Mutations in the glycosyltransferase domain of GLT8D1 are associated with familial amyotrophic lateral sclerosis

Johnathan Cooper-Knock, Tobias Moll, Tennore Ramesh, Lydia Castelli, Alexander Beer, Henry Robins, Ian Fox, Isabell Niedermoser, Philip Van Damme, Matthieu Moisse, Wim Robberecht, Orla Hardiman, Monica P. Panades, Abdelilah Assialioui, Jesus S. Mora, A. Nazli Basak, Karen E. Morrison, Christopher E. Shaw, Ammar Al-Chalabi, John E. LandersMatthew Wyles, Paul R. Heath, Adrian Higginbottom, Theresa Walsh, Mbombe Kazoka, Christopher J. McDermott, Guillaume M. Hautbergue, Janine Kirby, Pamela J. Shaw

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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. Amyotrophic lateral sclerosis (ALS) is an incurable neurodegeneration. Cooper-Knock et al. report ALS-causing mutations within GLT8D1. Mutations are associated with the substrate binding site and impair enzyme activity. Mutated GLT8D1 is neurotoxic and induces an ALS-like zebrafish phenotype.
Original languageEnglish
Pages (from-to)2298-2306.e5
JournalCell Reports
Volume26
Issue number9
DOIs
Publication statusPublished - 26 Feb 2019

Keywords

  • amyotrophic lateral sclerosis
  • cell model
  • genetics
  • GLT8D1
  • glycosyltransferase
  • zebrafish

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