Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2021 |
| 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/10362/129676 |
Resumo: | Funding Information: This work was funded by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020 , and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia / Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project PTDC/DTP-PIC/2638/2017 ( POCI-01-0145-FEDER-016592 ); GenomePT ( POCI-01-0145-FEDER-022184 ); ICVS Scientific Microscopy Platform , member of the national infrastructure PPBI - Portuguese Platform of Bioimaging ( PPBI-POCI-01-0145-FEDER-022122 ; by National funds , through the Foundation for Science and Technology (FCT) - project UIDB/50026/2020 and UIDP/50026/2020 ; and by the project NORTE-01-0145-FEDER-000013 , supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) . MR is supported by FCT ( CEECIND/03018/2018 ). ARVM ( SFRH/BD/129547/2017 ) and AFF ( SFRH/BD/121101/2016 ) are supported by a PhD grant financed by FCT . CB is supported by the Multiple System Atrophy Trust and Alzheimer's Research UK . MDC received funding from National Ataxia Foundation (NAF) and from FCT ( SFRH/BPD/101925/2014 ); DV-C received a grant from FCT ( SFRH/BD/147826/2019 ). Publisher Copyright: © 2021 |
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Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencingAge at onsetGenetic modifierMJDPolyglutamine diseaseSCA3Spinocerebellar ataxiaNeurologyFunding Information: This work was funded by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020 , and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia / Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project PTDC/DTP-PIC/2638/2017 ( POCI-01-0145-FEDER-016592 ); GenomePT ( POCI-01-0145-FEDER-022184 ); ICVS Scientific Microscopy Platform , member of the national infrastructure PPBI - Portuguese Platform of Bioimaging ( PPBI-POCI-01-0145-FEDER-022122 ; by National funds , through the Foundation for Science and Technology (FCT) - project UIDB/50026/2020 and UIDP/50026/2020 ; and by the project NORTE-01-0145-FEDER-000013 , supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) . MR is supported by FCT ( CEECIND/03018/2018 ). ARVM ( SFRH/BD/129547/2017 ) and AFF ( SFRH/BD/121101/2016 ) are supported by a PhD grant financed by FCT . CB is supported by the Multiple System Atrophy Trust and Alzheimer's Research UK . MDC received funding from National Ataxia Foundation (NAF) and from FCT ( SFRH/BPD/101925/2014 ); DV-C received a grant from FCT ( SFRH/BD/147826/2019 ). Publisher Copyright: © 2021Machado-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.Comprehensive Health Research Centre (CHRC) - pólo NMSCentro de Estudos de Doenças Crónicas (CEDOC)NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)RUNRaposo, MafaldaBettencourt, ConceiçãoMelo, Ana Rosa VieiraFerreira, Ana F.Alonso, IsabelSilva, PauloVasconcelos, JoãoKay, TeresaSaraiva-Pereira, Maria LuizaCosta, Marta D.Vilasboas-Campos, DanielaBettencourt, Bruno FilipeBruges-Armas, JácomeHoulden, HenryHeutink, PeterJardim, Laura BannachSequeiros, JorgeMaciel, PatríciaLima, Manuela2021-12-22T23:26:08Z2022-012022-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/129676eng0969-9961PURE: 35481045https://doi.org/10.1016/j.nbd.2021.105578info: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:RCAAP2024-03-11T05:08:47Zoai:run.unl.pt:10362/129676Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:46:37.206010Repositório 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 |
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 Age at onset Genetic modifier MJD Polyglutamine disease SCA3 Spinocerebellar ataxia Neurology |
| 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 Silva, Paulo Vasconcelos, João Kay, Teresa Saraiva-Pereira, Maria Luiza Costa, Marta D. Vilasboas-Campos, Daniela Bettencourt, Bruno Filipe Bruges-Armas, Jácome Houlden, Henry 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 Silva, Paulo Vasconcelos, João Kay, Teresa Saraiva-Pereira, Maria Luiza Costa, Marta D. Vilasboas-Campos, Daniela Bettencourt, Bruno Filipe Bruges-Armas, Jácome Houlden, Henry 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.none.fl_str_mv |
Comprehensive Health Research Centre (CHRC) - pólo NMS Centro de Estudos de Doenças Crónicas (CEDOC) NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM) RUN |
| dc.contributor.author.fl_str_mv |
Raposo, Mafalda Bettencourt, Conceição Melo, Ana Rosa Vieira Ferreira, Ana F. Alonso, Isabel Silva, Paulo Vasconcelos, João Kay, Teresa Saraiva-Pereira, Maria Luiza Costa, Marta D. Vilasboas-Campos, Daniela Bettencourt, Bruno Filipe Bruges-Armas, Jácome Houlden, Henry Heutink, Peter Jardim, Laura Bannach Sequeiros, Jorge Maciel, Patrícia Lima, Manuela |
| dc.subject.por.fl_str_mv |
Age at onset Genetic modifier MJD Polyglutamine disease SCA3 Spinocerebellar ataxia Neurology |
| topic |
Age at onset Genetic modifier MJD Polyglutamine disease SCA3 Spinocerebellar ataxia Neurology |
| description |
Funding Information: This work was funded by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020 , and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia / Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project PTDC/DTP-PIC/2638/2017 ( POCI-01-0145-FEDER-016592 ); GenomePT ( POCI-01-0145-FEDER-022184 ); ICVS Scientific Microscopy Platform , member of the national infrastructure PPBI - Portuguese Platform of Bioimaging ( PPBI-POCI-01-0145-FEDER-022122 ; by National funds , through the Foundation for Science and Technology (FCT) - project UIDB/50026/2020 and UIDP/50026/2020 ; and by the project NORTE-01-0145-FEDER-000013 , supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) . MR is supported by FCT ( CEECIND/03018/2018 ). ARVM ( SFRH/BD/129547/2017 ) and AFF ( SFRH/BD/121101/2016 ) are supported by a PhD grant financed by FCT . CB is supported by the Multiple System Atrophy Trust and Alzheimer's Research UK . MDC received funding from National Ataxia Foundation (NAF) and from FCT ( SFRH/BPD/101925/2014 ); DV-C received a grant from FCT ( SFRH/BD/147826/2019 ). Publisher Copyright: © 2021 |
| publishDate |
2021 |
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2021-12-22T23:26:08Z 2022-01 2022-01-01T00:00:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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http://hdl.handle.net/10362/129676 |
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eng |
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eng |
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0969-9961 PURE: 35481045 https://doi.org/10.1016/j.nbd.2021.105578 |
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