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

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

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.

amyotrophic lateral sclerosis, cell model, genetics, GLT8D1, glycosyltransferase, zebrafish
2211-1247
2298-2306.e5
Cooper-Knock, Johnathan
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Moll, Tobias
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Ramesh, Tennore
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Castelli, Lydia
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Beer, Alexander
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Robins, Henry
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Fox, Ian
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Niedermoser, Isabell
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Van Damme, Philip
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Moisse, Matthieu
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Robberecht, Wim
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Hardiman, Orla
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Panades, Monica P.
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Assialioui, Abdelilah
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Mora, Jesus S.
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Basak, A. Nazli
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Morrison, Karen E.
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Shaw, Christopher E.
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Al-Chalabi, Ammar
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Landers, John E.
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Wyles, Matthew
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Heath, Paul R.
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Higginbottom, Adrian
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Walsh, Theresa
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Kazoka, Mbombe
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McDermott, Christopher J.
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Hautbergue, Guillaume M.
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Kirby, Janine
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Shaw, Pamela J.
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Cooper-Knock, Johnathan
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Moll, Tobias
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Ramesh, Tennore
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Castelli, Lydia
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Beer, Alexander
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Robins, Henry
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Fox, Ian
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Niedermoser, Isabell
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Van Damme, Philip
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Moisse, Matthieu
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Robberecht, Wim
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Hardiman, Orla
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Panades, Monica P.
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Assialioui, Abdelilah
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Mora, Jesus S.
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Basak, A. Nazli
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Morrison, Karen E.
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Shaw, Christopher E.
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Al-Chalabi, Ammar
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Landers, John E.
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Wyles, Matthew
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Heath, Paul R.
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Higginbottom, Adrian
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Walsh, Theresa
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Kazoka, Mbombe
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McDermott, Christopher J.
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Hautbergue, Guillaume M.
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Kirby, Janine
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Shaw, Pamela J.
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Cooper-Knock, Johnathan, Moll, Tobias, Ramesh, Tennore, Castelli, Lydia, Beer, Alexander, Robins, Henry, Fox, Ian, Niedermoser, Isabell, Van Damme, Philip, Moisse, Matthieu, Robberecht, Wim, Hardiman, Orla, Panades, Monica P., Assialioui, Abdelilah, Mora, Jesus S., Basak, A. Nazli, Morrison, Karen E., Shaw, Christopher E., Al-Chalabi, Ammar, Landers, John E., Wyles, Matthew, Heath, Paul R., Higginbottom, Adrian, Walsh, Theresa, Kazoka, Mbombe, McDermott, Christopher J., Hautbergue, Guillaume M., Kirby, Janine and Shaw, Pamela J. (2019) Mutations in the glycosyltransferase domain of GLT8D1 are associated with familial amyotrophic lateral sclerosis. Cell Reports, 26 (9), 2298-2306.e5. (doi:10.1016/j.celrep.2019.02.006).

Record type: Article

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.

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Accepted/In Press date: 30 January 2019
e-pub ahead of print date: 26 February 2019
Published date: 26 February 2019
Keywords: amyotrophic lateral sclerosis, cell model, genetics, GLT8D1, glycosyltransferase, zebrafish

Identifiers

Local EPrints ID: 428598
URI: https://eprints.soton.ac.uk/id/eprint/428598
ISSN: 2211-1247
PURE UUID: 85f01046-f38d-413d-99ee-7db76ee3fd31
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 04 Mar 2019 17:30
Last modified: 14 Mar 2019 01:31

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Contributors

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

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