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A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant

dc.rights.licenseopenen_US
dc.contributor.authorMORANGE, Pierre-Emmanuel
dc.contributor.authorPEIRETTI, Franck
dc.contributor.authorGOURHANT, Lenaick
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorPROUST, Carole
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorSOUKARIEH, Omar
dc.contributor.authorPULCRANO-NICOLAS, Anne-Sophie
dc.contributor.authorSARIPELLA, Ganapathi-Varma
dc.contributor.authorSTEFANUCCI, Luca
dc.contributor.authorLACROIX, Romaric
dc.contributor.authorIBRAHIM KOSTA, Manal
dc.contributor.authorLEMARIE, Catherine A.
dc.contributor.authorFRONTINI, Mattia
dc.contributor.authorALESSI, Marie-Christine
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorCOUTURAUD, Francis
dc.date.accessioned2021-03-30T09:05:00Z
dc.date.available2021-03-30T09:05:00Z
dc.date.issued2021-01-19
dc.identifier.issn1553-7404 (Electronic) 1553-7390 (Linking)en_US
dc.identifier.urioai:crossref.org:10.1371/journal.pgen.1009284
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/26821
dc.description.abstractEnRare variants outside the classical coagulation cascade might cause inherited thrombosis. We aimed to identify the variant(s) causing venous thromboembolism (VTE) in a family with multiple relatives affected with unprovoked VTE and no thrombophilia defects. We identified by whole exome sequencing an extremely rare Arg to Gln variant (Arg89Gln) in the Microtubule Associated Serine/Threonine Kinase 2 (MAST2) gene that segregates with VTE in the family. Free-tissue factor pathway inhibitor (f-TFPI) plasma levels were significantly decreased in affected family members compared to healthy relatives. Conversely, plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in affected members than in healthy relatives. RNA sequencing analysis of RNA interference experimental data conducted in endothelial cells revealed that, of the 13,387 detected expressed genes, 2,354 have their level of expression modified by MAST2 knockdown, including SERPINE1 coding for PAI-1 and TFPI. In HEK293 cells overexpressing the MAST2 Gln89 variant, TFPI and SERPINE1 promoter activities were respectively lower and higher than in cells overexpressing the MAST2 wild type. This study identifies a novel thrombophilia-causing Arg89Gln variant in the MAST2 gene that is here proposed as a new molecular player in the etiology of VTE by interfering with hemostatic balance of endothelial cells.
dc.description.sponsorshipMedical Genomics - ANR-10-LABX-0013en_US
dc.description.sponsorshipFrance-Génomiqueen_US
dc.language.isoENen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.sourcecrossref
dc.title.enA rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant
dc.typeArticle de revueen_US
dc.identifier.doi10.1371/journal.pgen.1009284en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed33465109en_US
bordeaux.journalPLoS Geneticsen_US
bordeaux.pagee1009284en_US
bordeaux.volume17en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.issue1en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.teamVINTAGE
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.identifier.funderIDBritish Heart Foundationen_US
bordeaux.identifier.funderIDUniversité de Bordeauxen_US
bordeaux.import.sourcedissemin
hal.exportfalse
workflow.import.sourcedissemin
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