Targeted genetic screen in Amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2017 |
| Outros Autores: | , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/51479 |
Resumo: | Copyright © 2017 Cooper-Knock, Robins, Niedermoser, Wyles, Heath, Higginbottom, Walsh, Kazoka, Project MinE ALS Sequencing Consortium, Ince, Hautbergue, McDermott, Kirby and Shaw. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| id |
RCAP_c4d88868bd280e788837011cc3e925c2 |
|---|---|
| oai_identifier_str |
oai:repositorio.ul.pt:10451/51479 |
| network_acronym_str |
RCAP |
| network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| repository_id_str |
7160 |
| spelling |
Targeted genetic screen in Amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotypeC9ORF72DNA sequencingRNA binding proteinsAmyotrophic Lateral SclerosisOligogenic inheritanceCopyright © 2017 Cooper-Knock, Robins, Niedermoser, Wyles, Heath, Higginbottom, Walsh, Kazoka, Project MinE ALS Sequencing Consortium, Ince, Hautbergue, McDermott, Kirby and Shaw. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.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.We acknowledge grants from EU Framework 7 (Euro-Motor), and the JPND/MRC SOPHIA, STRENGTH and ALS-CarE projects. JC-K holds a NIHR Clinical Lectureship and PS is supported as an NIHR Senior Investigator. This work was also supported by the NIHR Sheffield Biomedical Research Centre and the Sheffield NIHR Clinical Research Facility.FrontiersRepositório da Universidade de LisboaCooper-Knock, JohnathanRobins, HenryNiedermoser, IsabellWyles, MatthewHeath, Paul R.Higginbottom, AdrianWalsh, TheresaKazoka, MbombeInce, Paul G.Hautbergue, Guillaume M.McDermott, Christopher J.Kirby, JanineShaw, Pamela J.Project MinE ALS Sequencing ConsortiumCarvalho, MamedePinto, Susana2022-02-23T15:53:27Z20172017-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/51479engFront Mol Neurosci. 2017 Nov 9;10:37010.3389/fnmol.2017.003701662-5099info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:56:10Zoai:repositorio.ul.pt:10451/51479Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:02:44.989948Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| dc.title.none.fl_str_mv |
Targeted genetic screen in Amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype |
| title |
Targeted genetic screen in Amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype |
| spellingShingle |
Targeted genetic screen in Amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype Cooper-Knock, Johnathan C9ORF72 DNA sequencing RNA binding proteins Amyotrophic Lateral Sclerosis Oligogenic inheritance |
| 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 |
| author |
Cooper-Knock, Johnathan |
| author_facet |
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 Shaw, Pamela J. Project MinE ALS Sequencing Consortium Carvalho, Mamede Pinto, Susana |
| author_role |
author |
| author2 |
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 Shaw, Pamela J. Project MinE ALS Sequencing Consortium Carvalho, Mamede Pinto, Susana |
| author2_role |
author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
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 Shaw, Pamela J. Project MinE ALS Sequencing Consortium Carvalho, Mamede Pinto, Susana |
| dc.subject.por.fl_str_mv |
C9ORF72 DNA sequencing RNA binding proteins Amyotrophic Lateral Sclerosis Oligogenic inheritance |
| topic |
C9ORF72 DNA sequencing RNA binding proteins Amyotrophic Lateral Sclerosis Oligogenic inheritance |
| description |
Copyright © 2017 Cooper-Knock, Robins, Niedermoser, Wyles, Heath, Higginbottom, Walsh, Kazoka, Project MinE ALS Sequencing Consortium, Ince, Hautbergue, McDermott, Kirby and Shaw. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| publishDate |
2017 |
| dc.date.none.fl_str_mv |
2017 2017-01-01T00:00:00Z 2022-02-23T15:53:27Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/51479 |
| url |
http://hdl.handle.net/10451/51479 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
Front Mol Neurosci. 2017 Nov 9;10:370 10.3389/fnmol.2017.00370 1662-5099 |
| dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
Frontiers |
| publisher.none.fl_str_mv |
Frontiers |
| dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
| instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
| instacron_str |
RCAAP |
| institution |
RCAAP |
| reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
| repository.mail.fl_str_mv |
|
| _version_ |
1799134577142267904 |