function
Ana-Maria Cujba, Mario Enrique Alvarèz Fallas, Sergio Pedraza‐Arévalo, Anna Laddach, Maggie Shepherd, Andrew T. Hattersley, Fiona M. Watt, Rocı́o Sancho
Abstract
The HNF1α p291fsinsC 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 HNF1α p291fsinsC 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 HNF1α p291fsinsC affects hiPSC differentiation during pancreatic development. HNF1α p291fsinsC hiPSCs shows reduced pancreatic progenitor and β cell differentiation. Mechanistically, HNF1α p291fsinsC interacts with HNF1β and inhibits its function, and disrupting this interaction partially rescues HNF1β-dependent transcription. HNF1β overexpression in the HNF1α p291fsinsC patient organoid line increases PDX1 + progenitors, while HNF1β overexpression in the HNF1α p291fsinsC 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.