Cooper-Knock, J., Moll, T., Ramesh, T. et al. (26 more authors) (2019) Mutations in the glycosyltransferase domain of GLT8D1 are associated with familial amyotrophic lateral sclerosis. Cell Reports, 26 (9). 2298-2306.e5. ISSN 2211-1247
Abstract
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding the glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C mutations in GLT8D1, which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site, and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro cytotoxicity and induces motor deficits in zebrafish consistent with ALS. Relative toxicity of mutations in model systems mirrors clinical severity. In conclusion, we have linked ALS pathophysiology to inherited mutations that diminish the activity of a glycosyltransferase enzyme.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
Keywords: | Amyotrophic lateral sclerosis; genetics; GLT8D1; glycosyltransferase; cell model; zebrafish |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number MOTOR NEURONE DISEASE ASSOCIATION Ramesh/Apr17/854-791 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 28 Feb 2019 10:10 |
Last Modified: | 13 Jan 2020 11:55 |
Published Version: | https://doi.org/10.1016/j.celrep.2019.02.006 |
Status: | Published |
Publisher: | Elsevier |
Refereed: | Yes |
Identification Number: | 10.1016/j.celrep.2019.02.006 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:142642 |