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Article History

Received: 12 March 2024

Accepted: 21 August 2024

First Online: 9 November 2024

Acknowledgements

: We thank the Advanced Light and Electron Microscopy BioImaging Center (ALEMBIC) at San Raffaele Scientific Institute, Milan (Italy), for confocal immunofluorescence images and the Flow cytometry Resource, Advanced Cytometry Technical Applications Laboratory (FRACTAL), at San Raffaele Scientific Institute, Milan (Italy), for cell sorting experiments. We also thank F. Giannese and D. Lazarevic at the Center for Omics Sciences (COSR) of San Raffaele Scientific Institute, Milan (Italy), for providing support in library preparation, deep sequencing and bioinformatic analysis. We are grateful to A. Lombardo at the San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), San Raffaele Scientific Institute, Milan (Italy), for the access to BLS2 work areas and the use of the 4D-Nucleofector System. S. Torchio conducted this study as partial fulfilment of an international PhD in Molecular Medicine at Vita-Salute San Raffaele University.

: The in silico predicted N-terminal domain structure file of WT wolframin was deposited in the ModelArchive, together with procedures, ramachandran plots, inter-residue distance deviation and IDDT scores, and Gromacs configuration files (doi/10.5452/ma-cg3qd). The deep-sequencing data as fastq files used to generate consensus sequences of AS isoforms of <i>WFS1</i> are available in the SRA database (BioProject PRJNA1109747). All raw data that were not directly included in the manuscript or that have not been deposited in online repositories, are available on request from the corresponding authors.

: This study was supported by a private family donation financing investigation on Wolfram syndrome 1 at the Diabetes Research Institute (DRI) of the IRCCS San Raffaele Hospital. Part of the activities were also supported through the funds from the European Union - Next Generation EU - PNRR M6C2 - Investment 2.1 Enhancement and strengthening of NHS biomedical research (PNRR-MR1-2022-12375914).

: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

: RC, GF and LP were responsible for the conception and design of the study. ST contributed to the experimental design and to the collection and analysis of the data, together with RC and GS. RC, ST, GS, VZ, LM, MTL, FM and FC conducted wet experiments. SP supported collection of data during revision activities. RC performed bioinformatic analysis. RC, ST, GS and LP interpreted the results. PC followed genetic testing in clinical practice. Medical evaluations and patient specimen collection was performed by GF and RB. GR and VB supported cell reprogramming activities. VZ, LM, MTL, SP and VS performed stem cell differentiation and beta cell function analysis. GC contributed to data interpretation. RC and ST wrote the original draft, and all authors contributed to the critical review and editing of the manuscript. All authors approved the final version to be published. LP takes responsibility for the integrity of the data and is the guarantor of this work.