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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2021
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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 |
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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 |
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