Zhang Juan-Juan, Dai Tong-Tong, Wang Jun-Qi, Yin Ming-Yue, Yang Yuan-Yan, Jiang Li, Xia Bei-Jun, Cui Zhuo-Zhou, Lu Wen-Li, Hu Rong-Gui, Li Chuan-Yin, Dong Zhi-Ya, Xiao Yuan
Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai 200025, China.
Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Hangzhou, Zhejiang Province, China.
Pediatr Diabetes. 2025 Jul 31;2025:9955995. doi: 10.1155/pedi/9955995. eCollection 2025.
Wolfram syndrome type 1 gene (), which encodes a transmembrane (TM) structural protein (wolframin), is essential for several biological processes. Mutations of , 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 , 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 variants from ClinVar were included to analyze variant-phenotype association. Genetic testing revealed 3 mutations with unclear pathogenicity in 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) (=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 (=0.008, OR 22.013 [95% CI: 2.270-213.428]). The functional analysis of the three variants of uncertain significance in 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 -associated disease.
1型沃夫勒姆综合征基因（）编码一种跨膜（TM）结构蛋白（沃尔弗拉姆蛋白），对多种生物学过程至关重要。该基因的突变，无论是常染色体显性还是隐性遗传，都与广泛的临床谱相关。进行了分子遗传学检测，并评估了3例与WFS1相关病例的临床表型。揭示了MIN6细胞的表达、活力以及内质网（ER）应激情况，还对变异型WFS1蛋白进行了结构分析。此外，纳入了来自ClinVar的总共75个致病变异，以分析变异-表型关联。基因检测在3例早发性糖尿病患者的中发现了3个致病性不明的突变，包括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细胞活力降低以及内质网应激增强。蛋白质稳定性和结构分析显示，内质网腔结构域中的p.R685C变异以及ATP6VIA相互作用区域中的p.A57T变异的蛋白质稳定性增加且分子灵活性增强，而细胞质区域EF-手结构域中的p.G205S变异使蛋白质不稳定且结构僵化。值得注意的是，拓扑结构被发现是泌尿系统症状（USs）的一个独立危险因素（=0.007，比值比[OR]4.768[95%置信区间（CI）：1.531 - 14.854]）。令人惊讶的是，细胞质中的变异比内质网腔结构域中的变异具有更高的泌尿系统症状风险（=0.008，OR 22.013[95%CI：2.270 - 213.428]）。对中3个意义不明确的变异进行的功能分析表明，沃尔弗拉姆蛋白存在定量和定性损伤，具有已证实的致病性。WFS1蛋白的拓扑结构可能在相关疾病中β细胞和泌尿系统缺陷的发病机制中起重要作用。
