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Mutations in the Glycosyltransferase Domain of GLT8D1 Cause Amyotrophic Lateral Sclerosis

37 Pages Posted: 10 Sep 2018 Sneak Peek Status: Review Complete

See all articles by Johnathan Cooper-Knock

Johnathan Cooper-Knock

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Tobias Moll

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Tennore Ramesh

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Lydia Castelli

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Alexander Beer

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Henry Robins

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Ian Fox

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Isabell Niedermoser

KU Leuven - VIB & KU Leuven Center for Brain & Disease Research

Philip Van Damme

KU Leuven - Laboratory of Neurobiology

Wim Robberecht

KU Leuven - Laboratory of Neurobiology

Orla Hardiman

Trinity College (Dublin) - Academic Unit of Neurology

Monica P. Panades

University Hospital of Bellvitge

Jesús S. Mora

Hospital San Rafael - ALS Unit/Neurology

A. Nazli Basak

Bogazici University - Suna and Inan Kırac Foundation

Karen E. Morrison

University of Southampton - Faculty of Medicine, Health and Life Sciences

Christopher E. Shaw

University of Massachusetts Worcester - Department of Neurology

Ammar Al-Chalabi

University of London - Maurice Wohl Clinical Neuroscience Institute

John E. Landers

University of Massachusetts Worcester - Department of Neurology

Matthew Wyles

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Paul R. Heath

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Adrian Higginbottom

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Theresa Walsh

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Mbombe Kazoka

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Christopher J. McDermott

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Guillaume M. Hautbergue

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Janine Kirby

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Pamela J. Shaw

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

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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. 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.

Suggested Citation

Cooper-Knock, Johnathan and Moll, Tobias and Ramesh, Tennore and Castelli, Lydia and Beer, Alexander and Robins, Henry and Fox, Ian and Niedermoser, Isabell and Van Damme, Philip and Robberecht, Wim and Hardiman, Orla and Panades, Monica P. and Mora, Jesús S. and Basak, A. Nazli and Morrison, Karen E. and Shaw, Christopher E. and Al-Chalabi, Ammar and Landers, John E. and Wyles, Matthew and Heath, Paul R. and Higginbottom, Adrian and Walsh, Theresa and Kazoka, Mbombe and McDermott, Christopher J. and Hautbergue, Guillaume M. and Kirby, Janine and Shaw, Pamela J., Mutations in the Glycosyltransferase Domain of GLT8D1 Cause Amyotrophic Lateral Sclerosis (September 6, 2018). Available at SSRN: https://ssrn.com/abstract=3245222 or http://dx.doi.org/10.2139/ssrn.3245222
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Johnathan Cooper-Knock (Contact Author)

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Tobias Moll

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Tennore Ramesh

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Lydia Castelli

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Alexander Beer

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Henry Robins

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Ian Fox

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Isabell Niedermoser

KU Leuven - VIB & KU Leuven Center for Brain & Disease Research

Campus Gasthuisberg O&N4
Herestraat 49, box 602
Leuven, 3000
Belgium

Philip Van Damme

KU Leuven - Laboratory of Neurobiology

Oude Markt 13
Leuven, Vlaams-Brabant 3000
Belgium

Wim Robberecht

KU Leuven - Laboratory of Neurobiology

Oude Markt 13
Leuven, Vlaams-Brabant 3000
Belgium

Orla Hardiman

Trinity College (Dublin) - Academic Unit of Neurology ( email )

Trinity College Dublin
52 - 160 Pearse St
Ireland

Monica P. Panades

University Hospital of Bellvitge

Carrer de la Feixa Llarga, s/n, 08907
L'Hospitalet de Llobregat
Barcelona
Spain

Jesús S. Mora

Hospital San Rafael - ALS Unit/Neurology

Calle de Serrano
199, 28016
Madrid, Community of Madrid
Spain

A. Nazli Basak

Bogazici University - Suna and Inan Kırac Foundation

Bebek, İstanbul 34342
Turkey

Karen E. Morrison

University of Southampton - Faculty of Medicine, Health and Life Sciences

Southampton
United Kingdom

Christopher E. Shaw

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

Ammar Al-Chalabi

University of London - Maurice Wohl Clinical Neuroscience Institute

Strand
London, England WC2R 2LS
United Kingdom

John E. Landers

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

Matthew Wyles

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Paul R. Heath

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Adrian Higginbottom

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Theresa Walsh

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Mbombe Kazoka

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Christopher J. McDermott

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Guillaume M. Hautbergue

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Janine Kirby

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Pamela J. Shaw

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

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