Journal article
Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B
Annals of Clinical and Translational Neurology, Vol.5(4), pp.445-455
03/10/2018
DOI: 10.1002/acn3.543
PMCID: PMC5899917
PMID: 29687021
Abstract
Objective:
To determine the prevalence of MPZ mutations that cause Charcot Marie Tooth neuropathy type 1B (CMT1B) and activate the unfolded protein Response (UPR).
Background:
CMT1B is caused by >200 heterozygous mutations in MPZ, the major protein in peripheral nerve myelin. Mutations Ser63del MPZ and Arg98Cys MPZ cause the mutant protein to be retained in the ER and activate the generally adaptive UPR. Treatments that modulate UPR activation have improved cellular and rodent models of CMT1B raising the possibility that other MPZ mutations that activate the UPR would also respond favorably to similar treatment. The prevalence of MPZ mutations that activate the UPR is unknown.
Methods:
We developed a dual luciferase reporter assay of Xbp1 splicing using stably transfected RT4 Schwann cells to assay the ability of cDNA constructs bearing 46 distinct MPZ mutations to activate the UPR. Constructs also carried an HA tag to permit detection of ER retention of mutant proteins. UPR activation and ER retention were correlated with clinical phenotypes.
Results:
Eighteen mutations demonstrated ER retention and UPR activation to a similar degree as Ser63del and Arg98Cys MPZ. Thirty‐five of the mutations activated the UPR > 1.5 fold compared to that of wild‐type MPZ. Correlation was high between firefly and Nano‐luciferase reporters and between both reporters and ER localization. UPR activity did not correlate with clinical onset or severity.
Conclusion:
Many CMT1B causing mutations activate the UPR and may be susceptible to therapeutic efforts to facilitate UPR function.
Details
- Title: Subtitle
- Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B
- Creators
- Yunhong Bai - University of Iowa, NeurologyXingyao Wu - University of IowaKathryn M. Brennan - University of IowaDavid S. Wang - University of IowaMaurizio D'AntonioJohn MoranJohn SvarenMichael E Shy - University of Iowa, Neurology
- Resource Type
- Journal article
- Publication Details
- Annals of Clinical and Translational Neurology, Vol.5(4), pp.445-455
- DOI
- 10.1002/acn3.543
- PMID
- 29687021
- PMCID
- PMC5899917
- NLM abbreviation
- Ann Clin Transl Neurol
- ISSN
- 2328-9503
- eISSN
- 2328-9503
- Publisher
- John Wiley & Sons, Inc; Bognor Regis
- Copyright
- © 2018 The Authors.
- Grant note
- Funding Information: This work was supported by Research Grants from the Charcot Marie Tooth Association (CMTA), the Muscular Dystrophy Association MDA). Patient evaluations were supported by grant U54NS065712 from the National Institutes of Neurological Diseases and Stroke and the office of Rare Diseases. Conflict of Interest: No author had a conflict of interest to declare for any of the experiments in this manuscript.
- Language
- English
- Date published
- 03/10/2018
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9983763491702771
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