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Mutations in Wolfram syndrome 1 (<jats:italic>WFS1<\/jats:italic>) gene may cause dysregulated endoplasmic reticulum (ER)-stress and cell apoptosis, contributing to WS symptoms. The aim of this study was to identify the molecular etiology of a case of WS and to explore the functional consequence of the mutant<jats:italic>WFS1<\/jats:italic>gene in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A 27\u2009years-old Chinese man was diagnosed as wolfram syndrome type 1 based on clinical data and laboratory data. DNA sequencing of<jats:italic>WFS1<\/jats:italic>gene and mitochondrial m.3337G\u2009&gt;\u2009A, m.3243A\u2009&gt;\u2009G mutations were performed in the patient and his 4 family members. Functional analysis was performed to assessed the in vitro effect of the newly identified mutant. ER stress were evaluated by ER stress response element (ERSE)-luciferase assay. Cell apoptosis were performed by CCK-8, TUNEL staining and flow cytometric analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A novel heterozygous 10-base deletion (c. 2067_2076 del10, p.W690fsX706) was identified in the patient. In vitro studies showed that mutant p.W690fsX706 increased ERSE reporter activity in the presence or absence of thapsigargin instead of wild type<jats:italic>WFS1<\/jats:italic>. Knockdown of<jats:italic>WFS1<\/jats:italic>activated the unfolded protein response (UPR) pathway and increased the cell apoptosis, which could not be restored by transfection with<jats:italic>WFS1<\/jats:italic>mutant (p.W690fsX706) comparable to the wild type<jats:italic>WFS1<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A novel heterozygous mutation of<jats:italic>WFS1<\/jats:italic>detected in the patient resulted in loss-of-function of wolframin, thereby inducing dysregulated ER stress signaling and cell apoptosis. These findings increase the spectrum of<jats:italic>WFS1<\/jats:italic>gene mutations and broaden our insights into the roles of mutant<jats:italic>WFS1<\/jats:italic>in the pathogenesis of WS.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12902-021-00748-z","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T02:03:26Z","timestamp":1618970606000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["A novel mutation of WFS1 gene leading to increase ER stress and cell apoptosis is associated an autosomal dominant form of Wolfram syndrome type 1"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7965-2236","authenticated-orcid":false,"given":"Yingying","family":"Gong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiujun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4188-336X","authenticated-orcid":false,"given":"Haipeng","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,21]]},"reference":[{"issue":"10","key":"748_CR1","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1136\/jmg.34.10.838","volume":"34","author":"TG Barrett","year":"1997","unstructured":"Barrett TG, Bundey SE. 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