A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype
| Autor: | Eliska Ceznerova, Miroslava Dobrotova, Dusan Loderer, Monika Brunclikova, Tomas Simurda, Alessandro Casini, Peter Kubisz, Zuzana Kolková, Jana Zolkova, Ingrid Skornova, Jan Stasko, Rui Vilar, Marguerite Neerman-Arbez, Marian Grendar |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
hypofibrinogenemia Nonsense mutation Medicine (miscellaneous) 030204 cardiovascular system & hematology Fibrinogen medicine.disease_cause Article General Biochemistry Genetics and Molecular Biology Fibrin functional analysis 03 medical and health sciences Exon protein modelling 0302 clinical medicine medicine ddc:576.5 lcsh:QH301-705.5 Gene ddc:616 Mutation Bβ-chain gene biology business.industry novel nonsense mutation Hypofibrinogenemia Molecular biology 030104 developmental biology lcsh:Biology (General) bleeding phenotype Hemostasis biology.protein business medicine.drug |
| Zdroj: | Biomedicines Biomedicines, Vol 8, Iss 605, p 605 (2020) Biomedicines, Vol. 8, No 12 (2020) P. 605 |
| ISSN: | 2227-9059 |
| DOI: | 10.3390/biomedicines8120605 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|