{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T20:08:14Z","timestamp":1768421294138,"version":"3.49.0"},"reference-count":55,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2023QH104"],"award-info":[{"award-number":["ZR2023QH104"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023M742158"],"award-info":[{"award-number":["2023M742158"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023TQ0202"],"award-info":[{"award-number":["2023TQ0202"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2506006"],"award-info":[{"award-number":["2023YFC2506006"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2506000"],"award-info":[{"award-number":["2023YFC2506000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270839"],"award-info":[{"award-number":["82270839"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Diabetes"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Mutations in the <jats:italic>WFS1<\/jats:italic> gene are implicated in Wolfram syndrome (WS), Wolfram\u2010like syndrome (WFLS), and maturity\u2010onset diabetes of the young (MODY). Wolfram syndrome 1 (<jats:italic>WFS1<\/jats:italic>) is a diabetes\u2010related gene encoding wolframin, a glycoprotein with nine transmembrane domains localized in the endoplasmic reticulum. However, the relationship between <jats:italic>WFS1<\/jats:italic> mutations and their associated phenotypes remains incompletely understood, requiring additional patient data collection for further investigation. Here we collected and analyzed clinical data from three diabetes pedigrees, and to assess the genotype\u2010phenotype correlation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>High\u2010throughput sequencing was employed to detect <jats:italic>WFS1<\/jats:italic> gene mutations, followed by pathogenicity and conservation analysis using bioinformatics software. A three\u2010dimensional wolframin protein structure was constructed to investigate the potential effects of the mutations. Moreover, the distribution of <jats:italic>WFS1<\/jats:italic> mutations and their associated clinical phenotypes were analyzed by summarizing genetic variations of the <jats:italic>WFS1<\/jats:italic> gene recorded in the Human Gene Mutation Database.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four heterozygous <jats:italic>WFS1<\/jats:italic> mutations were identified in three diabetes families. Among these, c.1523_1524del\/p.Y508Cfs*34 was identified as a frameshift mutation, while the others were missense mutations. Bioinformatics predictions revealed that c.766A&gt;G\/p.K256E is a benign and novel mutation, whereas the remaining mutations were classified as pathogenic. Furthermore, c.985T&gt;A\/p.F329I was validated as a MODY\u2010associated mutation within a specific family. A comprehensive summary of all reported <jats:italic>WFS1<\/jats:italic> mutations indicated that mutations associated with WS phenotypes are approximately 18.7 times more frequent than those associated with MODY phenotypes. Missense mutations accounted for the highest proportion of <jats:italic>WFS1<\/jats:italic> mutations associated with different clinical phenotypes, with the majority located in exon 8.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study identified a novel <jats:italic>WFS1<\/jats:italic> mutation, c.766A&gt;G\/p.K256E, expanding the known mutation spectrum of the <jats:italic>WFS1<\/jats:italic> gene. The findings suggest that inactivating mutations and benign missense mutations are associated with more severe WS phenotypes compared to purely pathogenic missense mutations. Moreover, c.985T&gt;A\/p.F329I was validated as a MODY associated mutation. Finally, by summarizing the genotype\u2013phenotype relationships of <jats:italic>WFS1<\/jats:italic>, it is concluded that the <jats:italic>WFS1<\/jats:italic> gene shows a different association with WS, WFSL and MODY.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1753-0407.70114","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T04:13:46Z","timestamp":1752207226000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Characterization of Novel <scp><i>WFS1<\/i><\/scp> Variants in Three Diabetes Pedigrees"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8617-907X","authenticated-orcid":false,"given":"ChangQing","family":"Liu","sequence":"first","affiliation":[{"name":"Shandong First Medical University and Shandong Academy of Medical Sciences Jinan, China. Endocrine and Metabolic Diseases Hospital of Shandong First Medical University. Shandong Institute of Endocrine &amp; Metabolic Disease  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"HangYu","family":"Fang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endocrine Glucose &amp; Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology Shandong Provincial Hospital Affiliated to Shandong First Medical University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong First Medical University and Shandong Academy of Medical Sciences Jinan, China. Endocrine and Metabolic Diseases Hospital of Shandong First Medical University. Shandong Institute of Endocrine &amp; Metabolic Disease  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"YiPing","family":"Cheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endocrine Glucose &amp; Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology Shandong Provincial Hospital Affiliated to Shandong First Medical University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Shi","sequence":"additional","affiliation":[{"name":"Shandong Key Laboratory of Endocrinology and Lipid Metabolism  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"ChunXiao","family":"Yu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endocrine Glucose &amp; Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology Shandong Provincial Hospital Affiliated to Shandong First Medical University  Jinan Shandong China"},{"name":"Shandong Key Laboratory of Endocrinology and Lipid Metabolism  Jinan Shandong China"},{"name":"Shandong Institute of Endocrine and Metabolic Diseases  Jinan Shandong China"},{"name":"\u201cChuangxin China\u201d Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases  Jinan Shandong China"},{"name":"Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"XiaoHong","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endocrine Glucose &amp; Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology Shandong Provincial Hospital Affiliated to Shandong First Medical University  Jinan Shandong China"},{"name":"Shandong Key Laboratory of Endocrinology and Lipid Metabolism  Jinan Shandong China"},{"name":"Shandong Institute of Endocrine and Metabolic Diseases  Jinan Shandong China"},{"name":"\u201cChuangxin China\u201d Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases  Jinan Shandong China"},{"name":"Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Shandong