| Autor: |
Pamela J. Shaw, Ammar Al-Chalabi, Orla Hardiman, Tobias Moll, Paul R. Heath, Mbombe Kazoka, Matthew Wyles, Mónica Povedano Panades, Jesus S. Mora, A. Nazli Basak, Ian Fox, Lydia M. Castelli, Philip Van Damme, Tennore Ramesh, John Landers, Wim Robberecht, Isabell Niedermoser, Karen E. Morrison, Theresa Walsh, Johnathan Cooper-Knock, Adrian Higginbottom, Alexander Beer, Christopher Shaw, Christopher J McDermott, Henry Robins, Guillaume M. Hautbergue, Janine Kirby |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
SSRN Electronic Journal. |
| ISSN: |
1556-5068 |
| Popis: |
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. Here we report mutations in a new ALS gene encoding the glycosyltransferase GLT8D1; this class of proteins has not previously been associated with neurodegeneration. 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 R92C reduces GLT8D1 enzyme activity ~2-fold. 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 discovered a previously uncharacterised pathophysiological pathway for ALS caused by inherited mutations within a glycosyltransferase enzyme. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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