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

English version

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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