{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T18:39:53Z","timestamp":1786991993843,"version":"build-2736575974"},"reference-count":32,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,8,19]],"date-time":"2020-08-19T00:00:00Z","timestamp":1597795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2014\/15\/B\/NZ5\/01579"],"award-info":[{"award-number":["2014\/15\/B\/NZ5\/01579"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: Wolfram syndrome (WFS, OMIM: #222300) is an ultrarare autosomal recessive disorder characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy and deafness. It has been reported that the average retinal thickness in WFS patients decreases with the progression of the disease. Aim: To investigate retinal thickness and wolframin expression disorders in Wolfram syndrome 1 gene knockout (Wfs1KO) mice compared to their wild-type (WT) littermates. Materials and methods: Both bulbs with optic nerves of three mice Wfs1WT and three Wfs1KO were taken for the histopathological examination. A strain of knockout mice with mutation in exon 8 was used. Results: No expression of wolframin protein in the retina and neurodegeneration of the optic nerve of Wfs1KO mice as compared among Wfs1WT mice was observed. The mean central retinal thickness was thinner and the retinal thickness\/longitudinal diameter ratio was significantly lower in hte Wfs1KO as compared to the Wfs1WT mice. In four (67%) eyeballs of Wfs1KO mice, intra-retinal neovessels were observed. Conclusions: Wfs1KO mice retina with mutation in exon 8 present similar clinical features as patients with WFS in the form of reduced retinal thickness and neurodegeneration of the optic nerve. The presence of proliferative retinopathy observed in Wfs1KO mice requires further investigation.<\/jats:p>","DOI":"10.3390\/diagnostics10090607","type":"journal-article","created":{"date-parts":[[2020,8,19]],"date-time":"2020-08-19T09:22:31Z","timestamp":1597828951000},"page":"607","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Multiple Retinal Anomalies in Wfs1-Deficient Mice"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4950-6390","authenticated-orcid":false,"given":"Arleta","family":"Waszczykowska","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Vision Rehabilitation, Medical University of \u0141\u00f3d\u017a, \u017beromskiego 113 Street, 90-549 \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8781-4469","authenticated-orcid":false,"given":"Agnieszka","family":"Zmys\u0142owska","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Medical University of \u0141\u00f3d\u017a, Pomorska 251 Street, 92-213 \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3804-7042","authenticated-orcid":false,"given":"Marcin","family":"Braun","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical University of \u0141\u00f3d\u017a, Pomorska 251 Street, 92-213 \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3512-5052","authenticated-orcid":false,"given":"Marilin","family":"Ivask","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulev","family":"Koks","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Jurowski","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Vision Rehabilitation, Medical University of \u0141\u00f3d\u017a, \u017beromskiego 113 Street, 90-549 \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2714-5851","authenticated-orcid":false,"given":"Wojciech","family":"M\u0142ynarski","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Oncology and Hematology, Medical University of \u0141\u00f3d\u017a, Sporna 36\/50 Street, 91-738 \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1016\/S0140-6736(95)92473-6","article-title":"Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome","volume":"346","author":"Barrett","year":"1995","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1007\/s00592-017-1042-6","article-title":"Retinal thickness as a marker of disease progression in longitudinal observation of patients with Wolfram syndrome","volume":"54","author":"Zmyslowska","year":"2017","journal-title":"Acta Diabetol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1093\/hmg\/ddh125","article-title":"Disruption of the WFS1 gene in mice causes progressive -cell loss and impaired stimulus-secretion coupling in insulin secretion","volume":"13","author":"Ishihara","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1002\/cne.21777","article-title":"Distribution of Wfs1 protein in the central nervous system of the mouse and its relation to clinical symptoms of the Wolfram syndrome","volume":"509","author":"Luuk","year":"2008","journal-title":"J. Comp. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1007\/s00125-005-1947-4","article-title":"Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis","volume":"48","author":"Riggs","year":"2005","journal-title":"Diabetologia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1152\/physiolgenomics.90407.2008","article-title":"Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway","volume":"37","author":"Soomets","year":"2009","journal-title":"Physiol. Genom."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.ajo.2020.04.012","article-title":"Corneal Abnormalities Are Novel Clinical Feature in Wolfram Syndrome","volume":"217","author":"Waszczykowska","year":"2020","journal-title":"Am. J. