Publication
Genetic Variation in ATXN3 (Ataxin-3) 3′UTR: Insights into the Downstream Regulatory Elements of the Causative Gene of Machado-Joseph Disease/Spinocerebellar Ataxia Type 3
| dc.contributor.author | Melo, Ana Rosa Vieira | |
| dc.contributor.author | Raposo, Mafalda | |
| dc.contributor.author | Ventura, Marta | |
| dc.contributor.author | Martins, Sandra | |
| dc.contributor.author | Pavão, Sara | |
| dc.contributor.author | Alonso, Isabel | |
| dc.contributor.author | Bettencourt, Conceição | |
| dc.contributor.author | Lima, Manuela | |
| dc.date.accessioned | 2023-03-21T14:46:15Z | |
| dc.date.available | 2023-03-21T14:46:15Z | |
| dc.date.issued | 2022-01-16 | |
| dc.description.abstract | Untranslated regions are involved in the regulation of transcriptional and post-transcriptional processes. Characterization of these regions remains poorly explored for ATXN3, the causative gene of Machado-Joseph disease (MJD). Although a few genetic modifiers have been identified for MJD age at onset (AO), they only explain a small fraction of the AO variance. Our aim was to analyse variation at the 3'UTR of ATXN3 in MJD patients, analyse its impact on AO and attempt to build haplotypes that might discriminate between normal and expanded alleles.After assessing ATXN3 3'UTR variants in molecularly confirmed MJD patients, an in silico analysis was conducted to predict their functional impact (e.g. their effect on miRNA-binding sites). Alleles in cis with the expanded (CAG)n were inferred from family data, and haplotypes were built. The effect of the alternative alleles on the AO and on SARA and NESSCA ataxia scales was tested.Nine variants, all previously described, were found. For eight variants, in silico analyses predicted (a) deleterious effects (rs10151135; rs55966267); (b) changes on miRNA-binding sites (rs11628764; rs55966267; rs709930) and (c) alterations of RNA-binding protein (RBP)-binding sites (rs1055996; rs910369; rs709930; rs10151135; rs3092822; rs7158733). Patients harbouring the alternative allele at rs10151135 had significantly higher SARA Axial subscores (p = 0.023), comparatively with those homozygous for the reference allele. Ten different haplotypes were obtained, one of which was exclusively found in cis with the expanded and four with the normal allele. These findings, which are relevant for the design of allele-specific therapies, warrant further investigation in independent MJD cohorts. | pt_PT |
| dc.description.sponsorship | This work was fnanced 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 Tecnologia in the framework of the EXOS3 project: PTDC/DTP-PIC/2638/2017 (POCI-01–0145-FEDER-016592). ARVM is supported by a PhD grant (SFRH/BD/129547/2017) fnanced by FCT – Fundação para a Ciência e Tecnologia. MR and SM are supported by Fundação para a Ciência e Tecnologia (CEEC IND/03018/2018 and CEECIND/00684/2017, respectively). CB is supported by the Multiple System Atrophy Trust, and Alzheimer’s Research UK. fundação para a ciência e a tecnologia, SFRH/BD/129547/2017, Ana Rosa Vieira Melo, PTDC/DTP-PIC/2638/2017 (POCI-01–0145- FEDER-016592), CEECIND/03018/2018, Mafalda Raposo, CEECIND/00684/2017, Sandra Martins, multiple system atrophy trust. | pt_PT |
| dc.description.version | info:eu-repo/semantics/publishedVersion | pt_PT |
| dc.identifier.citation | Cerebellum. 2023 Feb;22(1):37-45. doi: 10.1007/s12311-021-01358-0. Epub 2022 Jan 16. | pt_PT |
| dc.identifier.doi | 10.1007/s12311-021-01358-0 | pt_PT |
| dc.identifier.issn | 1473-4222 | |
| dc.identifier.uri | http://hdl.handle.net/10400.18/8590 | |
| dc.language.iso | eng | pt_PT |
| dc.peerreviewed | yes | pt_PT |
| dc.publisher | Springer | pt_PT |
| dc.relation | Unveiling the role of methylation prone MPRs and untranslated UTRs regions in the clinical variability of Spinocerebellar Ataxia Type 3SCA3: a genome-wide approach. | |
| dc.relation | Not Available | |
| dc.relation | Not Available | |
| dc.relation.publisherversion | https://link.springer.com/article/10.1007/s12311-021-01358-0 | pt_PT |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | pt_PT |
| dc.subject | Gametic Phase | pt_PT |
| dc.subject | Genetic Modifiers | pt_PT |
| dc.subject | MJD | pt_PT |
| dc.subject | Polyglutamine Disease | pt_PT |
| dc.subject | SCA3 | pt_PT |
| dc.subject | Transcription Regulation | pt_PT |
| dc.subject | Untranslated Regions | pt_PT |
| dc.subject | miRNA | pt_PT |
| dc.title | Genetic Variation in ATXN3 (Ataxin-3) 3′UTR: Insights into the Downstream Regulatory Elements of the Causative Gene of Machado-Joseph Disease/Spinocerebellar Ataxia Type 3 | pt_PT |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.awardTitle | Unveiling the role of methylation prone MPRs and untranslated UTRs regions in the clinical variability of Spinocerebellar Ataxia Type 3SCA3: a genome-wide approach. | |
| oaire.awardTitle | Not Available | |
| oaire.awardTitle | Not Available | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FDTP-PIC%2F2638%2F2014/PT (2017) | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/POR_NORTE/SFRH%2FBD%2F129547%2F2017/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/CEEC IND 2018/CEECIND%2F03018%2F2018%2FCP1556%2FCT0009/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/CEEC IND 2017/CEECIND%2F00684%2F2017%2FCP1400%2FCT0003/PT | |
| oaire.citation.endPage | 45 | pt_PT |
| oaire.citation.issue | 1 | pt_PT |
| oaire.citation.startPage | 37 | pt_PT |
| oaire.citation.title | The Cerebellum | pt_PT |
| oaire.citation.volume | 22 | pt_PT |
| oaire.fundingStream | 9471 - RIDTI | |
| oaire.fundingStream | POR_NORTE | |
| oaire.fundingStream | CEEC IND 2018 | |
| oaire.fundingStream | CEEC IND 2017 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| rcaap.embargofct | Acesso de acordo com política editorial da revista. | pt_PT |
| rcaap.rights | embargoedAccess | pt_PT |
| rcaap.type | article | pt_PT |
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