Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/238319 |
Resumo: | Machado-Joseph disease (MJD/SCA3) is a neurodegenerative polyglutamine disorder exhibiting a wide spectrum of phenotypes. The abnormal size of the (CAG)n at ATXN3 explains ~55% of the age at onset variance, suggesting the involvement of other factors, namely genetic modifiers, whose identification remains limited. Our aim was to find novel genetic modifiers, analyse their epistatic effects and identify disease-modifying pathways contributing to MJD variable expressivity. We performed whole-exome sequencing in a discovery sample of four age at onset concordant and four discordant first-degree relative pairs of Azorean patients, to identify candidate variants which genotypes differed for each discordant pair but were shared in each concordant pair. Variants identified by this approach were then tested in an independent multi-origin cohort of 282 MJD patients. Whole-exome sequencing identified 233 candidate variants, from which 82 variants in 53 genes were prioritized for downstream analysis. Eighteen disease-modifying pathways were identified; two of the most enriched pathways were relevant for the nervous system, namely the neuregulin signaling and the agrin interactions at neuromuscular junction. Variants at PARD3, NFKB1, CHD5, ACTG1, CFAP57, DLGAP2, ITGB1, DIDO1 and CERS4 modulate age at onset in MJD, with those identified in CFAP57, ACTG1 and DIDO1 showing consistent effects across cohorts of different geographical origins. Network analyses of the nine novel MJD modifiers highlighted several important molecular interactions, including genes/proteins previously related with MJD pathogenesis, namely between ACTG1/APOE and VCP/ITGB1. We describe novel pathways, modifiers, and their interaction partners, providing a broad molecular portrait of age at onset modulation to be further exploited as new disease-modifying targets for MJD and related diseases. |
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Raposo, MafaldaBettencourt, ConceiçãoMelo, Ana Rosa VieiraFerreira, Ana F.Alonso, Isabel da Conceição Moreira PereiraSilva, PauloVasconcelos, JoãoKay, TeresaPereira, Maria Luiza SaraivaCosta, Marta DanielaVilasboas Campos, DanielaBettencourt, Bruno FilipeBruges-Armas, JácomeHoulden, Henry H.Heutink, PeterJardim, Laura BannachSequeiros, JorgeMaciel, PatríciaLima, Manuela2022-05-07T04:50:58Z20220969-9961http://hdl.handle.net/10183/238319001139602Machado-Joseph disease (MJD/SCA3) is a neurodegenerative polyglutamine disorder exhibiting a wide spectrum of phenotypes. The abnormal size of the (CAG)n at ATXN3 explains ~55% of the age at onset variance, suggesting the involvement of other factors, namely genetic modifiers, whose identification remains limited. Our aim was to find novel genetic modifiers, analyse their epistatic effects and identify disease-modifying pathways contributing to MJD variable expressivity. We performed whole-exome sequencing in a discovery sample of four age at onset concordant and four discordant first-degree relative pairs of Azorean patients, to identify candidate variants which genotypes differed for each discordant pair but were shared in each concordant pair. Variants identified by this approach were then tested in an independent multi-origin cohort of 282 MJD patients. Whole-exome sequencing identified 233 candidate variants, from which 82 variants in 53 genes were prioritized for downstream analysis. Eighteen disease-modifying pathways were identified; two of the most enriched pathways were relevant for the nervous system, namely the neuregulin signaling and the agrin interactions at neuromuscular junction. Variants at PARD3, NFKB1, CHD5, ACTG1, CFAP57, DLGAP2, ITGB1, DIDO1 and CERS4 modulate age at onset in MJD, with those identified in CFAP57, ACTG1 and DIDO1 showing consistent effects across cohorts of different geographical origins. Network analyses of the nine novel MJD modifiers highlighted several important molecular interactions, including genes/proteins previously related with MJD pathogenesis, namely between ACTG1/APOE and VCP/ITGB1. We describe novel pathways, modifiers, and their interaction partners, providing a broad molecular portrait of age at onset modulation to be further exploited as new disease-modifying targets for MJD and related diseases.application/pdfengNeurobiology of disease. San Diego. Vol. 162 (Jan. 2022), 105578, 10 p.Doença de Machado-JosephSequenciamento do exomaIdade de inícioGenes modificadoresMJDSCA3Spinocerebellar ataxiaPolyglutamine diseaseAge at onsetGenetic modifierNovel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencingEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001139602.pdf.txt001139602.pdf.txtExtracted Texttext/plain57517http://www.lume.ufrgs.br/bitstream/10183/238319/2/001139602.pdf.txtc3380a5abce5ab98c4d489f3542850a7MD52ORIGINAL001139602.pdfTexto completo (inglês)application/pdf2173737http://www.lume.ufrgs.br/bitstream/10183/238319/1/001139602.pdfd3e2a38575ba0829bfed672eb25975a5MD5110183/2383192023-11-19 04:21:39.642013oai:www.lume.ufrgs.br:10183/238319Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2023-11-19T06:21:39Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing |