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"36","DOI":"10.2337\/dc14-1898","article-title":"Retinal Thinning as a Marker of Disease Progression in Patients With Wolfram Syndrome","volume":"38","author":"Fendler","year":"2015","journal-title":"Diabetes Care"},{"key":"ref_9","first-page":"359","article-title":"Optical coherence tomography and magnetic resonance imaging visual pathway evaluation in Wolfram syndrome","volume":"61","author":"Waszczykowska","year":"2018","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.lfs.2015.10.025","article-title":"Men and mice: Relating their ages","volume":"152","author":"Dutta","year":"2016","journal-title":"Life Sci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"S\u00f6ker, T., Dalke, C., Puk, O., Floss, T., Becker, L., Bolle, I., Favor, J., Hans, W., H\u00f6lter, S.M., and Horsch, M. (2008). Pleiotropic effects in Eya3 knockout mice. BMC Dev. Biol., 8.","DOI":"10.1186\/1471-213X-8-118"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1093\/hmg\/ddr473","article-title":"An alpha 2 collagen VIII transgenic knock-in mouse model of Fuchs endothelial corneal dystrophy shows early endothelial cell unfolded protein response and apoptosis","volume":"21","author":"Jun","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","first-page":"250","article-title":"Inflammatory cytokine expression on the ocular surface in the Botulium toxin B induced murine dry eye model","volume":"15","author":"Zhu","year":"2009","journal-title":"Mol. Vis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s10456-007-9063-3","article-title":"Effects of topical administration of 12-methyl tetradecanoic acid (12-MTA) on the development of corneal angiogenesis","volume":"10","author":"Cole","year":"2007","journal-title":"Angiogenesis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8936","DOI":"10.1523\/JNEUROSCI.18-21-08936.1998","article-title":"The Major Cell Populations of the Mouse Retina","volume":"18","author":"Jeon","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/0042-6989(85)90076-8","article-title":"A schematic eye for the mouse, and comparisons with the rat","volume":"25","author":"Remtulla","year":"1985","journal-title":"Vis. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1007\/s12185-017-2315-0","article-title":"Polymorphism in IKZF1 gene affects clinical outcome in diffuse large B-cell lymphoma","volume":"106","author":"Bielska","year":"2017","journal-title":"Int. J. Hematol."},{"key":"ref_18","first-page":"504","article-title":"MiR-21, miR-34a, miR-125b, miR-181d and miR-648 levels inversely correlate with MGMT and TP53 expression in primary glioblastoma patients","volume":"15","author":"Braun","year":"2017","journal-title":"Arch. Med Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wersinger, D.B., Benkafadar, N., Jagodzinska, J., Hamel, C., Tanizawa, Y., Lenaers, G., and Delettre, C. (2014). Impairment of Visual Function and Retinal ER Stress Activation in Wfs1-Deficient Mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097222"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1086\/302609","article-title":"Clinical and Molecular Genetic Analysis of 19 Wolfram Syndrome Kindreds Demonstrating a Wide Spectrum of Mutations in WFS1","volume":"65","author":"Hardy","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3389\/fnmol.2015.00045","article-title":"Prohormone convertase 2 activity is increased in the hippocampus of Wfs1 knockout mice","volume":"8","author":"Tein","year":"2015","journal-title":"Front. Mol. Neurosci."},{"key":"ref_22","first-page":"831","article-title":"Wolfram (DIDMOAD) syndrome with diabetic retinopathy","volume":"42","author":"Gupta","year":"1994","journal-title":"J. Assoc. Physicians India"},{"key":"ref_23","first-page":"548","article-title":"A Chinese family with Wolfram syndrome presenting with rapidly progressing diabetic retinopathy and renal failure","volume":"19","author":"Lim","year":"1990","journal-title":"Ann. Acad. Med. Singap."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1038\/eye.1997.226","article-title":"Optic atrophy in Wolfram (DIDMOAD) syndrome","volume":"11","author":"Barrett","year":"1997","journal-title":"Eye"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1093\/hmg\/ddg214","article-title":"Wolfram syndrome: Structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product","volume":"12","author":"Hofmann","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3294","DOI":"10.1167\/iovs.18-23831","article-title":"SWATH-MS Proteomic Analysis of Oxygen-Induced Retinopathy Reveals Novel Potential Therapeutic Targets","volume":"59","author":"Aapola","year":"2018","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_27","first-page":"101","article-title":"Oxygen-induced retinopathy in the mouse","volume":"35","author":"Wesolowski","year":"1994","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1002\/cne.22530","article-title":"Characterization of retinal function and glial cell response in a mouse model of oxygen-induced retinopathy","volume":"519","author":"Vessey","year":"2010","journal-title":"J. Comp. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e12473","DOI":"10.1111\/jpi.12473","article-title":"Melatonin attenuated retinal neovascularization and neuroglial dysfunction by inhibition of HIF-1\u03b1-VEGF pathway in oxygen-induced retinopathy mice","volume":"64","author":"Xu","year":"2018","journal-title":"J. Pineal Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.preteyeres.2014.11.004","article-title":"Retinal microglia: Just bystander or target for therapy?","volume":"45","author":"Karlstetter","year":"2015","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_31","first-page":"467","article-title":"Microglia and macrophages are increased in response to ischemia-induced retinopathy in the mouse retina","volume":"12","author":"Davies","year":"2006","journal-title":"Mol. Vis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3595","DOI":"10.1167\/iovs.05-1522","article-title":"Potential Role of Microglia in Retinal Blood Vessel Formation","volume":"47","author":"Checchin","year":"2006","journal-title":"Investig. Opthalmol. Vis. Sci."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/10\/9\/607\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:02:48Z","timestamp":1760176968000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/10\/9\/607"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,19]]},"references-count":32,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["diagnostics10090607"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics10090607","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,19]]}}}