Two novel mutations in the fibrinogen γ nodule

Area of Science:

• Hematology
• Molecular Biology
• Genetics

Background:

• Congenital dysfibrinogenemia and hypofibrinogenemia are rare inherited disorders affecting fibrinogen function or levels.
• These conditions result from abnormalities in the fibrinogen molecule, impacting blood clotting.
• Understanding these mutations is crucial for diagnosing and managing bleeding or thrombotic risks.

Purpose of the Study:

• To characterize two novel fibrinogen mutations: fibrinogen Hranice (γ Phe204Val) and fibrinogen Praha IV (γ Ser313Gly).
• To investigate the structural and functional consequences of these mutations on fibrinogen.
• To correlate genotype with clinical manifestations in affected individuals.

Main Methods:

• Genetic analysis to identify mutations in fibrinogen γ chains.
• Functional assays including fibrin polymerization kinetics and fibrinolysis.
• Advanced microscopy techniques (SEM, confocal) to visualize fibrin fiber structure.
• Clinical assessment of patients carrying the mutations.

Main Results:

• Fibrinogen Hranice (γ Phe204Val) presented as hypofibrinogenemia without clinical symptoms.
• Fibrinogen Praha IV (γ Ser313Gly) manifested as dysfibrinogenemia with a history of idiopathic thrombosis.
• Both mutations resulted in significantly wider fibrin fibers compared to controls.
• Mutation sites are in conserved regions of the fibrinogen γ chain, suggesting critical roles in structure and function.

Conclusions:

• The identified mutations induce conformational changes in fibrinogen.
• Fibrinogen Hranice mutation impairs fibrinogen assembly, leading to reduced levels.
• Fibrinogen Praha IV mutation results in abnormal fibrinogen function, associated with thrombosis.