Topology of WFS1 Variants Linked With Islet Function and Higher Risk of Urological Symptoms in WFS1-Associated Disease.

IF 5.6 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Pediatric Diabetes Pub Date : 2025-07-31 eCollection Date: 2025-01-01 DOI:10.1155/pedi/9955995
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
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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.

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与胰岛功能相关的WFS1变异的拓扑结构和WFS1相关疾病泌尿系统症状的高风险
Wolfram综合征1型基因(WFS1)编码一种跨膜(TM)结构蛋白(wolframin),对多种生物过程至关重要。WFS1的突变,常染色体显性或隐性遗传,与广泛的临床谱有关。进行了分子遗传学检测,并评估了3例wfs1相关病例的临床表型。研究结果显示,MIN6细胞中WFS1的表达、生存能力、内质网(ER)应激以及变异WFS1蛋白的结构分析。此外,我们还纳入了来自ClinVar的75个致病WFS1变异体来分析变异体与表型的关联。基因检测显示3例早发性糖尿病患者WFS1中有3个致病性不明确的突变,分别为c.613G >A (p.G205S)、c.2053C >T (p.R685C)和c.169G >A (p.A57T)。在所有变异中均发现表达降低、β细胞活力降低和内质网应激增强。蛋白质稳定性和结构分析表明,变异体p.R685C在er -管腔结构域和p.A57T在atp6via -相互作用区增加了蛋白质稳定性和分子灵活性,而变异体p.G205S在胞质区EF-hand结构域破坏了蛋白质稳定性和结构刚性。值得注意的是,拓扑学是泌尿系统症状(USs)的独立危险因素(p=0.007,优势比[OR] 4.768[95%可信区间(CI): 1.531-14.854])。令人惊讶的是,细胞质中的变异比er -管腔域的变异与US的风险最高(p=0.008, OR 22.013 [95% CI: 2.270-213.428])。对WFS1中三个意义不确定的变异的功能分析表明,对黑钨矿蛋白的定量和定性损害具有明确的致病性。WFS1蛋白的拓扑结构可能在WFS1相关疾病中β细胞和泌尿系统缺陷的发病机制中起重要作用。
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来源期刊
Pediatric Diabetes
Pediatric Diabetes 医学-内分泌学与代谢
CiteScore
6.60
自引率
14.70%
发文量
141
审稿时长
4-8 weeks
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.
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