Defects of WFS1-mediated peptide hormones secretion contribute to the manifestations of Wolfram syndrome.

Aims: The study aims to investigate whether WFS1 is involved in the regulation of the exportation and secretion of other peptide hormones, as well as to elucidate the precise molecular mechanisms underlying WS caused by pathogenic mutations in the WFS1 gene.

Materials And Methods: The plasma proteome from the WS patients (n = 2, male) and WFS1-deficient mice (n = 5, male) were analyzed using liquid-chromatography tandem mass spectrometry (LC-MS/MS), while age- and gender-matched healthy individuals and wildtype (WT) mice serve as controls. WFS1-deficient mice were intraperitoneally injected with IGF1 starting from 4 weeks of age. Body weight was monitored every 2 days, fasting blood glucose and glucose tolerance test were performed on the day 30 and day 40 after injection of IGF1, respectively. BiFC (bimolecular fluorescence complementation) and Co-immunoprecipitation (IP) were used to analyze the interaction between WFS1 and peptide hormones. Confocal microscopy was employed to analyze the colocalization of IGF1 with ER and Golgi.

Key Findings: Peptide hormones are deficient in both the plasma of WS patients and WFS1-deficient mice. WFS1 binds to and mediates the secretion of these peptide hormones, suggesting that WFS1 serves as a general COPII vesicular receptor for sorting peptide hormones. Interestingly, the WFS1 pathogenic mutations significantly disrupt its interaction with these peptide hormones. Furthermore, intraperitoneal administration of IGF1 partially attenuates high blood glucose levels in WFS1-deficient male mice.

Significance: This study suggests that WS is characterized by defective peptide hormone secretion and proposes administration of these deficient peptide hormones as a promising treatment regimen for WS.