title: Electrospray ionization mass spectrometry identification of fibrinogen Banks Peninsula (gamma280Tyr-->Cys): a new variant with defective polymerization.
abstract: 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 Aalpha and Bbeta 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 Aalpha and Bbeta chains. However ESI-MS revealed a mass of 48345 D for the isolated gamma chains, 31 D less than the measured mass of control chains (48376 D). Since normal and abnormal gamma 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 gamma 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 gamma280 and gamma275 make contact across the D:D interface, suggesting a similar mechanism for the polymerization defects in fibrinogens Banks Peninsula and Tokyo II (gamma275Arg-->Cys).
authors.affiliation: Molecular Pathology Laboratory, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: A P
authors.initials: AP
authors.lastname: Fellowes
authors.forename: S O
authors.initials: SO
authors.lastname: Brennan
authors.forename: H J
authors.initials: HJ
authors.lastname: Ridgway
authors.forename: D C
authors.initials: DC
authors.lastname: Heaton
authors.forename: P M
authors.initials: PM
authors.lastname: George
mesh_terms: D000347:Afibrinogenemia / Q000235:genetics*; D004844:Epistaxis / Q000209:etiology; D005260:Female; D015241:Fibrinogens, Abnormal / Q000235:genetics*; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D009154:Mutation; D012008:Recurrence; D017422:Sequence Analysis, DNA
chemical_list: D015241:Fibrinogens, Abnormal