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

Research output: Contribution to journalArticlepeer-review


  • Kun Hu
  • Nicola Beer
  • Archana Kulkarni
  • John Ainsworth
  • Benjamin Wright
  • Anna Majander
  • Patrick Yu-Wai-Man
  • Denise Williams

External organisations

  • University of Oxford
  • University of Helsinki
  • Birmingham Children’s Hospital NHS Foundation Trust,
  • University Hospital Birmingham NHS Foundation Trust
  • Moorfields Eye Hospital NHS Foundation Trust, London
  • University College London


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.

Bibliographic note

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.


Original languageEnglish
JournalJournal of Medical Genetics
Early online date18 May 2021
Publication statusE-pub ahead of print - 18 May 2021


  • diabetes mellitus, genetics, medical, neurodegenerative diseases

ASJC Scopus subject areas

Sustainable Development Goals