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dc.contributor.authorMorange, Pierre-Emmanuel
dc.contributor.authorPeiretti, Franck
dc.contributor.authorGourhant, Lenaick
dc.contributor.authorProust, Carole
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.authorLemarié, Catherine A.
dc.contributor.authorFrontini, Mattia
dc.contributor.authorAlessi, Marie-Christine
dc.contributor.authorTrégouët, David-Alexandre
dc.contributor.authorCouturaud, Francis
dc.description.abstractRare 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.publisherPublic Library of Science
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.subjectResearch Article
dc.subjectBiology and life sciences
dc.subjectMedicine and health sciences
dc.subjectResearch and analysis methods
dc.titleA rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant
prism.publicationNamePLOS Genetics
datacite.contributor.supervisoreditor: Zeller, Tanja
dc.contributor.orcidMorange, Pierre-Emmanuel [0000-0002-9065-722X]
dc.contributor.orcidPeiretti, Franck [0000-0001-7198-0534]
dc.contributor.orcidGourhant, Lenaick [0000-0002-5761-8480]
dc.contributor.orcidSoukarieh, Omar [0000-0003-4923-4353]
dc.contributor.orcidSaripella, Ganapathi-Varma [0000-0003-3504-9333]
dc.contributor.orcidStefanucci, Luca [0000-0002-4352-1151]
dc.contributor.orcidLemarié, Catherine A. [0000-0002-3897-4287]
dc.contributor.orcidFrontini, Mattia [0000-0001-8074-6299]
dc.contributor.orcidAlessi, Marie-Christine [0000-0003-3927-5792]
dc.contributor.orcidTrégouët, David-Alexandre [0000-0001-9084-7800]
dc.contributor.orcidCouturaud, Francis [0000-0002-1855-8032]

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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)