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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3597-3601
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Fibrinogen Hillsborough: a novel  Gly309Asp dysfibrinogen
with impaired clotting
Jennifer L. Mullin,
Stephen
O. Brennan,
Peter S. Ganly, and
Peter M. George
From the Molecular Pathology Laboratory, Canterbury
Health Laboratories, Christchurch Hospital, Christchurch, New Zealand.
We present a novel  -chain dysfibrinogen that was discovered in a
32-year-old asymptomatic man admitted to the hospital after a car
accident. He presented with a low fibrinogen concentration, 0.5 mg/mL,
and a prolonged thrombin clotting time, 58 seconds. Analysis of
purified fibrinogen by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis revealed a -chain variant with an apparently higher
molecular weight. Isoelectric focusing (IEF) demonstrated an anodal
shift in the banding pattern of the chains and electrospray ionization
mass spectrometry (ESIMS) showed a 27-Da increase in the average mass
of the unresolved variant and normal chains. DNA sequence analysis
showed a heterozygous mutation of GGC (Gly) GAC (Asp) at codon 309 of
the chain gene. This Gly Asp substitution was consistent with
the charge change shown by IEF as well as the mass change identified by
ESIMS. Functional analysis revealed that thrombin-catalyzed
polymerization occurred with a longer lag time, lower rate of lateral
aggregation, and similar final turbidity compared to normal and that
factor XIII cross-linking was normal. The polymerization results
suggest that residue 309 is necessary for proper alignment of
fibrinogen molecules, specifically in protofibril formation and D:D
interactions. Gly309 is highly conserved and x-ray structures
support the conclusion that the lack of a side chain at this position
helps facilitate the close contact between abutting D domains of
condensing fibrin monomers during polymerization.
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