First Medical University and Shandong Academy of Medical Sciences Jinan, China. Endocrine and Metabolic Diseases Hospital of Shandong First Medical University. Shandong Institute of Endocrine &amp; Metabolic Disease  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Hou","sequence":"additional","affiliation":[{"name":"The Cancer Prevention and Control Hospital of Tai'an  Tai'an Shangdong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"ZhenKui","family":"Guo","sequence":"additional","affiliation":[{"name":"Shandong First Medical University and Shandong Academy of Medical Sciences Jinan, China. Endocrine and Metabolic Diseases Hospital of Shandong First Medical University. Shandong Institute of Endocrine &amp; Metabolic Disease  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6743-8881","authenticated-orcid":false,"given":"Chao","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endocrine Glucose &amp; Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology Shandong Provincial Hospital Affiliated to Shandong First Medical University  Jinan Shandong China"},{"name":"Shandong Key Laboratory of Endocrinology and Lipid Metabolism  Jinan Shandong China"},{"name":"Shandong Institute of Endocrine and Metabolic Diseases  Jinan Shandong China"},{"name":"\u201cChuangxin China\u201d Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases  Jinan Shandong China"},{"name":"Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"QingBo","family":"Guan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endocrine Glucose &amp; Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology Shandong Provincial Hospital Affiliated to Shandong First Medical University  Jinan Shandong China"},{"name":"Shandong Key Laboratory of Endocrinology and Lipid Metabolism  Jinan Shandong China"},{"name":"Shandong Institute of Endocrine and Metabolic Diseases  Jinan Shandong China"},{"name":"\u201cChuangxin China\u201d Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases  Jinan Shandong China"},{"name":"Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.survophthal.2023.01.012"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2020-107257"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/2441"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.13.2021"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/302609"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2005.06.008"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M310331200"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2006.09.007"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M507426200"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27344-y"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2010.11.005"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-21-0097"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-015-0702-6"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)92473-6"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201491"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-5448.2009.00518.x"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-021-02622-3"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.34.10.838"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph19063225"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.13860"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-023-00421-w"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.13378"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc24-S002"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa710"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.2337\/db13-0571"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25168790"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-023-02938-5"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-024-06307-0"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aax9106"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abh3763"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1089\/109065702761403423"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.22.2501"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10038-007-0144-3"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2024.2341588"},{"key":"e_1_2_9_36_1","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.2147\/DMSO.S179793","article-title":"Maturity\u2010Onset Diabetes of the Young (MODY): Current Perspectives on Diagnosis and Treatment","volume":"12","author":"Urakami T.","year":"2019","journal-title":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10258"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2021.145891"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2015.04.040"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0033-1357160"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.2337\/db19-0510"},{"issue":"1","key":"e_1_2_9_42_1","first-page":"102","article-title":"Early Diagnosis of Wolfram Syndrome by Ophthalmologic Screening in a Patient With Type 1B Diabetes Mellitus: A Case Report","volume":"16","author":"Kokumai T.","year":"2024","journal-title":"Journal of Clinical Research in Pediatric Endocrinology"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc10-1937"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcz066"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00592-015-0757-5"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adp2332"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(93)92918-J"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaq1380"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50502-x"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-0593-1"},{"issue":"49","key":"e_1_2_9_51_1","first-page":"E5292","article-title":"A Calcium\u2010Dependent Protease as a Potential Therapeutic Target for Wolfram Syndrome","volume":"111","author":"Lu S.","year":"2014","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-1519"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.10.001"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007196"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.81779"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-024-01851-7"}],"container-title":["Journal of Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/1753-0407.70114","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T05:00:33Z","timestamp":1754283633000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/1753-0407.70114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":55,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1111\/1753-0407.70114"],"URL":"https:\/\/doi.org\/10.1111\/1753-0407.70114","archive":["Portico"],"relation":{},"ISSN":["1753-0393","1753-0407"],"issn-type":[{"value":"1753-0393","type":"print"},{"value":"1753-0407","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7]]},"assertion":[{"value":"2024-06-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70114"}}