Open AccessA rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant
Author(s) -
PierreEmmanuel Morange,
Franck Peiretti,
Lénaïck Gourhant,
Carole Proust,
Omar Soukarieh,
Anne-Sophie Pulcrano-Nicolas,
Ganapathi-Varma Saripella,
Luca Stefanucci,
Romaric Lacroix,
Manal IbrahimKosta,
Catherine A. Lemarié,
Mattia Frontini,
MarieChristine Alessi,
DavidAlexandre Trégouët,
Francis Couturaud
Publication year - 2021
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1009284
Subject(s) - thrombophilia , biology , genetics , exome sequencing , plasminogen activator inhibitor 1 , gene , tissue factor pathway inhibitor , venous thrombosis , plasminogen activator , exome , gene knockdown , microbiology and biotechnology , cancer research , bioinformatics , mutation , coagulation , medicine , tissue factor , thrombosis , pregnancy
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.