Morphological, behavioral and cellular analyses revealed different phenotypes in Wolfram syndrome wfs1a and wfs1b zebrafish mutant lines. Issue 16 (22nd April 2022)

• Record Type: Journal Article
• Authors: Crouzier, Lucie; Richard, Elodie M; Diez, Camille; Alzaeem, Hala; Denus, Morgane; Cubedo, Nicolas; Delaunay, Thomas; Glendenning, Emily; Baxendale, Sarah; Liévens, Jean-Charles; Whitfield, Tanya T; Maurice, Tangui; Delprat, Benjamin
• Is Part Of: Human molecular genetics. Volume 31:Issue 16(2022)
• Page Start: 2711
• Page End: 2727
• Publication Date: 2022-04-22
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddac065
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: Wolfram syndrome (WS) is a rare genetic disease characterized by diabetes, optic atrophy and deafness. Patients die at 35 years of age, mainly from respiratory failure or dysphagia. Unfortunately, there is no treatment to block the progression of symptoms and there is an urgent need for adequate research models. Here, we report on the phenotypical characterization of two loss-of-function zebrafish mutant lines: wfs1a C825X and wfs1b W493X . We observed that wfs1a deficiency altered the size of the ear and the retina of the fish. We also documented a decrease in the expression level of unfolded protein response (UPR) genes in basal condition and in stress condition, i.e. after tunicamycin treatment. Interestingly, both mutants lead to a decrease in their visual function measured behaviorally. These deficits were associated with a decrease in the expression level of UPR genes in basal and stress conditions. Interestingly, basal, ATP-linked and maximal mitochondrial respirations were transiently decreased in the wfs1b mutant. Taken together, these zebrafish lines highlight the critical role of wfs1a and wfs1b in UPR, mitochondrial function and visual physiology. These models will be useful tools to better understand the cellular function of Wfs1 and to develop novel therapeutic approaches for WS.