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The majority of patients harbour recessive mutations in the\n                    <jats:italic>WFS1<\/jats:italic>\n                    gene, which encodes for Wolframin, a transmembrane endoplasmic reticulum protein. There is limited availability of human ocular and brain tissues, and there are few animal models for WS that replicate the neuropathology and clinical phenotype seen in this disorder. We, therefore, characterised two\n                    <jats:italic>wfs1<\/jats:italic>\n                    zebrafish knockout models harbouring nonsense\n                    <jats:italic>wfs1a<\/jats:italic>\n                    and\n                    <jats:italic>wfs1b<\/jats:italic>\n                    mutations. Both homozygous mutant\n                    <jats:italic>wfs1a<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    and\n                    <jats:italic>wfs1<\/jats:italic>\n                    b\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    embryos showed significant morphological abnormalities in early development. The\n                    <jats:italic>wfs1<\/jats:italic>\n                    b\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    zebrafish exhibited a more pronounced neurodegenerative phenotype with delayed neuronal development, progressive loss of retinal ganglion cells and clear evidence of visual dysfunction on functional testing. At 12\u00a0months of age,\n                    <jats:italic>wfs1b<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    zebrafish had a significantly lower RGC density per 100 \u03bcm\n                    <jats:sup>2<\/jats:sup>\n                    (mean\u2009\u00b1\u2009standard deviation; 19\u2009\u00b1\u20091.7) compared with wild-type (WT) zebrafish (25\u2009\u00b1\u20092.3, p\u2009&lt;\u20090.001). The optokinetic response for\n                    <jats:italic>wfs1b<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    zebrafish was significantly reduced at 8 and 16\u00a0rpm testing speeds at both 4 and 12\u00a0months of age compared with WT zebrafish. An upregulation of the unfolded protein response was observed in mutant zebrafish indicative of increased endoplasmic reticulum stress. Mutant\n                    <jats:italic>wfs1<\/jats:italic>\n                    b\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    zebrafish exhibit some of the key features seen in patients with WS, providing a versatile and cost-effective in vivo model that can be used to further investigate the underlying pathophysiology of WS and potential therapeutic interventions.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-99781-0","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T06:09:16Z","timestamp":1634191756000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A mutant wfs1 zebrafish model of Wolfram syndrome manifesting visual dysfunction and developmental delay"],"prefix":"10.1038","volume":"11","author":[{"given":"G.","family":"Cairns","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Burt\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"O\u2019Connor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Toms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Mishra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Moosajee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Pyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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