A mutant wfs1 zebrafish model of Wolfram syndrome manifesting visual dysfunction and developmental delay

Wolfram syndrome (WS) is an ultra-rare progressive neurodegenerative disorder defined by early-onset diabetes mellitus and optic atrophy. The majority of patients harbour recessive mutations in the WFS1 gene, which encodes for Wolframin, a transmembrane endoplasmic reticulum protein. There is limite...

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Bibliographic Details
Published in:Scientific reports 2021-10, Vol.11 (1), p.20491-20491, Article 20491
Main Authors: Cairns, G., Burté, F., Price, R., O’Connor, E., Toms, M., Mishra, R., Moosajee, M., Pyle, A., Sayer, J. A., Yu-Wai-Man, P.
Format: Article
Language:English
Subjects:
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Age
Animal models
Animals
Atrophy
Codon, Nonsense
Danio rerio
Diabetes mellitus
Disease Models, Animal
Embryos
Endoplasmic reticulum
Gene Knockout Techniques
Humanities and Social Sciences
Membrane Proteins - genetics
Membrane Proteins - metabolism
multidisciplinary
Mutants
Mutation
Neurodegenerative diseases
Optic Atrophy
Optokinetic response
Patients
Phenotypes
Protein folding
Retinal ganglion cells
Science
Science (multidisciplinary)
Therapeutic applications
Unfolded Protein Response
Wolfram Syndrome - genetics
Wolfram Syndrome - metabolism
Wolfram Syndrome - physiopathology
Zebrafish
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Summary:Wolfram syndrome (WS) is an ultra-rare progressive neurodegenerative disorder defined by early-onset diabetes mellitus and optic atrophy. The majority of patients harbour recessive mutations in the WFS1 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 wfs1 zebrafish knockout models harbouring nonsense wfs1a and wfs1b mutations. Both homozygous mutant wfs1a −/− and wfs1 b −/− embryos showed significant morphological abnormalities in early development. The wfs1 b −/− 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 months of age, wfs1b −/− zebrafish had a significantly lower RGC density per 100 μm 2 (mean ± standard deviation; 19 ± 1.7) compared with wild-type (WT) zebrafish (25 ± 2.3, p 
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-99781-0