A WFS1 variant disrupting acceptor splice site uncovers the impact of alternative splicing on beta cell apoptosis in a patient with Wolfram syndrome – published online 09/11/2024

Raniero Chimienti, Silvia Torchio, Gabriel Siracusano, Valentina Zamarian, Laura Monaco, Marta Tiffany Lombardo, Silvia Pellegrini, Fabio Manenti, Federica Cuozzo, Greta Rossi, Paola Carrera, Valeria Sordi, Vania Broccoli, Riccardo Bonfanti, Giorgio Casari, Giulio Frontino, Lorenzo Piemonti

Wolfram syndrome 1 (WS1), a rare inherited disorder, severely impacts the survival of pancreatic beta cells, contributing to early-onset diabetes in affected individuals. In this issue, Chimienti and Torchio et al (https://doi.org/10.1007/s00125-024-06307-0) investigate how an acceptor splice site mutation in the WFS1 gene promotes the production of both incomplete proteins and premature termination codon (PTC)-carrying transcripts. Using patient-derived induced pluripotent stem cells differentiated into pancreatic beta cells, the authors demonstrate that, under cell stress and inflammatory conditions, these PTC-carrying transcripts evade the nonsense-mediated decay (NMD) mechanism, leading to their dramatic accumulation and predisposing beta cells to the defective unfolded protein response and apoptosis. As several WFS1 gene mutations introduce a PTC, the authors conclude that NMD inhibition and the accumulation of PTC-carrying mRNAs may represent new molecular targets for effective WS1 therapies and for mitigating beta cell damage under conditions of stress and inflammation.