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. Landers; Matthew Wyles; Paul R. Heath; Adrian Higginbottom; Theresa Walsh; Mbombe Kazoka; Christopher J. McDermott; Guillaume M. Hautbergue; Janine Kirby; Pamela J. Shaw

doi:10.1016/j.celrep.2019.02.006

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	2298-2306.e5
Journal	Cell Reports
Volume	26
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2019.02.006
Publication status	Published - 26 Feb 2019

Keywords

amyotrophic lateral sclerosis
cell model
genetics
GLT8D1
glycosyltransferase
zebrafish

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10.1016/j.celrep.2019.02.006

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Cooper-Knock, J., Moll, T., Ramesh, T., Castelli, L., Beer, A., Robins, H., Fox, I., Niedermoser, I., Van Damme, P., Moisse, M., Robberecht, W., Hardiman, O., Panades, M. P., Assialioui, A., Mora, J. S., Basak, A. N., Morrison, K. E., Shaw, C. E., Al-Chalabi, A., ... Shaw, P. J. (2019). Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis. Cell Reports, 26(9), 2298-2306.e5. https://doi.org/10.1016/j.celrep.2019.02.006

@article{034363a705174f3aa19403e70fddb13d,

title = "Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis",

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.",

keywords = "amyotrophic lateral sclerosis, cell model, genetics, GLT8D1, glycosyltransferase, zebrafish",

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

year = "2019",

month = feb,

day = "26",

doi = "10.1016/j.celrep.2019.02.006",

language = "English",

volume = "26",

pages = "2298--2306.e5",

journal = "Cell Reports",

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Cooper-Knock, J, Moll, T, Ramesh, T, Castelli, L, Beer, A, Robins, H, Fox, I, Niedermoser, I, Van Damme, P, Moisse, M, Robberecht, W, Hardiman, O, Panades, MP, Assialioui, A, Mora, JS, Basak, AN, Morrison, KE, Shaw, CE , Al-Chalabi, A, Landers, JE, Wyles, M, Heath, PR, Higginbottom, A, Walsh, T, Kazoka, M, McDermott, CJ, Hautbergue, GM, Kirby, J & Shaw, PJ 2019, 'Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis', Cell Reports, vol. 26, no. 9, pp. 2298-2306.e5. https://doi.org/10.1016/j.celrep.2019.02.006

TY - JOUR

T1 - Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis

AU - Cooper-Knock, Johnathan

AU - Moll, Tobias

AU - Ramesh, Tennore

AU - Castelli, Lydia

AU - Beer, Alexander

AU - Robins, Henry

AU - Fox, Ian

AU - Niedermoser, Isabell

AU - Van Damme, Philip

AU - Moisse, Matthieu

AU - Robberecht, Wim

AU - Hardiman, Orla

AU - Panades, Monica P.

AU - Assialioui, Abdelilah

AU - Mora, Jesus S.

AU - Basak, A. Nazli

AU - Morrison, Karen E.

AU - Shaw, Christopher E.

AU - Al-Chalabi, Ammar

AU - Landers, John E.

AU - Wyles, Matthew

AU - Heath, Paul R.

AU - Higginbottom, Adrian

AU - Walsh, Theresa

AU - Kazoka, Mbombe

AU - McDermott, Christopher J.

AU - Hautbergue, Guillaume M.

AU - Kirby, Janine

AU - Shaw, Pamela J.

PY - 2019/2/26

Y1 - 2019/2/26

N2 - 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.

AB - 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.

KW - amyotrophic lateral sclerosis

KW - cell model

KW - genetics

KW - GLT8D1

KW - glycosyltransferase

KW - zebrafish

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U2 - 10.1016/j.celrep.2019.02.006

DO - 10.1016/j.celrep.2019.02.006

M3 - Article

C2 - 30811981

AN - SCOPUS:85061337780

SN - 2211-1247

VL - 26

SP - 2298-2306.e5

JO - Cell Reports

JF - Cell Reports

IS - 9

ER -

Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis

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