UMMS Affiliation
Department of Neurology
Publication Date
2019-02-26
Document Type
Article
Disciplines
Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Enzymes and Coenzymes | Genetic Phenomena | Genetics and Genomics | Nervous System Diseases | Neuroscience and Neurobiology | Nucleic Acids, Nucleotides, and Nucleosides
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.
Keywords
GLT8D1, amyotrophic lateral sclerosis, cell model, genetics, glycosyltransferase, zebrafish
Rights and Permissions
Copyright 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/).
DOI of Published Version
10.1016/j.celrep.2019.02.006
Source
Cell Rep. 2019 Feb 26;26(9):2298-2306.e5. doi: 10.1016/j.celrep.2019.02.006. Link to article on publisher's site
Journal/Book/Conference Title
Cell reports
Related Resources
PubMed ID
30811981
Repository Citation
Cooper-Knock, Johnathan; Landers, John E.; and Shaw, Pamela J., "Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis" (2019). Open Access Articles. 3769.
https://escholarship.umassmed.edu/oapubs/3769
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Biochemistry, Biophysics, and Structural Biology Commons, Enzymes and Coenzymes Commons, Genetic Phenomena Commons, Genetics and Genomics Commons, Nervous System Diseases Commons, Neuroscience and Neurobiology Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons
Comments
Full author list omitted for brevity. For the full list of authors, see article.