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Int. J. Mol. Sci. 2018, 19(1), 100; doi:10.3390/ijms19010100

Identification of Two Novel Fibrinogen Bβ Chain Mutations in Two Slovak Families with Quantitative Fibrinogen Disorders

1
National Centre of Haemostasis and Thrombosis, Department of Haematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine and University Hospital in Martin, Kollarova Str. N. 2, Martin 036 59, Slovakia
2
Department of Molecular Biology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, BioMed Martin Mala Hora 4, Martin 036 01, Slovakia
*
Author to whom correspondence should be addressed.
Received: 15 November 2017 / Revised: 21 December 2017 / Accepted: 23 December 2017 / Published: 29 December 2017
(This article belongs to the Special Issue Genetic Basis of Fibrinogen Disorders)
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Abstract

Congenital fibrinogen disorders are caused by mutations in one of the three fibrinogen genes that affect the synthesis, assembly, intracellular processing, stability or secretion of fibrinogen. Functional studies of mutant Bβ-chains revealed the importance of individual residues as well as three-dimensional structures for fibrinogen assembly and secretion. This study describes two novel homozygous fibrinogen Bβ chain mutations in two Slovak families with afibrinogenemia and hypofibrinogenemia. Peripheral blood samples were collected from all subjects with the aim of identifying the causative mutation. Coagulation-related tests and rotational thromboelastometry were performed. All exons and exon–intron boundaries of the fibrinogen genes (FGA, FGB and FGG) were amplified by PCR followed by direct sequencing. Sequence analysis of the three fibrinogen genes allowed us to identify two novel homozygous mutations in the FGB gene. A novel Bβ chain truncation (BβGln180Stop) was detected in a 28-year-old afibrinogenemic man with bleeding episodes including repeated haemorrhaging into muscles, joints, and soft tissues, and mucocutaneous bleeding and a novel Bβ missense mutation (BβTyr368His) was found in a 62-year-old hypofibrinogenemic man with recurrent deep and superficial venous thromboses of the lower extremities. The novel missense mutation was confirmed by molecular modelling. Both studying the molecular anomalies and the modelling of fibrinogenic mutants help us to understand the extremely complex machinery of fibrinogen biosynthesis and finally better assess its correlation with the patient’s clinical course. View Full-Text
Keywords: hypofibrinogenemia; afibrinogenemia Bβ-chain gene; novel mutation; genetic analysis; bleeding; thrombosis hypofibrinogenemia; afibrinogenemia Bβ-chain gene; novel mutation; genetic analysis; bleeding; thrombosis
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MDPI and ACS Style

Simurda, T.; Zolkova, J.; Snahnicanova, Z.; Loderer, D.; Skornova, I.; Sokol, J.; Hudecek, J.; Stasko, J.; Lasabova, Z.; Kubisz, P. Identification of Two Novel Fibrinogen Bβ Chain Mutations in Two Slovak Families with Quantitative Fibrinogen Disorders. Int. J. Mol. Sci. 2018, 19, 100.

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