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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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, Lemarié, Catherine A., Frontini, Mattia, Alessi, Marie-Christine, Trégouët, David-Alexandre, Couturaud, Francis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846112/
https://www.ncbi.nlm.nih.gov/pubmed/33465109
http://dx.doi.org/10.1371/journal.pgen.1009284
_version_ 1783644677361106944
author 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
Lemarié, Catherine A.
Frontini, Mattia
Alessi, Marie-Christine
Trégouët, David-Alexandre
Couturaud, Francis
author_facet 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
Lemarié, Catherine A.
Frontini, Mattia
Alessi, Marie-Christine
Trégouët, David-Alexandre
Couturaud, Francis
author_sort Morange, Pierre-Emmanuel
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7846112
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-78461122021-02-04 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 Lemarié, Catherine A. Frontini, Mattia Alessi, Marie-Christine Trégouët, David-Alexandre Couturaud, Francis PLoS Genet Research Article 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. Public Library of Science 2021-01-19 /pmc/articles/PMC7846112/ /pubmed/33465109 http://dx.doi.org/10.1371/journal.pgen.1009284 Text en © 2021 Morange et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
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
Lemarié, Catherine A.
Frontini, Mattia
Alessi, Marie-Christine
Trégouët, David-Alexandre
Couturaud, Francis
A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant
title A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant
title_full A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant
title_fullStr A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant
title_full_unstemmed A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant
title_short A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant
title_sort rare coding mutation in the mast2 gene causes venous thrombosis in a french family with unexplained thrombophilia: the breizh mast2 arg89gln variant
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846112/
https://www.ncbi.nlm.nih.gov/pubmed/33465109
http://dx.doi.org/10.1371/journal.pgen.1009284
work_keys_str_mv AT morangepierreemmanuel ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT peirettifranck ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT gourhantlenaick ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT proustcarole ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT soukariehomar ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT pulcranonicolasannesophie ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT saripellaganapathivarma ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT stefanucciluca ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT lacroixromaric ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT ibrahimkostamanal ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT lemariecatherinea ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT frontinimattia ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT alessimariechristine ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT tregouetdavidalexandre ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT couturaudfrancis ararecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT morangepierreemmanuel rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT peirettifranck rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT gourhantlenaick rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT proustcarole rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT soukariehomar rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT pulcranonicolasannesophie rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT saripellaganapathivarma rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT stefanucciluca rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT lacroixromaric rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT ibrahimkostamanal rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT lemariecatherinea rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT frontinimattia rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT alessimariechristine rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT tregouetdavidalexandre rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant
AT couturaudfrancis rarecodingmutationinthemast2genecausesvenousthrombosisinafrenchfamilywithunexplainedthrombophiliathebreizhmast2arg89glnvariant