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A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype

Congenital hypofibrinogenemia is a rare bleeding disorder characterized by a proportional decrease of functional and antigenic fibrinogen levels. Hypofibrinogenemia can be considered the phenotypic expression of heterozygous loss of function mutations occurring within one of the three fibrinogen gen...

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Autores principales: Simurda, Tomas, Vilar, Rui, Zolkova, Jana, Ceznerova, Eliska, Kolkova, Zuzana, Loderer, Dusan, Neerman-Arbez, Marguerite, Casini, Alessandro, Brunclikova, Monika, Skornova, Ingrid, Dobrotova, Miroslava, Grendar, Marian, Stasko, Jan, Kubisz, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763967/
https://www.ncbi.nlm.nih.gov/pubmed/33322159
http://dx.doi.org/10.3390/biomedicines8120605
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author Simurda, Tomas
Vilar, Rui
Zolkova, Jana
Ceznerova, Eliska
Kolkova, Zuzana
Loderer, Dusan
Neerman-Arbez, Marguerite
Casini, Alessandro
Brunclikova, Monika
Skornova, Ingrid
Dobrotova, Miroslava
Grendar, Marian
Stasko, Jan
Kubisz, Peter
author_facet Simurda, Tomas
Vilar, Rui
Zolkova, Jana
Ceznerova, Eliska
Kolkova, Zuzana
Loderer, Dusan
Neerman-Arbez, Marguerite
Casini, Alessandro
Brunclikova, Monika
Skornova, Ingrid
Dobrotova, Miroslava
Grendar, Marian
Stasko, Jan
Kubisz, Peter
author_sort Simurda, Tomas
collection PubMed
description Congenital hypofibrinogenemia is a rare bleeding disorder characterized by a proportional decrease of functional and antigenic fibrinogen levels. Hypofibrinogenemia can be considered the phenotypic expression of heterozygous loss of function mutations occurring within one of the three fibrinogen genes (FGA, FGB, and FGG). Clinical manifestations are highly variable; most patients are usually asymptomatic, but may appear with mild to severe bleeding or thrombotic complications. We have sequenced all exons of the FGA, FGB, and FGG genes using the DNA isolated from the peripheral blood in two unrelated probands with mild hypofibrinogenemia. Coagulation screening, global hemostasis, and functional analysis tests were performed. Molecular modeling was used to predict the defect of synthesis and structural changes of the identified mutation. DNA sequencing revealed a novel heterozygous variant c.1421G>A in exon 8 of the FGB gene encoding a Bβ chain (p.Trp474Ter) in both patients. Clinical data from patients showed bleeding episodes. Protein modelling confirmed changes in the secondary structure of the molecule, with the loss of three β sheet arrangements. As expected by the low fibrinogen levels, turbidity analyses showed a reduced fibrin polymerisation and imaging difference in thickness fibrin fibers. We have to emphasize that our patients have a quantitative fibrinogen disorder; therefore, the reduced function is due to the reduced concentration of fibrinogen, since the Bβ chains carrying the mutation predicted to be retained inside the cell. The study of fibrinogen molecules using protein modelling may help us to understand causality and effect of novel genetic mutations.
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spelling pubmed-77639672020-12-27 A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype Simurda, Tomas Vilar, Rui Zolkova, Jana Ceznerova, Eliska Kolkova, Zuzana Loderer, Dusan Neerman-Arbez, Marguerite Casini, Alessandro Brunclikova, Monika Skornova, Ingrid Dobrotova, Miroslava Grendar, Marian Stasko, Jan Kubisz, Peter Biomedicines Article Congenital hypofibrinogenemia is a rare bleeding disorder characterized by a proportional decrease of functional and antigenic fibrinogen levels. Hypofibrinogenemia can be considered the phenotypic expression of heterozygous loss of function mutations occurring within one of the three fibrinogen genes (FGA, FGB, and FGG). Clinical manifestations are highly variable; most patients are usually asymptomatic, but may appear with mild to severe bleeding or thrombotic complications. We have sequenced all exons of the FGA, FGB, and FGG genes using the DNA isolated from the peripheral blood in two unrelated probands with mild hypofibrinogenemia. Coagulation screening, global hemostasis, and functional analysis tests were performed. Molecular modeling was used to predict the defect of synthesis and structural changes of the identified mutation. DNA sequencing revealed a novel heterozygous variant c.1421G>A in exon 8 of the FGB gene encoding a Bβ chain (p.Trp474Ter) in both patients. Clinical data from patients showed bleeding episodes. Protein modelling confirmed changes in the secondary structure of the molecule, with the loss of three β sheet arrangements. As expected by the low fibrinogen levels, turbidity analyses showed a reduced fibrin polymerisation and imaging difference in thickness fibrin fibers. We have to emphasize that our patients have a quantitative fibrinogen disorder; therefore, the reduced function is due to the reduced concentration of fibrinogen, since the Bβ chains carrying the mutation predicted to be retained inside the cell. The study of fibrinogen molecules using protein modelling may help us to understand causality and effect of novel genetic mutations. MDPI 2020-12-13 /pmc/articles/PMC7763967/ /pubmed/33322159 http://dx.doi.org/10.3390/biomedicines8120605 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Simurda, Tomas
Vilar, Rui
Zolkova, Jana
Ceznerova, Eliska
Kolkova, Zuzana
Loderer, Dusan
Neerman-Arbez, Marguerite
Casini, Alessandro
Brunclikova, Monika
Skornova, Ingrid
Dobrotova, Miroslava
Grendar, Marian
Stasko, Jan
Kubisz, Peter
A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype
title A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype
title_full A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype
title_fullStr A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype
title_full_unstemmed A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype
title_short A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype
title_sort novel nonsense mutation in fgb (c.1421g>a; p.trp474ter) in the beta chain of fibrinogen causing hypofibrinogenemia with bleeding phenotype
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763967/
https://www.ncbi.nlm.nih.gov/pubmed/33322159
http://dx.doi.org/10.3390/biomedicines8120605
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