WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome

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http://hdl.handle.net/10138/338110

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Hu , K , Zatyka , M , Astuti , D , Beer , N , Dias , R P , Kulkarni , A , Ainsworth , J , Wright , B , Majander , A , Yu-Wai-Man , P , Williams , D & Barrett , T 2022 , ' WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome ' , Journal of Medical Genetics , vol. 59 , no. 1 , pp. 65-74 . https://doi.org/10.1136/jmedgenet-2020-107257

Title: WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome
Author: Hu, Kun; Zatyka, Malgorzata; Astuti, Dewi; Beer, Nicola; Dias, Renuka P.; Kulkarni, Archana; Ainsworth, John; Wright, Benjamin; Majander, Anna; Yu-Wai-Man, Patrick; Williams, Denise; Barrett, Timothy
Contributor organization: HUS Head and Neck Center
Department of Ophthalmology and Otorhinolaryngology
Clinicum
Date: 2022-01
Language: eng
Number of pages: 10
Belongs to series: Journal of Medical Genetics
ISSN: 0022-2593
DOI: https://doi.org/10.1136/jmedgenet-2020-107257
URI: http://hdl.handle.net/10138/338110
Abstract: Background Wolfram syndrome (WFS) is a rare disorder characterised by childhood-onset diabetes mellitus and progressive optic atrophy. Most patients have variants in the WFS1 gene. We undertook functional studies of WFS1 variants and correlated these with WFS1 protein expression and phenotype. Methods 9 patients with a clinical diagnosis of WFS were studied with quantitative PCR for markers of endoplasmic reticulum (ER) stress and immunoblotting of fibroblast protein extracts for WFS1 protein expression. Luciferase reporter assay was used to assess ATF-6 dependent unfolded protein response (UPR) activation. Results 6 patients with compound heterozygous nonsense mutations in WFS1 had no detectable WFS1 protein expression; 3 patients with missense variants had 4%, 45% and 48% WFS1 protein expression. One of these also had an OPA1 mutation and was reclassified as autosomal dominant optic atrophy-plus syndrome. There were no correlations between ER stress marker mRNA and WFS1 protein expression. ERSE-luciferase reporter indicated activation of the ATF6 branch of UPR in two patients tested. Patients with partial WFS1 expression showed milder visual acuity impairment (asymptomatic or colour blind only), compared with those with absent expression (registered severe vision impaired) (p=0.04). These differences remained after adjusting for duration of optic atrophy. Conclusions Patients with WFS who have partial WFS1 protein expression present with milder visual impairment. This suggests a protective effect of partial WFS1 protein expression on the severity and perhaps progression of vision impairment and that therapies to increase residual WFS1 protein expression may be beneficial.
Subject: diabetes mellitus
genetics
medical
neurodegenerative diseases
HEARING IMPAIRMENT
DIABETES-MELLITUS
MUTATIONS
GENE
NEURODEGENERATION
RETICULUM
SPECTRUM
DISEASE
1184 Genetics, developmental biology, physiology
3125 Otorhinolaryngology, ophthalmology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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