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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


Autoři: Pierre-Emmanuel Morange aff001;  Franck Peiretti aff001;  Lenaick Gourhant aff003;  Carole Proust aff005;  Omar Soukarieh aff006;  Anne-Sophie Pulcrano-Nicolas aff005;  Ganapathi-Varma Saripella aff005;  Luca Stefanucci aff007;  Romaric Lacroix aff001;  Manal Ibrahim-Kosta aff001;  Catherine A. Lemarié aff003;  Mattia Frontini aff007;  Marie-Christine Alessi aff001;  David-Alexandre Trégouët aff005;  Francis Couturaud aff003
Působiště autorů: Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France aff001;  Hematology laboratory, CHU Timone, Marseille, France aff002;  EA3878-GETBO, Univ Brest, Department of internal medicine and chest diseases, FCRIN_INNOVTE, CHU Brest, Brest, France aff003;  INSERM U1078, Brest, France aff004;  Sorbonne Université, UPMC, INSERM UMR_S 1166, Paris, France aff005;  INSERM UMR 1219, Bordeaux Population Health Research Center, University of Bordeaux, France aff006;  National Institute for Health Research BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom aff007;  NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom aff008;  British Heart Foundation Centre of Excellence, Cambridge Biomedical Campus, United Kingdom aff009
Vyšlo v časopise: A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant. PLoS Genet 17(1): e1009284. doi:10.1371/journal.pgen.1009284
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009284

Souhrn

Rare 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.

Klíčová slova:

Blood plasma – Endothelial cells – Gene expression – Gene regulation – RNA sequencing – Small interfering RNA – Transfection – Venous thromboembolism


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