{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T21:52:35Z","timestamp":1781646755966,"version":"3.54.5"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":40,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370828"],"award-info":[{"award-number":["82370828"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jiangsu Provincial Medical Key Discipline","award":["ZDXK202202"],"award-info":[{"award-number":["ZDXK202202"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Wolfram syndrome is a rare disease caused by the mutation of WFS1 gene, characterized as s spectrum of disorders. We aim to investigate the clinical features and pathogenic mechanisms of a WFS1 missense mutation inducing atypical phenotype characterized solely by isolated diabetes mellitus (DM).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Proband and her extended families were investigated to identify mutations in the WFS1 gene. Islet function analysis was conducted to assess beta-cell function of the proband and other mutation carriers and the proband was follow-up for five years. HOMA-IR and HOMA-\u03b2 were calculated to reflect insulin sensitivity and beta-cell function. In vitro experiments were conducted to evaluate the effects of WFS1 mutations. Through transfection of wild type (WT) and mutant WFS1 plasmids into MIN6 cells, we investigate the effects of mutations on endoplasmic reticulum (ER) stress and insulin processing. A missense mutation in WFS1 (c.173\u00a0C\u2009&gt;\u2009T, p.A58V) was identified in a patient with non-syndromic diabetes and five of her family members. Islet function analysis suggested heterogeneity of beta-cell function, with notable differences of HOMA-IR and HOMA-\u03b2 among the proband and family members. In vitro experiments demonstrated that the WFS1 mutations activates ER stress response, leading to an increase in the levels of p-PERK, XBP1s, ATF4 and pIRE1-\u03b1. WFS1 mutations also led to impaired insulin biosynthesis, manifested by the accumulation of proinsulin and an increased proinsulin-to-insulin ratio.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The p.A58V WFS1 mutation is implicated in a non-syndromic DM phenotype and variable beta-cell function. This mutation activates ER stress pathways and disrupts proinsulin processing, offering insights into the molecular pathogenesis of this unique form of WS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04291-9","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T13:10:45Z","timestamp":1774617045000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["WFS1-related isolated diabetes induced by a WFS1 missense mutation: focus on the isolated diabetes phenotype"],"prefix":"10.1186","volume":"21","author":[{"given":"Mei","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianying","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2717-7167","authenticated-orcid":false,"given":"Mei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"4291_CR1","first-page":"1","volume":"17","author":"MT Pallotta","year":"2019","unstructured":"Pallotta MT, Tascini G, Crispoldi R, Orabona C, Mondanelli G, Grohmann U, et al. Wolfram syndrome, a rare neurodegenerative disease: From pathogenesis to future treatment perspectives. J Translational Med [Internet]. 2019;17:1\u201312.","journal-title":"J Translational Med [Internet]"},{"key":"4291_CR2","doi-asserted-by":"publisher","first-page":"1458","DOI":"10.1016\/S0140-6736(95)92473-6","volume":"346","author":"T Barrett","year":"1995","unstructured":"Barrett T, Bundey SE, Macleod AF. Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet. 1995;346:1458\u201363.","journal-title":"Lancet"},{"key":"4291_CR3","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.2337\/diacare.18.12.1566","volume":"18","author":"L Estabrooks","year":"1995","unstructured":"Estabrooks L. Morbidity and Mortality in the Wolfram Syndrome. Diabetes Care. 1995;18:1566\u201370.","journal-title":"Diabetes Care"},{"key":"4291_CR4","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1210\/clinem\/dgac002","volume":"107","author":"NK Shrestha","year":"2022","unstructured":"Shrestha NK, Burke PC, Nowacki AS, Terpeluk P, Gordon SM. WFS1 gene associated diabetes phenotypes and identification of a founder mutation in Southern India. J Clin Endocrinol Metab. 