Wolfram syndrome 1 (WS1) is a rare genetic disorder caused by WFS1 variants that disrupt wolframin, an endoplasmic reticulum-associated protein essential for cellular stress responses, Ca2+ homeostasis, and autophagy. Here, we investigated how the c.316-1G>A and c.757A>T WFS1 mutations, which yield partially functional wolframin, affect the molecular functions of β-cells and explored the therapeutic potential of the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide. Pancreatic β-cells obtained from patient-derived induced pluripotent stem cells (iPSCs) carrying this WFS1 variant exhibited reduced insulin processing and impaired secretory granule maturation, as evidenced by proinsulin accumulation and decreased prohormone convertase PC1/3. Moreover, they exhibited dysregulated Ca2+ fluxes due to altered transcription of Ca2+-related genes, including CACNA1D, and significantly reduced SNAP25 levels, leading to uncoordinated oscillations and poor glucose responsiveness. Affected cells also showed increased autophagic flux and heightened susceptibility to inflammatory cytokine-induced apoptosis. Notably, liraglutide treatment rescued these defects by normalizing Ca2+ handling, enhancing insulin processing and secretion, and reducing apoptosis, likely through modulation of the unfolded protein response. These findings underscore the importance of defining mutation-specific dysfunctions in WS1 and support targeting the GLP-1/GLP-1R axis as a therapeutic strategy.
Article highlights: The molecular basis of WFS1-related mutations remains poorly investigated, and no definitive therapies exist for Wolfram syndrome 1. We dissected the molecular defects associated with c.316-1G>A and c.757A>T WFS1 mutations in patient-derived induced pluripotent stem cell islets and analyzed whether they are potential therapeutic targets of the glucagon-like peptide 1 receptor agonist liraglutide. We found impaired insulin granule maturation, altered Ca2+ fluxes, increased autophagic activity, and heightened susceptibility to inflammatory apoptosis in mutated cells. Liraglutide restored critical β-cell functions suggesting a route for personalized therapy based on WFS1 mutations.
© 2025 by the American Diabetes Association.