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Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset

dc.contributor.authorSantos, D.
dc.contributor.authorCoelho, T.
dc.contributor.authorAlves-Ferreira, M.
dc.contributor.authorSequeiros, J.
dc.contributor.authorMendonça, D.
dc.contributor.authorAlonso, I.
dc.contributor.authorLemos, C.
dc.contributor.authorSousa, A.
dc.date.accessioned2017-04-24T14:30:26Z
dc.date.available2017-04-24T14:30:26Z
dc.date.issued2017
dc.description.abstractOBJECTIVES: Familial amyloid polyneuropathy (FAP ATTRV30M) shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We will now explore some candidate genes involved in altered disease pathways in order to assess their role as genetic modifiers of AO, using a family-centered approach. METHODS: We analyzed 62 tagging SNPs from nine genes-NGAL,MMP-9,BGN,MEK1,MEK2,ERK1,ERK2,HSP27, and YWHAZ - in a sample of 318 V30M Portuguese patients (106 families), currently under follow-up. A generalized estimating equation analysis was used to take into account nonindependency of AO between relatives. Also, an in silico analysis was performed in order to assess the functional impact of significant variants associated with AO. RESULTS: We found for the first time variants from six genes (NGAL,BGN (in the female group), MEK1,MEK2,HSP27, and YWHAZ) that were significantly associated with early- and/or late-onset. Then, we confirmed a strong synergistic interaction between NGAL and MMP-9 genes. Additionally, by an in silico analysis, we found some variants for MEK1 gene that may alter binding of the transcription factors and that influence the regulation of gene expression regarding microRNA binding sites and splicing regulatory factors. INTERPRETATION: These findings showed that different genetic factors can modulate differently the onset of disease's symptoms and revealed new mechanisms with clinical implications in the genetic counseling and follow-up of mutation carriers and could contribute for development of potential therapeutical targets.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAnn Clin Transl Neurol. 2017 20;4(2):98-105pt_PT
dc.identifier.doi10.1002/acn3.380pt_PT
dc.identifier.issn2328-9503
dc.identifier.urihttp://hdl.handle.net/10400.16/2075
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Neurological Associationpt_PT
dc.relationTHE ROLE OF GENETIC AND EPIGENETIC MECHANISMS AS MODIFIERS OF AGE-AT-ONSET AO IN FAMILIAL AMYLOID POLYNEUROPATHY FAP ATTRV30M
dc.relation.publisherversionhttp://onlinelibrary.wiley.com/doi/10.1002/acn3.380/pdfpt_PT
dc.titleFamilial amyloid polyneuropathy in Portugal: New genes modulating age-at-onsetpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleTHE ROLE OF GENETIC AND EPIGENETIC MECHANISMS AS MODIFIERS OF AGE-AT-ONSET AO IN FAMILIAL AMYLOID POLYNEUROPATHY FAP ATTRV30M
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FSAU-GMG%2F100240%2F2008/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F91160%2F2012/PT
oaire.citation.conferencePlaceUnited States of Americapt_PT
oaire.citation.endPage105pt_PT
oaire.citation.issue2pt_PT
oaire.citation.startPage98pt_PT
oaire.citation.titleAnnals of Clinical and Translational Neurologypt_PT
oaire.citation.volume4pt_PT
oaire.fundingStream5876-PPCDTI
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicationc92c872d-d8a0-4149-ad47-e5fcec81e8a7
relation.isProjectOfPublication0c468d2c-29a3-4fb4-8abe-6640fce19a42
relation.isProjectOfPublication.latestForDiscovery0c468d2c-29a3-4fb4-8abe-6640fce19a42

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