2022;107:1328\u201336.","journal-title":"J Clin Endocrinol Metab"},{"key":"4291_CR5","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.gene.2015.04.040","volume":"566","author":"ME Blanco-Aguirre","year":"2015","unstructured":"Blanco-Aguirre ME, la Parra DR, De, Tapia-Garcia H, Gonzalez-Rodriguez J, Welskin D, Arroyo-Yllanes ME, et al. Identification of unsuspected Wolfram syndrome cases through clinical assessment and WFS1 gene screening in type 1 diabetes mellitus patients. Gene [Internet]. 2015;566:63\u20137.","journal-title":"Gene [Internet]"},{"key":"4291_CR6","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/2441","volume":"20","author":"H Inoue","year":"1998","unstructured":"Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, Bernal-Mizrachi E, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998;20:143\u20138.","journal-title":"Nat Genet"},{"key":"4291_CR7","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.1093\/hmg\/ddg214","volume":"12","author":"S Hofmann","year":"2003","unstructured":"Hofmann S, Philbrook C, Gerbitz KD, Bauer MF. Wolfram syndrome: Structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. Hum Mol Genet. 2003;12:2003\u201312.","journal-title":"Hum Mol Genet"},{"key":"4291_CR8","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1172\/JCI39678","volume":"120","author":"SG Fonseca","year":"2010","unstructured":"Fonseca SG, Ishigaki S, Oslowski CM, Lu S, Lipson KL, Ghosh R, et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest. 2010;120:744\u201355.","journal-title":"J Clin Invest"},{"key":"4291_CR9","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.1007\/s00125-005-1947-4","volume":"48","author":"AC Riggs","year":"2005","unstructured":"Riggs AC, Bernal-Mizrachi E, Ohsugi M, Wasson J, Fatrai S, Welling C, et al. Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis. Diabetologia. 2005;48:2313\u201321.","journal-title":"Diabetologia"},{"key":"4291_CR10","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1093\/hmg\/ddq568","volume":"20","author":"M Hatanaka","year":"2011","unstructured":"Hatanaka M, Tanabe K, Yanai A, Ohta Y, Kondo M, Akiyama M, et al. Wolfram syndrome 1 gene (WFS1) product localizes to secretory granules and determines granule acidification in pancreatic \u03b2-cells. Hum Mol Genet. 2011;20:1274\u201384.","journal-title":"Hum Mol Genet"},{"key":"4291_CR11","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1006\/mgme.2000.3107","volume":"72","author":"M G\u00f3mez-Zaera","year":"2001","unstructured":"G\u00f3mez-Zaera M, Strom TM, Rodr\u00edguez B, Estivill X, Meitinger T, Nunes V. Presence of a major WFS1 mutation in Spanish Wolfram Syndrome pedigrees. Mol Genet Metab. 2001;72:72\u201381.","journal-title":"Mol Genet Metab"},{"key":"4291_CR12","doi-asserted-by":"publisher","unstructured":"Urano F. Diabetes: targeting endoplasmic reticulum to combat juvenile diabetes. Nature Reviews Endocrinology [Internet]. 2014;10:129\u201330. Available from: https:\/\/doi.org\/10.1038\/nrendo.2013.261.","DOI":"10.1038\/nrendo.2013.261"},{"key":"4291_CR13","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/j.tips.2019.07.011","volume":"40","author":"D Abreu","year":"2019","unstructured":"Abreu D, Urano F. Current Landscape of Treatments for Wolfram Syndrome. Trends Pharmacol Sci [Internet]. 2019;40:711\u20134.","journal-title":"Trends Pharmacol Sci [Internet]"},{"key":"4291_CR14","doi-asserted-by":"publisher","first-page":"4012","DOI":"10.1093\/hmg\/ddn304","volume":"17","author":"PA Zalloua","year":"2008","unstructured":"Zalloua PA, Azar ST, Deel\u00e9pine M, Makhoul NJ, Blanc H, Sanyoura M, et al. WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon. Hum Mol Genet. 2008;17:4012\u201321.","journal-title":"Hum Mol Genet"},{"key":"4291_CR15","doi-asserted-by":"publisher","first-page":"3943","DOI":"10.2337\/db13-0571","volume":"62","author":"LL Bonnycastle","year":"2013","unstructured":"Bonnycastle LL, Chines PS, Hara T, Huyghe JR, Swift AJ, Heikinheimo P, et al. Autosomal dominant diabetes arising from a wolfram syndrome 1 mutation. Diabetes. 