遺伝症候群と遺伝子治療のジャーナル
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概要

Readthrough Intervention Increases ER Stress in Wolfram Syndrome

Agnieszka Zmyslowska, Maciej Borowiec, Ewa Polakowska, Aleksandra Lesiak and Wojciech Mlynarski

Aim: Wolfram syndrome (WFS) is an example of inherited endocrine and neurodegenerative disease due
to increased ER stress with no causal treatment. WFS is an autosomal recessive syndrome caused by biallelic
mutations in WFS1 gene. Some of these mutations result in premature termination codons (PTCs). Some prospects
for the causal treatment of WFS patients could give a PTCs readthrough intervention. The use of ataluren (formerly
PTC124) can result in bypassing the PTCs and lead to a continuation of translation. The aim of the study was to
evaluate the repairing potential of ataluren in a cell model of WFS caused by PTCs.
Materials and methods: Diagnosis of WFS was confirmed by Sanger sequencing of the WFS1 gene. ER stress
induction (Tunicamycin; Sigma-Aldrich, Germany) with subsequently using PTC124 (Ataluren, Selleckchem, USA)
were performed on fibroblasts obtained from skin biopsies of WFS patients and healthy individuals. The evaluation
of ER stress induction was conducted by analysis of mRNA expression of recognized markers of the ER stress
(7900HT Real Time PCR; Applied Biosystems, USA).
Results: Expression of specific markers of ER stress in patients with WFS was increased after using tunicamycin,
with the highest value after 8 hours of the ER stress induction. The highest increase in mRNA expression after
application of PTC124 in combination with DMSO in relation to DMSO itself was observed for GRP78 (p=0.0013).
Fold change was 3.41 ± 0.73.
Conclusion: It seems that PTC124 by the ER stress increasing cannot be used as a potential causal treatment
for the WFS patients