Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration

Abstract

Wolfram syndrome (WS) is a rare autosomal-recessive disorder that is caused by mutations in the WFS1 gene and is characterized by juvenile-onset diabetes, optic atrophy, hearing loss and a number of other complications. Here, we describe the creation and phenotype of Wfs1 mutant rats, in which exon 5 of the Wfs1 gene is deleted, resulting in a loss of 27 amino acids from the WFS1 protein sequence. These Wfs1-ex5-KO232 rats show progressive glucose intolerance, which culminates in the development of diabetes mellitus, glycosuria, hyperglycaemia and severe body weight loss by 12 months of age. Beta cell mass is reduced in older mutant rats, which is accompanied by decreased glucose-stimulated insulin secretion from 3 months of age. Medullary volume is decreased in older Wfs1-ex5-KO232 rats, with the largest decreases at the level of the inferior olive. Finally, older Wfs1-ex5-KO232 rats show retinal gliosis and optic nerve atrophy at 15 months of age. Electron microscopy revealed axonal degeneration and disorganization of the myelin in the optic nerves of older Wfs1-ex5-KO232 rats. The phenotype of Wfs1-ex5-KO232 rats indicates that they have the core symptoms of WS. Therefore, we present a novel rat model of WS.

Preventive treatment with liraglutide protects against development of glucose intolerance in a rat model of Wolfram syndrome

“…Recently, a rat model of WS has been developed and validated 11 . Deletion of exon 5 of the Wfs1 gene resulted in development of the main symptoms of WS: diabetes mellitus (Fig.…”

“…Deletion of exon 5 of the Wfs1 gene resulted in development of the main symptoms of WS: diabetes mellitus (Fig. 1 ), medullary degeneration, and optic nerve atrophy 11 . Moreover, levels of ER stress were elevated in the pancreas and brainstem of this rat 11 .…”

“…1 ), medullary degeneration, and optic nerve atrophy 11 . Moreover, levels of ER stress were elevated in the pancreas and brainstem of this rat 11 . The progressive development of diabetes mellitus and other WS symptoms makes the Wfs1-ex5-KO232 rat a good tool to study treatment options.…”

Knockdown of wfs1, a fly homolog of Wolfram syndrome 1, in the nervous system increases susceptibility to age- and stress-induced neuronal dysfunction and degeneration in Drosophila

“…Wfs1 knockout mice recapitulate several aspects of the neurological manifestations of WS, including impaired behavioral adaptation to stress [ 29 , 30 ], stress-induced depressive behavior [ 31 ], and alterations in visual function [ 32 ]. A recent study used a rat model to demonstrate that deletion of exon 5 of the Wfs1 gene, which results in the loss of 27 amino acids from the Wfs1 protein, caused insulin-dependent diabetes, optic nerve atrophy, and medullary degeneration [ 33 ]. However, the mechanisms underlying the neurological manifestations of WFS1 deficiency remain elusive.…”

Metabolomics for Animal Models of Rare Human Diseases: An Expert Review and Lessons Learned

“…For Wolfram's syndrome only mouse models were available for a long time (Ishihara et al, 2004;Luuk et al, 2009;Riggs et al, 2005). Recently also a rat model became available (Plaas et al, 2017), and judged by the phenotype the rat model matches human disease better. By now the mice model has been more thoroughly described, but translating these results to humans will get an extra step-from the mouse model to rat and from rat model to human.…”