Impairment of visual function and retinal ER stress activation in Wfs1-deficient mice.

Delphine Bonnet Wersinger,Yukio Tanizawa,Guy Lenaers,Nesrine Benkafadar,Christian Hamel,Cécile Delettre,Jolanta Jagodzinska,Bertrand Mollereau

doi:10.1371/journal.pone.0097222

Abstract

Wolfram syndrome is an early onset genetic disease (1/180,000) featuring diabetes mellitus and optic neuropathy, associated to mutations in the WFS1 gene. Wfs1−/− mouse model shows pancreatic beta cell atrophy, but its visual performance has not been investigated, prompting us to study its visual function and histopathology of the retina and optic nerve. Electroretinogram and visual evoked potentials (VEPs) were performed in Wfs1−/− and Wfs1+/+ mice at 3, 6, 9 and 12 months of age. Fundi were pictured with Micron III apparatus. Retinal ganglion cell (RGC) abundance was determined from Brn3a immunolabeling of retinal sections. RGC axonal loss was quantified by electron microscopy in transversal optic nerve sections. Endoplasmic reticulum stress was assessed using immunoglobulin binding protein (BiP), protein disulfide isomerase (PDI) and inositol-requiring enzyme 1 alpha (Ire1α) markers. Electroretinograms amplitudes were slightly reduced and latencies increased with time in Wfs1−/− mice. Similarly, VEPs showed decreased N+P amplitudes and increased N-wave latency. Analysis of unfolded protein response signaling revealed an activation of endoplasmic reticulum stress in Wfs1 −/− mutant mouse retinas. Altogether, progressive VEPs alterations with minimal neuronal cell loss suggest functional alteration of the action potential in the Wfs1 −/− optic pathways.

Highlights

Wolfram syndrome (WS) (OMIM 222300) is a rare multisystem disorder (1/160,000 in Europe; 1/100,000 in North America) featuring systematically early-onset type I diabetes mellitus and optic neuropathy, variably associated with neurological dysfunctions [1,2,3,4]
In order to describe a mouse model for Wolfram syndrome optic atrophy, we explored visual function of Wfs1 deficient mice from 3 to 12 months of age
The longitudinal study of Wfs12/2 mutant mice depicted from the age of 9 months a reduction of visual evoked potentials (VEPs) signaling associated to a functional alteration of inner retinal function, with preserved visual acuities

Summary

Introduction

Wolfram syndrome (WS) (OMIM 222300) is a rare multisystem disorder (1/160,000 in Europe; 1/100,000 in North America) featuring systematically early-onset type I diabetes mellitus and optic neuropathy, variably associated with neurological dysfunctions [1,2,3,4]. Patients often develop in their second decade sensori-neural hearing impairment, diabetes insidipus and urinary dysfunctions. Psychiatric illness impairs live of most diagnosed patients and sometimes their relatives, as heterozygous carriers [5,6]. WS is an inherited condition transmitted by recessive point, frame-shift and missense mutations in WFS1 gene, which consists in 8 exons and extends on 33.4 kb of chromosome 4 q. In 2010, 219 WS patients had been described with 172 different reported mutations in WFS1, mostly (83%) in exon 8 [7,8,9]. Patient genotype do not present any mutation hotspot, highlighting the need to sequence first exon 8 for molecular diagnosis [10]. WFS1 translation starts in the second exon and produces a 890 aminoacid protein named Wolframin, consisting in 9 transmembrane domains, surrounded by large N- and C-terminal regions

Methods

Results

Conclusion