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

Cell Reports
Johnathan Cooper-KnockPamela J Shaw

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.

Citations

Nov 15, 2019·Brain : a Journal of Neurology·Tobias MollJohnathan Cooper-Knock
Nov 9, 2019·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration·Anne GieselerKarl-Heinz Zacher
Nov 9, 2019·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration·Jennifer RoggenbuckJonathan Glass
Jul 25, 2019·Current Opinion in Neurology·David Brenner, Jochen H Weishaupt
May 28, 2020·International Journal of Molecular Sciences·Francesca TrojsiGioacchino Tedeschi
Aug 1, 2020·Frontiers in Neuroscience·Ramya RanganathanJanine Kirby
Oct 21, 2020·Essays in Biochemistry·Yu SunGabriel Balmus
Nov 22, 2020·Neurobiology of Aging·Elisa TeyssouStéphanie Millecamps
Mar 15, 2021·Neurobiology of Aging·Mubalake YilihamuDongsheng Fan
Jun 15, 2021·Nucleic Acids Research·Jiajing HuAlfredo Iacoangeli
Jul 20, 2021·Neurobiology of Aging·Zhen LiuJunling Wang
Aug 11, 2021·International Journal of Urology : Official Journal of the Japanese Urological Association·Tzu-Ju ChenYow-Ling Shiue
Nov 18, 2021·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration
Aug 4, 2021·Current Opinion in Neurology·Johnathan Cooper-KnockJan H Veldink

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Methods Mentioned

BETA
exome sequencing
GTPase
PCR
transfection
Assay

Software Mentioned

wANNOVAR
Galaxy
GraphPad Prism
CADD
Viewpoint Zebralab
Gene
BWA
miR RNAi Block IT
SKAT

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Amyotrophic Lateral Sclerosis (ALS) is a progressive nervous system disease associated with the death of neurons that control voluntary muscles. Discover the latest research on ALS here.