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Effect of genetic variants of OPTN in the pathophysiology of Paget's disease of bone

2018Journal article Open access
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dc.contributor.authorSilva, Iris
dc.contributor.authorConceição, Natércia
dc.contributor.authorGagnon, Edith
dc.contributor.authorCaiado, Helena
dc.contributor.authorBrown, Jacques P.
dc.contributor.authorGianfrancesco, Fernando
dc.contributor.authorMichou, Laëtitia
dc.contributor.authorCancela, Leonor
dc.date.accessioned2018-06-12T12:19:35Z
dc.date.available2019-01-01T01:30:10Z
dc.date.issued2018
dc.description.abstractPaget's disease of bone (PDB) is the second most frequent metabolic bone disease after osteoporosis. Genetic factors play an important role in PDB, but to date PDB causing mutations were identified only in the Sequestosome 1 gene at the PDB3 locus. OPTN has been recently associated with PDB, however little is known about the effect of genetic variants in this gene in PDB pathophysiology. By sequencing OPTN in SQSTM1 non-carriers PDB patients we found 16 SNPs in regulatory, coding and non-coding regions. One of those was found to be associated with PDB in our cohort - rs2234968. Our results show that rs2238968 effect may be explained by a change in OPTN splicing that give rise to a predicted truncated protein. We also performed functional studies on the variants located in OPTN promoter - rs3829923 and the rare variant -9906 - to investigate putative regulators of OPTN. Our results show that OPTN expression seems to be regulated by SP1, RXR, E47, and the E2F family. In conclusion, our work suggests a potential pathophysiological role of SNPs in OPTN, giving a new perspective about the regulatory mechanisms of this gene. Ultimately we discovered a new variant associated with PDB in OPTN, reinforcing the relevance of this gene for the development of this bone disease.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1016/j.bbadis.2017.10.008pt_PT
dc.identifier.issn0925-4439
dc.identifier.otherAUT: LCA00739;
dc.identifier.urihttp://hdl.handle.net/10400.1/10678
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationGENETIC AND FUNCTIONAL ANALYSIS OF THE PDB610P13 LOCUS IN PAGET´S DISEASE OF BONE
dc.subjectCase-control studiespt_PT
dc.subjectCells culturedpt_PT
dc.subjectFemalept_PT
dc.subjectGenetic Association Studiespt_PT
dc.subjectGenetic predisposition to diseasept_PT
dc.subjectHEK293 Cellspt_PT
dc.subjectHumanspt_PT
dc.subjectMalept_PT
dc.subjectOsteitis deformanspt_PT
dc.subjectPromoter regions geneticpt_PT
dc.subjectTranscription Factor TFIIIApt_PT
dc.subjectPolymorphism single nucleotidept_PT
dc.titleEffect of genetic variants of OPTN in the pathophysiology of Paget's disease of bonept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleGENETIC AND FUNCTIONAL ANALYSIS OF THE PDB610P13 LOCUS IN PAGET´S DISEASE OF BONE
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04326%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F77227%2F2011/PT
oaire.citation.endPage151pt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage143pt_PT
oaire.citation.titleBiochimica et Biophysica Acta (BBA) - Molecular Cell Researchpt_PT
oaire.citation.volume1864pt_PT
oaire.fundingStream5876
person.familyNameSilva
person.familyNameCaiado
person.familyNameCancela
person.givenNameIris
person.givenNameHelena
person.givenNameM. Leonor
person.identifier.ciencia-id8319-EDFC-1260
person.identifier.ciencia-id7D19-F0E4-4166
person.identifier.orcid0000-0002-8062-5558
person.identifier.orcid0000-0002-2754-8266
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.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
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relation.isAuthorOfPublicationcac8ae37-2d50-4112-a9ab-da372b75209f
relation.isAuthorOfPublicationb9bbfe32-3dfe-4131-ad14-a4394008447f
relation.isAuthorOfPublication.latestForDiscoveryd1507f94-95c8-4bd1-ba2b-9e49188a87b9
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