Fibrinogen Otago: a major alpha chain truncation associated with severe hypofibrinogenaemia and recurrent miscarriage

A woman with a preliminary diagnosis of afibrinogenaemia was later found to have a functional fibrinogen of 0.06 mg/ml and markedly prolonged thrombin and reptilase times. The stoichiometry of fibrinopeptide release was normal but there was a gross delay in the polymerization of purified fibrin. Plasma protein electrophoresis showed an absence of normal fibrinogen and a novel anodal component which was confirmed as fibrinogen by immunofixation. Western blots of non-reducing SDS-PAGE gels indicated a molecular weight of 270 kD, compared to 340 kD for normal fibrinogen and similar analysis of reducing gels showed that the expected 67 kD A alpha chain was missing and replaced by a 30 kD band. This aberrant chain was not detected by the monoclonal antibody F-103, which recognizes the epitope formed by residues 259-276 of the A alpha chain. Cycle sequencing of the DNA encoding the F-103 epitope revealed the homozygous insertion of cytosine at position 4133 of the gene sequence. Predictably this translates as three new amino acids (268Gln-Glu-Pro) before termination at a new (TAG) stop codon. No abnormal A alpha chains could be detected in plasma from the woman's heterozygous son. The hypofibrinogenaemia observed is likely to be the result of diminished assembly and/or secretion of the truncated A alpha chains rather than enhanced extracellular degradation.