2013;62:3943\u201350.","journal-title":"Diabetes"},{"key":"4291_CR16","doi-asserted-by":"publisher","first-page":"2180","DOI":"10.1007\/s00125-018-4690-3","volume":"61","author":"V Bansal","year":"2018","unstructured":"Bansal V, Boehm BO, Darvasi A. Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals. Diabetologia. 2018;61:2180\u20138.","journal-title":"Diabetologia"},{"key":"4291_CR17","doi-asserted-by":"publisher","first-page":"121","DOI":"10.2337\/db19-0510","volume":"69","author":"M Li","year":"2020","unstructured":"Li M, Wang S, Xu K, Chen Y, Fu Q, Gu Y, et al. High prevalence of a monogenic cause in han Chinese diagnosed with type 1 diabetes, partly driven by nonsyndromic recessive wfs1 mutations. Diabetes. 2020;69:121\u20136.","journal-title":"Diabetes"},{"key":"4291_CR18","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1530\/EJE-21-0097","volume":"186","author":"M Zhu","year":"2021","unstructured":"Zhu M, Li Y, Dong G, Chen X, Huang K, Wu W, et al. Prevalence and phenotypic features of diabetes due to recessive, non-syndromic WFS1 mutations. Eur J Endocrinol. 2021;186:163\u201370.","journal-title":"Eur J Endocrinol"},{"key":"4291_CR19","doi-asserted-by":"publisher","unstructured":"Rigoli L, Bramanti P, Di Bella C, De Luca F. Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease. Pediatric Research [Internet]. 2018;83:921\u20139. Available from: https:\/\/doi.org\/10.1038\/pr.2018.17.","DOI":"10.1038\/pr.2018.17"},{"key":"4291_CR20","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1111\/cge.12437","volume":"87","author":"A Chaussenot","year":"2015","unstructured":"Chaussenot A, Rouzier C, Quere M, Plutino M, Ait-El-Mkadem S, Bannwarth S, et al. Mutation update and uncommon phenotypes in a French cohort of 96 patients with WFS1-related disorders. Clin Genet. 2015;87:430\u20139.","journal-title":"Clin Genet"},{"key":"4291_CR21","doi-asserted-by":"publisher","first-page":"39609","DOI":"10.1074\/jbc.M507426200","volume":"280","author":"SG Fonseca","year":"2005","unstructured":"Fonseca SG, Fukuma M, Lipson KL, Nguyen LX, Allen JR, Oka Y, et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pacreatic \u03b2-cells. J Biol Chem. 2005;280:39609\u201315.","journal-title":"J Biol Chem"},{"key":"4291_CR22","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1093\/hmg\/ddl081","volume":"15","author":"T Yamada","year":"2006","unstructured":"Yamada T, Ishihara H, Tamura A, Takahashi R, Yamaguchi S, Takei D, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic \u03b2-cells. Hum Mol Genet. 2006;15:1600\u20139.","journal-title":"Hum Mol Genet"},{"key":"4291_CR23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-021-27344-y","volume":"12","author":"L Wang","year":"2021","unstructured":"Wang L, Liu H, Zhang X, Song E, Wang Y, Xu T, et al. WFS1 functions in ER export of vesicular cargo proteins in pancreatic \u03b2-cells. Nat Commun. 2021;12:1\u201313.","journal-title":"Nat Commun"},{"key":"4291_CR24","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1111\/pedi.13291","volume":"23","author":"MK Ray","year":"2022","unstructured":"Ray MK, Chen L, White NH, Ni R, Hershey T, Marshall BA. Longitudinal progression of diabetes mellitus in Wolfram syndrome: The Washington University Wolfram Research Clinic experience. Pediatr Diabetes. 2022;23:212\u20138.","journal-title":"Pediatr Diabetes"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-026-04291-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04291-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04291-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T21:00:02Z","timestamp":1781643602000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13023-026-04291-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":24,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4291"],"URL":"https:\/\/doi.org\/10.1186\/s13023-026-04291-9","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]},"assertion":[{"value":"23 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (2019-SR-121.A1), in conformity with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent for publication was obtained from all participants.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that no conflicts of interest exist.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure of conflict of interest"}}],"article-number":"180"}}