Authors
Ksenia G Kuznetsova, Jakub Vašíček, Dafni Skiadopoulou, Lucas Unger, Rachel Anand Nethala, Michael Wierer, Luiza Ghila, Stefan Johansson, Pål Rasmus Njølstad, Simona Chera, Bente Berg Johansson, Alisa Manning, Marc Vaudel
Published in
Proteomics. Pages e70166. Aug 05, 2026. Epub Aug 05, 2026.
Abstract
This discovery study investigated the impact of MODY-associated mutations in hepatocyte nuclear factors HNF1A and HNF1B on the cellular proteome, aiming to identify affected pathways and advance understanding of diabetes pathogenesis. Human induced pluripotent stem cells (hiPSCs) carrying the HNF1A frameshift mutation (p.Pro291fsinsC) were differentiated into pancreatic progenitors, and renal proximal tubule epithelial cells (RPTECs) were engineered to overexpress HNF1B with the S148L point mutation. Label-free quantitative proteomics was performed using data-dependent and data-independent acquisition on Orbitrap and timsTOF mass spectrometers. Pathway enrichment was analyzed using Qiagen IPA, Hallmark gene sets, and STRING networks. Comprehensive proteome coverage (over 7000 proteins) revealed consistent downregulation of oxidative phosphorylation, mitochondrial function, and interferon signaling pathways. Both models exhibited suppression of innate immune responses, with overlapping downregulated proteins, including members of the OAS, IFIT, and MX1 families. Using label-free proteomics, we show that MODY-associated mutations in HNF1A and HNF1B suppress mitochondrial function and interferon signaling and are additionally associated with reduced abundance of predicted targets such as A1CF as well as diabetes-related proteins including SCGN, supporting their role in diabetes pathogenesis.
PMID:
42554236
Bibliographic data and abstract were imported from PubMed on 05 Aug 2026.
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