WFS1-related isolated diabetes induced by a WFS1 missense mutation: focus on the isolated diabetes phenotype.

backgroundWolfram syndrome is a rare disease caused by the mutation of WFS1 gene, characterized as s spectrum of disorders. We aim to investigate the clinical features and pathogenic mechanisms of a WFS1 missense mutation inducing atypical phenotype characterized solely by isolated diabetes mellitus (DM).

resultsProband and her extended families were investigated to identify mutations in the WFS1 gene. Islet function analysis was conducted to assess beta-cell function of the proband and other mutation carriers and the proband was follow-up for five years. HOMA-IR and HOMA-β were calculated to reflect insulin sensitivity and beta-cell function. In vitro experiments were conducted to evaluate the effects of WFS1 mutations. Through transfection of wild type (WT) and mutant WFS1 plasmids into MIN6 cells, we investigate the effects of mutations on endoplasmic reticulum (ER) stress and insulin processing. A missense mutation in WFS1 (c.173 C > T, p.A58V) was identified in a patient with non-syndromic diabetes and five of her family members. Islet function analysis suggested heterogeneity of beta-cell function, with notable differences of HOMA-IR and HOMA-β among the proband and family members. In vitro experiments demonstrated that the WFS1 mutations activates ER stress response, leading to an increase in the levels of p-PERK, XBP1s, ATF4 and pIRE1-α. WFS1 mutations also led to impaired insulin biosynthesis, manifested by the accumulation of proinsulin and an increased proinsulin-to-insulin ratio.

conclusionThe p.A58V WFS1 mutation is implicated in a non-syndromic DM phenotype and variable beta-cell function. This mutation activates ER stress pathways and disrupts proinsulin processing, offering insights into the molecular pathogenesis of this unique form of WS.