{"title":"Topology of <i>WFS1</i> Variants Linked With Islet Function and Higher Risk of Urological Symptoms in <i>WFS1</i>-Associated Disease.","authors":"Juan-Juan Zhang, Tong-Tong Dai, Jun-Qi Wang, Ming-Yue Yin, Yuan-Yan Yang, Li Jiang, Bei-Jun Xia, Zhuo-Zhou Cui, Wen-Li Lu, Rong-Gui Hu, Chuan-Yin Li, Zhi-Ya Dong, Yuan Xiao","doi":"10.1155/pedi/9955995","DOIUrl":null,"url":null,"abstract":"<p><p>Wolfram syndrome type 1 gene (<i>WFS1</i>), which encodes a transmembrane (TM) structural protein (wolframin), is essential for several biological processes. Mutations of <i>WFS1</i>, autosomal dominant or recessive inherited, are related to a broad clinical spectrum. Molecular genetic tests were performed, and clinical phenotypes of three WFS1-associated cases were evaluated. The expression of <i>WFS1</i>, viability, and endoplasmic reticulum (ER) stress of the MIN6 cell and structural analysis of the variant WFS1 protein were revealed. Furthermore, a total of 75 pathogenic <i>WFS1</i> variants from ClinVar were included to analyze variant-phenotype association. Genetic testing revealed 3 mutations with unclear pathogenicity in <i>WFS1</i> of the 3 patients with early-onset diabetes, including c.613G >A (p.G205S), c.2053C >T (p.R685C), and c.169G >A (p.A57T). Decreased expression, reduced β-cell viability and enhanced ER stress were found in all variants. Protein stability and structural analysis showed increased protein stability and molecule flexibility of variants p.R685C in the ER-lumenal domain and p.A57T in the ATP6VIA-interaction region, while destabilized protein and rigidificated structure by p.G205S variant in the EF-hand domain at the cytoplasm region. Remarkably, topology was found an independent risk factor with urological symptoms (USs) (<i>p</i>=0.007, odds ratio [OR] 4.768 [95% confidence interval (CI): 1.531-14.854]). Surprisingly, variants in the cytoplasm had the highest risk with US than ones in the ER-lumenal domain (<i>p</i>=0.008, OR 22.013 [95% CI: 2.270-213.428]). The functional analysis of the three variants of uncertain significance in <i>WFS1</i> indicated a quantitative and qualitative damage to wolframin with proven pathogenicity. The topology of the WFS1 protein may play an important role in the pathogenesis of β-cell and urological defects in <i>WFS1</i>-associated disease.</p>","PeriodicalId":19797,"journal":{"name":"Pediatric Diabetes","volume":"2025 ","pages":"9955995"},"PeriodicalIF":5.6000,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12331406/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pediatric Diabetes","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1155/pedi/9955995","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
Abstract
Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane (TM) structural protein (wolframin), is essential for several biological processes. Mutations of WFS1, autosomal dominant or recessive inherited, are related to a broad clinical spectrum. Molecular genetic tests were performed, and clinical phenotypes of three WFS1-associated cases were evaluated. The expression of WFS1, viability, and endoplasmic reticulum (ER) stress of the MIN6 cell and structural analysis of the variant WFS1 protein were revealed. Furthermore, a total of 75 pathogenic WFS1 variants from ClinVar were included to analyze variant-phenotype association. Genetic testing revealed 3 mutations with unclear pathogenicity in WFS1 of the 3 patients with early-onset diabetes, including c.613G >A (p.G205S), c.2053C >T (p.R685C), and c.169G >A (p.A57T). Decreased expression, reduced β-cell viability and enhanced ER stress were found in all variants. Protein stability and structural analysis showed increased protein stability and molecule flexibility of variants p.R685C in the ER-lumenal domain and p.A57T in the ATP6VIA-interaction region, while destabilized protein and rigidificated structure by p.G205S variant in the EF-hand domain at the cytoplasm region. Remarkably, topology was found an independent risk factor with urological symptoms (USs) (p=0.007, odds ratio [OR] 4.768 [95% confidence interval (CI): 1.531-14.854]). Surprisingly, variants in the cytoplasm had the highest risk with US than ones in the ER-lumenal domain (p=0.008, OR 22.013 [95% CI: 2.270-213.428]). The functional analysis of the three variants of uncertain significance in WFS1 indicated a quantitative and qualitative damage to wolframin with proven pathogenicity. The topology of the WFS1 protein may play an important role in the pathogenesis of β-cell and urological defects in WFS1-associated disease.
期刊介绍:
Pediatric Diabetes is a bi-monthly journal devoted to disseminating new knowledge relating to the epidemiology, etiology, pathogenesis, management, complications and prevention of diabetes in childhood and adolescence. The aim of the journal is to become the leading vehicle for international dissemination of research and practice relating to diabetes in youth. Papers are considered for publication based on the rigor of scientific approach, novelty, and importance for understanding mechanisms involved in the epidemiology and etiology of this disease, especially its molecular, biochemical and physiological aspects. Work relating to the clinical presentation, course, management and outcome of diabetes, including its physical and emotional sequelae, is considered. In vitro studies using animal or human tissues, whole animal and clinical studies in humans are also considered. The journal reviews full-length papers, preliminary communications with important new information, clinical reports, and reviews of major topics. Invited editorials, commentaries, and perspectives are a regular feature. The editors, based in the USA, Europe, and Australasia, maintain regular communications to assure rapid turnaround time of submitted manuscripts.