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Molecular effect of an OPTN common variant associated to Paget's disease of bone

2018-05Journal article Open access
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dc.contributor.authorSilva, Iris
dc.contributor.authorConceição, Natércia
dc.contributor.authorGagnon, Edith
dc.contributor.authorBrown, Jacques P.
dc.contributor.authorCancela, M. Leonor
dc.contributor.authorMichou, Laetitia
dc.date.accessioned2018-12-07T14:57:52Z
dc.date.available2018-12-07T14:57:52Z
dc.date.issued2018-05
dc.description.abstractPaget's disease of bone (PDB) is a chronic bone disorder and although genetic factors appear to play an important role in its pathogenesis, to date PDB causing mutations were identified only in the Sequestosome 1 (SQSTM1) gene at the PDB3 locus. PDB6 locus, also previously linked to PDB, contains several candidate genes for metabolic bone diseases. We focused our analysis in the most significantly associated variant with PDB, within the Optineurin (OPTN) gene, i.e. the common variant rs1561570. Although it was previously shown to be strongly associated with PDB in several populations, its contribution to PDB pathogenesis remains unclear. In this study we have shown that rs1561570 may contribute to PDB since its Tallele results in the loss of a methylation site in patients' DNA, leading to higher levels of OPTN gene expression and a corresponding increase in protein levels in patients' osteoclasts. This increase in OPTN expression leads to higher levels of NF-KB translocation into the nucleus and increasing expression of its target genes, which may contribute to the overactivity of osteoclasts observed in PDB. We also reported a tendency for a more severe clinical phenotype in the presence of a haplotype containing the rs1561570 T allele, which appear to be re-enforced with the presence of the SQSTM1/P392L mutation. In conclusion, our work provides novel insight towards understanding the functional effects of this variant, located in OPTN intron 7, and its implication in the contribution to PDB pathogenesis.
dc.description.sponsorshipnational funds from Foundation for Science and Technology (FCT) [UID/Multi/04326/2013]; Canadian Institutes for Health Research, Canada [MOP130457]; CHU de Quebec Foundation; Canadian Foundation for Innovation; Fonds de recherche du Quebec-sante; Laval University; CHU de Quebec-Universite Laval Research Centre; FCT [SFRH/BD/77227/2011, SFRH/BPD/111898/2015]; Fonds de recherche Quebec-Sante (FRQ-S), Quebec, Canada
dc.identifier.doi10.1371/journal.pone.0197543
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/10400.1/11738
dc.language.isoeng
dc.peerreviewedyes
dc.publisherPublic Library Science
dc.subjectKappa-B Activation
dc.subjectGenetic-Heterogeneity
dc.subjectTranscription Factor
dc.subjectAutophagy Receptor
dc.subjectChromosome 18Q
dc.subjectOptineurin
dc.subjectIdentification
dc.subjectBinding
dc.subjectLinkage
dc.subjectLocus
dc.titleMolecular effect of an OPTN common variant associated to Paget's disease of bone
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04326%2F2013/PT
oaire.citation.issue5
oaire.citation.startPagee0197543
oaire.citation.titlePlos One
oaire.citation.volume13
oaire.fundingStream5876
person.familyNameSilva
person.familyNameConceição
person.familyNameCancela
person.givenNameIris
person.givenNameNatércia
person.givenNameM. Leonor
person.identifier.ciencia-id8319-EDFC-1260
person.identifier.ciencia-id7C11-760D-F425
person.identifier.orcid0000-0002-8062-5558
person.identifier.orcid0000-0002-5057-0912
person.identifier.orcid0000-0003-3114-6662
person.identifier.ridU-5740-2017
person.identifier.scopus-author-id57196094239
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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