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

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.