Electrospray ionization mass spectrometry identification of fibrinogen Banks Peninsula (γ280Tyr→Cys): a new variant with defective polymerization.

Fibrinogen Banks Peninsula was identified in the mother of a patient referred for investigation following recurrent epistaxis. Coagulation tests revealed prolonged thrombin and reptilase times and a decreased functional fibrinogen level. Thrombin-catalysed release of fibrinopeptides A and B was normal, and no abnormalities were detected by DNA sequencing of the regions encoding the thrombin cleavage sites in the Aα and Bβ genes. Reducing SDS-PAGE and reverse-phase HPLC analysis of purified fibrinogen chains were normal, as was electrospray ionization mass spectrometry (ESI-MS) analysis of isolated Aα and Bβ chains. However ESI-MS revealed a mass of 48 345 D for the isolated γ chains, 31 D less than the measured mass of control chains (48 376 D). Since normal and abnormal γ chains were not resolved, this implies a 60–62 D mass decrease in 50% of the molecules. A 60 D decrease was confirmed when DNA sequencing indicated heterozygosity for a mutation of Tyr→Cys at codon 280 of the γ chain gene. Fibrin monomer polymerization revealed a delayed lag phase and reduced final turbidity and although factor XIIIa crosslinking of fibrinogen was normal, it is likely that this delay is due to impaired D:D self association. Recent crystallographic studies show residues γ280 and γ275 make contact across the D:D interface, suggesting a similar mechanism for the polymerization defects in fibrinogens Banks Peninsula and Tokyo II (γ275Arg→Cys). [ABSTRACT FROM AUTHOR]