Three new variants of the fibrinogen-related domain of the fibrinogen Bβ chain.

INTRODUCTION

Variants in genes coding fibrinogen chains may lead to a quantitative fibrinogen disorder-hypofibrinogenemia. The aim of the study was to determine the cause of congenital hypofibrinogenemia and characterize the underlying structure and function of fibrinogen.

METHODS

Genetic and proteomic analyses were performed to determine fibrinogen variants and detect their presence in plasma. Scanning electron microscopy was used to study fibrin clot morphology, and polymerization experiments were used to determine its effect on fibrin formation. Bioinformatics and in silico structural biology techniques were used to predict the impact of variant on the protein's stability and function.

RESULTS

We identified three previously undescribed variants of the fibrinogen-related domain (FReD) of the fibrinogen Bβ chain-FGB:p.Asp350His, FGB:p.Arg436Lys, and FGB:p.Tyr447Cys. Fibrin structure and fibrin polymerization were very slightly affected in FGB:p.Asp350His and FGB: p.Arg436Lys cases. The FGB:p.Tyr447Cys variant could have physiological manifestations because it destabilizes the binding site of the fibrinogen Bβ chain. The FGB:Arg436Lys variant does not destabilize the protein's structure, but it may disturb fibrin polymerization. High conservation of Arg436 may indicate its importance in fibrinogen biosynthesis or secretion. FGB:p.Asp350His is situated in the N-terminal residue of the third β-strand of the central antiparallel β-sheet of the FReD, forming a hydrogen bond with Asp346, and Asp350 seems to have a negligible effect on the formation of the correct Bβ chain structure.

CONCLUSION

The analyzed variants in the FReD of the fibrinogen Bβ chain seems to have an impact on the proper structure of the fibrinogen-related domain of the fibrinogen Bβ chain.