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Targeted genetic Screen in amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype

Targeted genetic Screen in amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype
Targeted genetic Screen in amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype

Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.

Journal Article
1662-5099
1-11
Cooper-Knock, Johnathan
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Robins, Henry
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Niedermoser, Isabell
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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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Ince, Paul G.
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Hautbergue, Guillaume M.
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McDermott, Christopher J.
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Kirby, Janine
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Shaw, Pamela J.
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Morrison, Karen
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Project MinE ALS Sequencing Consortium
Cooper-Knock, Johnathan
57a98514-d95e-4146-b354-906b25e09426
Robins, Henry
beefe740-5428-42d8-b0d5-366cedf3d2c6
Niedermoser, Isabell
20dcb7c2-71ba-445f-8044-bc8bf174d9af
Wyles, Matthew
8cc14278-1e59-4ecd-af55-35c15e24b283
Heath, Paul R.
2319288e-f9e4-4b85-a973-39ab32b4b282
Higginbottom, Adrian
eac36288-eb6c-4cbd-ad71-eda09a1bb096
Walsh, Theresa
d2a095e5-1a5a-4a7f-b337-d6969e56d109
Kazoka, Mbombe
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Ince, Paul G.
c1b8f33a-238f-46ae-8edc-da2594c53e48
Hautbergue, Guillaume M.
d99ed6bb-a825-4592-92c9-3ed40f2f3eac
McDermott, Christopher J.
107ae1fb-878d-4197-a620-ee4fbb66f41d
Kirby, Janine
59b4a438-0185-46a5-a76c-9f96b0ea3fe2
Shaw, Pamela J.
3d0a5c6f-9610-45be-a0bc-5b6888003028
Morrison, Karen
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Cooper-Knock, Johnathan, Robins, Henry, Niedermoser, Isabell, Wyles, Matthew, Heath, Paul R., Higginbottom, Adrian, Walsh, Theresa, Kazoka, Mbombe, Ince, Paul G., Hautbergue, Guillaume M., McDermott, Christopher J., Kirby, Janine and Shaw, Pamela J. , Project MinE ALS Sequencing Consortium (2017) Targeted genetic Screen in amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype. Frontiers in Molecular Neuroscience, 10, 1-11, [370]. (doi:10.3389/fnmol.2017.00370).

Record type: Article

Abstract

Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.

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Accepted/In Press date: 26 October 2017
e-pub ahead of print date: 9 November 2017
Keywords: Journal Article

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Local EPrints ID: 417052
URI: http://eprints.soton.ac.uk/id/eprint/417052
ISSN: 1662-5099
PURE UUID: 308d1f6b-8e9c-4553-81aa-0e9393d118f1
ORCID for Karen Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 18 Jan 2018 17:30
Last modified: 07 Oct 2020 02:09

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Contributors

Author: Johnathan Cooper-Knock
Author: Henry Robins
Author: Isabell Niedermoser
Author: Matthew Wyles
Author: Paul R. Heath
Author: Adrian Higginbottom
Author: Theresa Walsh
Author: Mbombe Kazoka
Author: Paul G. Ince
Author: Guillaume M. Hautbergue
Author: Christopher J. McDermott
Author: Janine Kirby
Author: Pamela J. Shaw
Author: Karen Morrison ORCID iD
Corporate Author: Project MinE ALS Sequencing Consortium

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