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BMP15 mutations associated with primary ovarian insufficiency reduce expression, activity, or synergy with gdf9

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dc.creatorPatiño, Liliana C.spa
dc.creatorWalton, Kelly L.spa
dc.creatorMueller, Thomas D.spa
dc.creatorJohnson, Katharine E.spa
dc.creatorStocker, Williamspa
dc.creatorRichani, Dulamaspa
dc.creatorAgapiou, Davidspa
dc.creatorGilchrist, Robert B.spa
dc.creatorLaissue, Paulspa
dc.creatorHarrison, Craig A.spa
dc.date.accessioned2020-05-25T23:56:02Z
dc.date.available2020-05-25T23:56:02Z
dc.date.created2017spa
dc.description.abstractContext: Bone morphogenetic protein (BMP)15 is an oocyte-specific growth factor, which, together with growth differentiation factor (GDF) 9, regulates folliculogenesis and ovulation rate. Multiple mutations in BMP15 have been identified in women with primary ovarian insufficiency (POI), supporting a pathogenic role; however, the underlying biological mechanism of many of these mutants remains unresolved. Objectives: To determine how mutations associated with ovarian dysfunction alter the biological activity of human BMP15. Design: The effects of 10 mutations in BMP15 on protein production, activation of granulosa cells, and synergy with GDF9 were assessed. Results: Sequencing of 35 patients with POI identified both an unrecognized BMP15 variant (c.986G.A, R329H) and a variant (c.581T.C, F194S) previously associated with the condition. Assessing expression and activity of these and 8 other BMP15 mutants identified: (1) multiple variants, including L148P, F194S, and Y235C, with reduced mature protein production; (2) three variants (R138H, A180T, and R329H) with ;fourfold lower activity than wild-type BMP15; and (3) 3 variants (R68W, F194S, and N196K) with a significantly reduced ability to synergize with GDF9. Conclusions: Mutations in BMP15 associated with POI reduce mature protein production, activity, or synergy with GDF9. The latter effect is perhaps most interesting given that interactions with GDF9 most likelyunderlie the physiologyofBMP15in thehumanovary. Copyright © 2017 by the Endocrine Society.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1210/jc.2016-3503
dc.identifier.issn0021972X
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/22298
dc.language.isoengspa
dc.publisherEndocrine Societyspa
dc.relation.citationEndPage1019
dc.relation.citationIssueNo. 3
dc.relation.citationStartPage1009
dc.relation.citationTitleJournal of Clinical Endocrinology and Metabolism
dc.relation.citationVolumeVol. 102
dc.relation.ispartofJournal of Clinical Endocrinology and Metabolism, ISSN:0021972X, Vol.102, No.3 (2017); pp. 1009-1019spa
dc.relation.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85015234095&doi=10.1210%2fjc.2016-3503&partnerID=40&md5=c1add5449b1fc62feb42511c40f80eebspa
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto Completo)spa
dc.source.instnameinstname:Universidad del Rosariospa
dc.source.reponamereponame:Repositorio Institucional EdocURspa
dc.subject.keywordBone morphogenetic protein 15spa
dc.subject.keywordmoleculareng
dc.subject.keywordGrowth differentiation factor 9spa
dc.subject.keywordGuaninespa
dc.subject.keywordHistonespa
dc.subject.keywordTyrosinespa
dc.subject.keywordBmp15 proteineng
dc.subject.keywordBone morphogenetic protein 15spa
dc.subject.keywordGdf9 proteineng
dc.subject.keywordGrowth differentiation factor 9spa
dc.subject.keywordAdultspa
dc.subject.keywordAmino acid substitutionspa
dc.subject.keywordArticlespa
dc.subject.keywordBmp15 genespa
dc.subject.keywordCell activationspa
dc.subject.keywordControlled studyspa
dc.subject.keywordDown regulationspa
dc.subject.keywordFemalespa
dc.subject.keywordGene expression regulationspa
dc.subject.keywordGene functionspa
dc.subject.keywordGene mutationspa
dc.subject.keywordGene sequencespa
dc.subject.keywordGenetic associationspa
dc.subject.keywordGenetic variabilityspa
dc.subject.keywordGranulosa cellspa
dc.subject.keywordHumanspa
dc.subject.keywordMajor clinical studyspa
dc.subject.keywordMutational analysisspa
dc.subject.keywordPremature ovarian failurespa
dc.subject.keywordProtein functionspa
dc.subject.keywordProtein secondary structurespa
dc.subject.keywordProtein secretionspa
dc.subject.keywordProtein synthesisspa
dc.subject.keywordWild typespa
dc.subject.keywordDrug effectspa
dc.subject.keywordGene expressionspa
dc.subject.keywordGeneticsspa
dc.subject.keywordMetabolismspa
dc.subject.keywordMolecular modelspa
dc.subject.keywordMutationspa
dc.subject.keywordPremature ovarian failurespa
dc.subject.keywordReverse transcription polymerase chain reactionspa
dc.subject.keywordTumor cell linespa
dc.subject.keywordAdultspa
dc.subject.keywordBone morphogenetic protein 15spa
dc.subject.keywordCell lineeng
dc.subject.keywordFemalespa
dc.subject.keywordGene expressionspa
dc.subject.keywordGranulosa cellsspa
dc.subject.keywordGrowth differentiation factor 9spa
dc.subject.keywordHumansspa
dc.subject.keywordModelseng
dc.subject.keywordMutationspa
dc.subject.keywordPrimary ovarian insufficiencyspa
dc.subject.keywordReverse transcriptase polymerase chain reactionspa
dc.titleBMP15 mutations associated with primary ovarian insufficiency reduce expression, activity, or synergy with gdf9spa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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