Characterization of Novel WFS1 Variants in Three Diabetes Pedigrees

作者：C. Liu, HangYu Fang, Dong Wang, Yiping Cheng, Ping Shi, Cui-Hua Yu, Xiaohong Li, Hui Zhao, Wei Hou, Zhen-kui Guo, Chao Xu, Qingbo Guan · 发表于：Journal of Diabetes · 年份：2025 · DOI：10.1111/1753-0407.70114 · 被引用次数：2 · 研究领域：Endoplasmic Reticulum Stress and Disease、Galectins and Cancer Biology、Glycosylation and Glycoproteins Research

BACKGROUND: Mutations in the WFS1 gene are implicated in Wolfram syndrome (WS), Wolfram-like syndrome (WFLS), and maturity-onset diabetes of the young (MODY). Wolfram syndrome 1 (WFS1) is a diabetes-related gene encoding wolframin, a glycoprotein with nine transmembrane domains localized in the endoplasmic reticulum. However, the relationship between WFS1 mutations and their associated phenotypes remains incompletely understood, requiring additional patient data collection for further investigation. Here we collected and analyzed clinical data from three diabetes pedigrees, and to assess the genotype-phenotype correlation. METHODS: High-throughput sequencing was employed to detect WFS1 gene mutations, followed by pathogenicity and conservation analysis using bioinformatics software. A three-dimensional wolframin protein structure was constructed to investigate the potential effects of the mutations. Moreover, the distribution of WFS1 mutations and their associated clinical phenotypes were analyzed by summarizing genetic variations of the WFS1 gene recorded in the Human Gene Mutation Database. RESULTS: Four heterozygous WFS1 mutations were identified in three diabetes families. Among these, c.1523_1524del/p.Y508Cfs*34 was identified as a frameshift mutation, while the others were missense mutations. Bioinformatics predictions revealed that c.766A>G/p.K256E is a benign and novel mutation, whereas the remaining mutations were classified as pathogenic. Furthermore, c.985T>A/p.F32...