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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

Morange, Pierre-Emmanuel and Peiretti, Franck and Gourhant, Lenaick and Proust, Carole and Soukarieh, Omar and Pulcrano-Nicolas, Anne-Sophie and Saripella, Ganapathi Varma and Stefanucci, Luca and Lacroix, Romaric and Ibrahim Kosta, Manal and Lemarie, Catherine A. and Frontini, Mattia and Alessi, Marie-Christine and Tregouet, David-Alexandre and Couturaud, Francis (2021). A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant. PLOS GENETICS. 17 , e1009284
[Research article]

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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.

Authors/Creators:Morange, Pierre-Emmanuel and Peiretti, Franck and Gourhant, Lenaick and Proust, Carole and Soukarieh, Omar and Pulcrano-Nicolas, Anne-Sophie and Saripella, Ganapathi Varma and Stefanucci, Luca and Lacroix, Romaric and Ibrahim Kosta, Manal and Lemarie, Catherine A. and Frontini, Mattia and Alessi, Marie-Christine and Tregouet, David-Alexandre and Couturaud, Francis
Title:A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant
Series Name/Journal:PLOS GENETICS
Year of publishing :2021
Volume:17
Article number:e1009284
Number of Pages:19
Publisher:PUBLIC LIBRARY SCIENCE
ISSN:1553-7404
Language:English
Publication Type:Research article
Article category:Scientific peer reviewed
Version:Published version
Copyright:Creative Commons: Attribution 4.0
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Medical Genetics
URN:NBN:urn:nbn:se:slu:epsilon-p-110661
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-110661
Additional ID:
Type of IDID
DOI10.1371/journal.pgen.1009284
Web of Science (WoS)000611971600007
ID Code:22432
Faculty:LTV - Fakulteten för landskapsarkitektur, trädgårds- och växtproduktionsvetenskap
Department:(LTJ, LTV) > Department of Plant Breeding (from 130101)
Deposited By: SLUpub Connector
Deposited On:19 Feb 2021 11:43
Metadata Last Modified:19 Feb 2021 11:51

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