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 cau...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2017-11-01
|
Series: | Frontiers in Molecular Neuroscience |
Subjects: | |
Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00370/full |
id |
doaj-37b028ed777e4060add426ccea440b63 |
---|---|
record_format |
Article |
spelling |
doaj-37b028ed777e4060add426ccea440b632020-11-24T22:49:12ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-11-011010.3389/fnmol.2017.00370304012Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical PhenotypeJohnathan Cooper-KnockHenry RobinsIsabell NiedermoserMatthew WylesPaul R. HeathAdrian HigginbottomTheresa WalshMbombe KazokaProject MinE ALS Sequencing ConsortiumPaul G. InceGuillaume M. HautbergueChristopher J. McDermottJanine KirbyPamela J. ShawAhmad Al KheifatAmmar Al-ChalabiNazli BasakIan BlairAnnelot DekkerOrla HardimanWinston HideAlfredo IacoangeliKevin KennaJohn LandersRussel McLaughlinJonathan MillBas MiddelkoopMattieu MoisseJesus Mora PardinaKaren MorrisonStephen NewhouseSara PulitAleksey ShatunovChris ShawWilliam SprovieroGijs TazelaarPhilip van DammeLeonard van den BergRick van der SpekKristelvan EijkMichael van EsWouter van RheenenJoke van VugtJan VeldinkMaarten KooymanJonathan GlassWim RobberechtMarc GotkineVivian DroryMatthew KiernanMiguel Mitne NetoMayana ZtazPhilippe CouratierPhilippe CorciaVincenzo SilaniAdriano ChioMamede de CarvalhoSusana PintoAlberto Garcia RedondoPeter AndersenMarkus WeberNicola TicozziAmyotrophic 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.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00370/fullamyotrophic lateral sclerosisRNA binding proteinsoligogenic inheritanceC9ORF72DNA sequencing |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Johnathan Cooper-Knock Henry Robins Isabell Niedermoser Matthew Wyles Paul R. Heath Adrian Higginbottom Theresa Walsh Mbombe Kazoka Project MinE ALS Sequencing Consortium Paul G. Ince Guillaume M. Hautbergue Christopher J. McDermott Janine Kirby Pamela J. Shaw Ahmad Al Kheifat Ammar Al-Chalabi Nazli Basak Ian Blair Annelot Dekker Orla Hardiman Winston Hide Alfredo Iacoangeli Kevin Kenna John Landers Russel McLaughlin Jonathan Mill Bas Middelkoop Mattieu Moisse Jesus Mora Pardina Karen Morrison Stephen Newhouse Sara Pulit Aleksey Shatunov Chris Shaw William Sproviero Gijs Tazelaar Philip van Damme Leonard van den Berg Rick van der Spek Kristelvan Eijk Michael van Es Wouter van Rheenen Joke van Vugt Jan Veldink Maarten Kooyman Jonathan Glass Wim Robberecht Marc Gotkine Vivian Drory Matthew Kiernan Miguel Mitne Neto Mayana Ztaz Philippe Couratier Philippe Corcia Vincenzo Silani Adriano Chio Mamede de Carvalho Susana Pinto Alberto Garcia Redondo Peter Andersen Markus Weber Nicola Ticozzi |
spellingShingle |
Johnathan Cooper-Knock Henry Robins Isabell Niedermoser Matthew Wyles Paul R. Heath Adrian Higginbottom Theresa Walsh Mbombe Kazoka Project MinE ALS Sequencing Consortium Paul G. Ince Guillaume M. Hautbergue Christopher J. McDermott Janine Kirby Pamela J. Shaw Ahmad Al Kheifat Ammar Al-Chalabi Nazli Basak Ian Blair Annelot Dekker Orla Hardiman Winston Hide Alfredo Iacoangeli Kevin Kenna John Landers Russel McLaughlin Jonathan Mill Bas Middelkoop Mattieu Moisse Jesus Mora Pardina Karen Morrison Stephen Newhouse Sara Pulit Aleksey Shatunov Chris Shaw William Sproviero Gijs Tazelaar Philip van Damme Leonard van den Berg Rick van der Spek Kristelvan Eijk Michael van Es Wouter van Rheenen Joke van Vugt Jan Veldink Maarten Kooyman Jonathan Glass Wim Robberecht Marc Gotkine Vivian Drory Matthew Kiernan Miguel Mitne Neto Mayana Ztaz Philippe Couratier Philippe Corcia Vincenzo Silani Adriano Chio Mamede de Carvalho Susana Pinto Alberto Garcia Redondo Peter Andersen Markus Weber Nicola Ticozzi Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype Frontiers in Molecular Neuroscience amyotrophic lateral sclerosis RNA binding proteins oligogenic inheritance C9ORF72 DNA sequencing |
author_facet |
Johnathan Cooper-Knock Henry Robins Isabell Niedermoser Matthew Wyles Paul R. Heath Adrian Higginbottom Theresa Walsh Mbombe Kazoka Project MinE ALS Sequencing Consortium Paul G. Ince Guillaume M. Hautbergue Christopher J. McDermott Janine Kirby Pamela J. Shaw Ahmad Al Kheifat Ammar Al-Chalabi Nazli Basak Ian Blair Annelot Dekker Orla Hardiman Winston Hide Alfredo Iacoangeli Kevin Kenna John Landers Russel McLaughlin Jonathan Mill Bas Middelkoop Mattieu Moisse Jesus Mora Pardina Karen Morrison Stephen Newhouse Sara Pulit Aleksey Shatunov Chris Shaw William Sproviero Gijs Tazelaar Philip van Damme Leonard van den Berg Rick van der Spek Kristelvan Eijk Michael van Es Wouter van Rheenen Joke van Vugt Jan Veldink Maarten Kooyman Jonathan Glass Wim Robberecht Marc Gotkine Vivian Drory Matthew Kiernan Miguel Mitne Neto Mayana Ztaz Philippe Couratier Philippe Corcia Vincenzo Silani Adriano Chio Mamede de Carvalho Susana Pinto Alberto Garcia Redondo Peter Andersen Markus Weber Nicola Ticozzi |
author_sort |
Johnathan Cooper-Knock |
title |
Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype |
title_short |
Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype |
title_full |
Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype |
title_fullStr |
Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype |
title_full_unstemmed |
Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype |
title_sort |
targeted genetic screen in amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Molecular Neuroscience |
issn |
1662-5099 |
publishDate |
2017-11-01 |
description |
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. |
topic |
amyotrophic lateral sclerosis RNA binding proteins oligogenic inheritance C9ORF72 DNA sequencing |
url |
http://journal.frontiersin.org/article/10.3389/fnmol.2017.00370/full |
work_keys_str_mv |
AT johnathancooperknock targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT henryrobins targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT isabellniedermoser targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT matthewwyles targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT paulrheath targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT adrianhigginbottom targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT theresawalsh targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT mbombekazoka targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT projectminealssequencingconsortium targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT paulgince targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT guillaumemhautbergue targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT christopherjmcdermott targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT janinekirby targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT pamelajshaw targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT ahmadalkheifat targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT ammaralchalabi targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT nazlibasak targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT ianblair targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT annelotdekker targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT orlahardiman targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT winstonhide targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT alfredoiacoangeli targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT kevinkenna targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT johnlanders targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT russelmclaughlin targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT jonathanmill targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT basmiddelkoop targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT mattieumoisse targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT jesusmorapardina targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT karenmorrison targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT stephennewhouse targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT sarapulit targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT alekseyshatunov targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT chrisshaw targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT williamsproviero targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT gijstazelaar targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT philipvandamme targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT leonardvandenberg targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT rickvanderspek targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT kristelvaneijk targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT michaelvanes targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT woutervanrheenen targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT jokevanvugt targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT janveldink targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT maartenkooyman targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT jonathanglass targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT wimrobberecht targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT marcgotkine targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT viviandrory targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT matthewkiernan targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT miguelmitneneto targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT mayanaztaz targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT philippecouratier targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT philippecorcia targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT vincenzosilani targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT adrianochio targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT mamededecarvalho targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT susanapinto targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT albertogarciaredondo targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT peterandersen targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT markusweber targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype AT nicolaticozzi targetedgeneticscreeninamyotrophiclateralsclerosisrevealsnovelgeneticvariantswithsynergisticeffectonclinicalphenotype |
_version_ |
1725676814084341760 |