{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T14:47:00Z","timestamp":1772981220514,"version":"3.50.1"},"reference-count":48,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":211,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Diabetes"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n                    Wolfram syndrome type 1 gene (\n                    <jats:italic>WFS1<\/jats:italic>\n                    ), which encodes a transmembrane (TM) structural protein (wolframin), is essential for several biological processes. Mutations of\n                    <jats:italic>WFS1<\/jats:italic>\n                    , autosomal dominant or recessive inherited, are related to a broad clinical spectrum. Molecular genetic tests were performed, and clinical phenotypes of three WFS1\u2010associated cases were evaluated. The expression of\n                    <jats:italic>WFS1<\/jats:italic>\n                    , 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\n                    <jats:italic>WFS1<\/jats:italic>\n                    variants from ClinVar were included to analyze variant\u2010phenotype association. Genetic testing revealed 3 mutations with unclear pathogenicity in\n                    <jats:italic>WFS1<\/jats:italic>\n                    of the 3 patients with early\u2010onset diabetes, including c.613G &gt;A (p.G205S), c.2053C &gt;T (p.R685C), and c.169G &gt;A (p.A57T). Decreased expression, reduced \u03b2\u2010cell 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\u2010lumenal domain and p.A57T in the ATP6VIA\u2010interaction region, while destabilized protein and rigidificated structure by p.G205S variant in the EF\u2010hand domain at the cytoplasm region. Remarkably, topology was found an independent risk factor with urological symptoms (USs) (\n                    <jats:italic>p<\/jats:italic>\n                    = 0.007, odds ratio [OR] 4.768 [95% confidence interval (CI): 1.531\u201314.854]). Surprisingly, variants in the cytoplasm had the highest risk with US than ones in the ER\u2010lumenal domain (\n                    <jats:italic>p<\/jats:italic>\n                    = 0.008, OR 22.013 [95% CI: 2.270\u2013213.428]). The functional analysis of the three variants of uncertain significance in\n                    <jats:italic>WFS1<\/jats:italic>\n                    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 \u03b2\u2010cell and urological defects in\n                    <jats:italic>WFS1<\/jats:italic>\n                    \u2010associated disease.\n                  <\/jats:p>","DOI":"10.1155\/pedi\/9955995","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T04:52:37Z","timestamp":1754023957000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Topology of\n                    <i>WFS1<\/i>\n                    Variants Linked With Islet Function and Higher Risk of Urological Symptoms in\n                    <i>WFS1<\/i>\n                    \u2010Associated 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