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Research article - Peer-reviewed, 2021

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

Morange, Pierre-Emmanuel; Peiretti, Franck; Gourhant, Lenaick; Proust, Carole; Soukarieh, Omar; Pulcrano-Nicolas, Anne-Sophie; Saripella, Ganapathi-Varma; Stefanucci, Luca; Lacroix, Romaric; Ibrahim Kosta, Manal; Lemarie, Catherine A.; Frontini, Mattia; Alessi, Marie-Christine; Tregouet, David-Alexandre; Couturaud, Francis

Abstract

Author summaryVenous thromboembolism (VTE) is a multifactorial disease in which the genetic burden is high. We here present the case of a French family with multiple relatives affected with unprovoked VTE (i.e. that occurred in the absence of clinical risk factors) in which no thrombophilia defects had been identified. Adopting a whole exome sequencing approach, we identified an extremely rare variant located in the Microtubule-associated serine/threonine-protein kinase-2 (MAST2) gene that perfectly segregates with the VTE phenotype and that interferes with hemostatic balance of endothelial cells. Our results pave the way for adding MAST2 to the list of genes to be sequenced and looked for in thrombophilia families with unprovoked VTE.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.

Published in

PLOS GENETICS
2021, volume: 17, number: 1, article number: e1009284
Publisher: PUBLIC LIBRARY SCIENCE

Authors' information

Morange, Pierre-Emmanuel
Aix-Marseille Universite
Peiretti, Franck
Institut National de la Sante et de la Recherche Medicale (Inserm)
Gourhant, Lenaick
Institut National de la Sante et de la Recherche Medicale (Inserm)
Proust, Carole
Sorbonne Universite
Soukarieh, Omar
Universite de Bordeaux
Pulcrano-Nicolas, Anne-Sophie
Sorbonne Universite
Swedish University of Agricultural Sciences, Department of Plant Breeding
Sorbonne Université
Stefanucci, Luca
University of Cambridge
Lacroix, Romaric
Institut National de la Sante et de la Recherche Medicale (Inserm)
Ibrahim Kosta, Manal
Institut National de la Sante et de la Recherche Medicale (Inserm)
Lemarie, Catherine A.
Institut National de la Sante et de la Recherche Medicale (Inserm)
Frontini, Mattia
University of Cambridge
Alessi, Marie-Christine
Aix-Marseille Universite
Tregouet, David-Alexandre
Universite de Bordeaux
Couturaud, Francis
Institut National de la Sante et de la Recherche Medicale (Inserm)

UK√Ą Subject classification

Medical Genetics

Publication Identifiers

DOI: https://doi.org/10.1371/journal.pgen.1009284

URI (permanent link to this page)

https://res.slu.se/id/publ/110661