Multiple Retinal Anomalies in Wfs1-Deficient Mice

Abstract

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.

MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice

“…No deep characterization of the Wfs1 mutant visual structures has been yet reported and the data available refers exclusively to eye morphology in relatively young animals ( Waszczykowska et al, 2020 ). At first, we evaluated the gross retinal architecture in 8 months old mice by optical coherence tomography (OCT) and fluorescein angiography (FA), in terms of both morphology and neovascularization.…”

“…Between the mouse models, the neurological and behavioral alterations of the Wfs1 exon8del targeted mice have been extensively characterized showing diabetic glucose intolerance and anxious-like behaviors upon stressful environment exposure ( Kato et al, 2008 ; Luuk et al, 2008 ). Visual impairment in these mice is less characterized with only a histopathological study that reported some thinning of the retinal tissue with lower retinal thickness/longitudinal diameter ratio in 4 months old Wfs1 -deficient mice ( Waszczykowska et al, 2020 ). More recently, a mutant rat line was obtained through Wfs1 exon 5 disruption showing the hallmarks of WS1, with diabetes, optic atrophy, and neurodegeneration ( Plaas et al, 2017 ).…”

Genomics of Wolfram Syndrome 1 (WFS1)

“…This mouse line very accurately recapitulated all aspects of WFS1, starting with the diabetes, infertility, eye problems, etc. [ 39 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Other rodent models for WFS1 syndrome have also been developed, but none of them recapitulates all the facets of WFS1 [ 55 , 56 ].…”

The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance

“…Some studies report a progressive loss of visual acuity ( Davies et al, 2007 ; Zaninello et al, 2020 ), although most do not investigate the presence of a visual phenotype. Many studies observe progressive degeneration of the RGCs which in some cases is accompanied by myelination defects of the optic and peripheral nerves ( Li et al, 2017 ; Waszczykowska et al, 2020 ). Most models exhibit extra-ocular symptoms common to syndromic-autosomal OA, including progressive motor and hearing impairments often attributed to neuropathy ( Sarzi et al, 2012 ; Mancini et al, 2019 ).…”