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A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease

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dc.contributor.authorVerheijen, Jan
dc.contributor.authorVan den Bossche, Tobi
dc.contributor.authorvan der Zee, Julie
dc.contributor.authorEngelborghs, Sebastiaan
dc.contributor.authorSanchez-Valle, Raquel
dc.contributor.authorLladó, Albert
dc.contributor.authorGraff, Caroline
dc.contributor.authorThonberg, Håkan
dc.contributor.authorPastor, Pau
dc.contributor.authorOrtega-Cubero, Sara
dc.contributor.authorPastor, Maria A.
dc.contributor.authorBenussi, Luisa
dc.contributor.authorGhidoni, Roberta
dc.contributor.authorBinetti, Giuliano
dc.contributor.authorClarimon, Jordi
dc.contributor.authorLleó, Alberto
dc.contributor.authorFortea, Juan
dc.contributor.authorDe Mendonça, Alexandre
dc.contributor.authorMartins, Madalena
dc.contributor.authorGrau-Rivera, Oriol
dc.contributor.authorGelpi, Ellen
dc.contributor.authorBettens, Karolien
dc.contributor.authorMateiu, Ligia
dc.contributor.authorDillen, Lubina
dc.contributor.authorCras, Patrick
dc.contributor.authorDe Deyn, Peter P.
dc.contributor.authorVan Broeckhoven, Christine
dc.contributor.authorSleegers, Kristel
dc.date.accessioned2021-06-25T11:33:35Z
dc.date.available2021-06-25T11:33:35Z
dc.date.issued2016
dc.description© The Author(s) 2016. This article is published with open access at Springerlink.com. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.pt_PT
dc.description.abstractThe sortilin-related receptor 1 (SORL1) gene has been associated with increased risk for Alzheimer's disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p.Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1.5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8.8 %; SkatOMeta p value 0.0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationActa Neuropathol. 2016 Aug;132(2):213-224pt_PT
dc.identifier.doi10.1007/s00401-016-1566-9pt_PT
dc.identifier.eissn1432-0533
dc.identifier.issn0001-6322
dc.identifier.urihttp://hdl.handle.net/10451/48749
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationIDENTIFICATION OF GENETIC RISK FACTORS FOR PARKINSONSDISEASE USING MICRORNOMICS AND PROTEOMICS
dc.relation.publisherversionhttps://www.springer.com/journal/401pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAlzheimerpt_PT
dc.subjectEarly onsetpt_PT
dc.subjectHaploinsufficiencypt_PT
dc.subjectLoss-of-functionpt_PT
dc.subjectMeta-analysispt_PT
dc.subjectRare variantspt_PT
dc.subjectSORL1pt_PT
dc.titleA comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s diseasept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberSFRH/BPD/29354/2006
oaire.awardTitleIDENTIFICATION OF GENETIC RISK FACTORS FOR PARKINSONSDISEASE USING MICRORNOMICS AND PROTEOMICS
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F29354%2F2006/PT
oaire.citation.endPage224pt_PT
oaire.citation.issue2pt_PT
oaire.citation.startPage213pt_PT
oaire.citation.titleActa Neuropathologicapt_PT
oaire.citation.volume132pt_PT
person.familyNamede Mendonça
person.familyNameda Rocha Martins
person.givenNameAlexandre
person.givenNameMadalena Cristina
person.identifier.ciencia-id1615-41B4-0848
person.identifier.ciencia-id3913-56BA-8AD6
person.identifier.orcid0000-0002-0488-1453
person.identifier.orcid0000-0001-8360-6806
person.identifier.scopus-author-id7003320823
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication53ca3547-99ce-4b68-9330-7879a54c47b7
relation.isAuthorOfPublicationd256ee78-61aa-4745-b73a-9763278e6e0c
relation.isAuthorOfPublication.latestForDiscoveryd256ee78-61aa-4745-b73a-9763278e6e0c
relation.isProjectOfPublication2c0ab178-63c2-4ba3-8505-edc527187a0c
relation.isProjectOfPublication.latestForDiscovery2c0ab178-63c2-4ba3-8505-edc527187a0c

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