title |
Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing |
spellingShingle |
Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing Raposo, Mafalda Doença de Machado-Joseph Sequenciamento do exoma Idade de início Genes modificadores MJD SCA3 Spinocerebellar ataxia Polyglutamine disease Age at onset Genetic modifier |
title_short |
Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing |
title_full |
Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing |
title_fullStr |
Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing |
title_full_unstemmed |
Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing |
title_sort |
Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing |
author |
Raposo, Mafalda |
author_facet |
Raposo, Mafalda Bettencourt, Conceição Melo, Ana Rosa Vieira Ferreira, Ana F. Alonso, Isabel da Conceição Moreira Pereira Silva, Paulo Vasconcelos, João Kay, Teresa Pereira, Maria Luiza Saraiva Costa, Marta Daniela Vilasboas Campos, Daniela Bettencourt, Bruno Filipe Bruges-Armas, Jácome Houlden, Henry H. Heutink, Peter Jardim, Laura Bannach Sequeiros, Jorge Maciel, Patrícia Lima, Manuela |
author_role |
author |
author2 |
Bettencourt, Conceição Melo, Ana Rosa Vieira Ferreira, Ana F. Alonso, Isabel da Conceição Moreira Pereira Silva, Paulo Vasconcelos, João Kay, Teresa Pereira, Maria Luiza Saraiva Costa, Marta Daniela Vilasboas Campos, Daniela Bettencourt, Bruno Filipe Bruges-Armas, Jácome Houlden, Henry H. Heutink, Peter Jardim, Laura Bannach Sequeiros, Jorge Maciel, Patrícia Lima, Manuela |
author2_role |
author author author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Raposo, Mafalda Bettencourt, Conceição Melo, Ana Rosa Vieira Ferreira, Ana F. Alonso, Isabel da Conceição Moreira Pereira Silva, Paulo Vasconcelos, João Kay, Teresa Pereira, Maria Luiza Saraiva Costa, Marta Daniela Vilasboas Campos, Daniela Bettencourt, Bruno Filipe Bruges-Armas, Jácome Houlden, Henry H. Heutink, Peter Jardim, Laura Bannach Sequeiros, Jorge Maciel, Patrícia Lima, Manuela |
dc.subject.por.fl_str_mv |
Doença de Machado-Joseph Sequenciamento do exoma Idade de início Genes modificadores |
topic |
Doença de Machado-Joseph Sequenciamento do exoma Idade de início Genes modificadores MJD SCA3 Spinocerebellar ataxia Polyglutamine disease Age at onset Genetic modifier |
dc.subject.eng.fl_str_mv |
MJD SCA3 Spinocerebellar ataxia Polyglutamine disease Age at onset Genetic modifier |
description |
Machado-Joseph disease (MJD/SCA3) is a neurodegenerative polyglutamine disorder exhibiting a wide spectrum of phenotypes. The abnormal size of the (CAG)n at ATXN3 explains ~55% of the age at onset variance, suggesting the involvement of other factors, namely genetic modifiers, whose identification remains limited. Our aim was to find novel genetic modifiers, analyse their epistatic effects and identify disease-modifying pathways contributing to MJD variable expressivity. We performed whole-exome sequencing in a discovery sample of four age at onset concordant and four discordant first-degree relative pairs of Azorean patients, to identify candidate variants which genotypes differed for each discordant pair but were shared in each concordant pair. Variants identified by this approach were then tested in an independent multi-origin cohort of 282 MJD patients. Whole-exome sequencing identified 233 candidate variants, from which 82 variants in 53 genes were prioritized for downstream analysis. Eighteen disease-modifying pathways were identified; two of the most enriched pathways were relevant for the nervous system, namely the neuregulin signaling and the agrin interactions at neuromuscular junction. Variants at PARD3, NFKB1, CHD5, ACTG1, CFAP57, DLGAP2, ITGB1, DIDO1 and CERS4 modulate age at onset in MJD, with those identified in CFAP57, ACTG1 and DIDO1 showing consistent effects across cohorts of different geographical origins. Network analyses of the nine novel MJD modifiers highlighted several important molecular interactions, including genes/proteins previously related with MJD pathogenesis, namely between ACTG1/APOE and VCP/ITGB1. We describe novel pathways, modifiers, and their interaction partners, providing a broad molecular portrait of age at onset modulation to be further exploited as new disease-modifying targets for MJD and related diseases. |
publishDate |
2022 |
dc.date.accessioned.fl_str_mv |
2022-05-07T04:50:58Z |
dc.date.issued.fl_str_mv |
2022 |
dc.type.driver.fl_str_mv |
Estrangeiro info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10183/238319 |
dc.identifier.issn.pt_BR.fl_str_mv |
0969-9961 |
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001139602 |
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0969-9961 001139602 |
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http://hdl.handle.net/10183/238319 |
dc.language.iso.fl_str_mv |
eng |
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eng |
dc.relation.ispartof.pt_BR.fl_str_mv |
Neurobiology of disease. San Diego. Vol. 162 (Jan. 2022), 105578, 10 p. |
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