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Purification and characterization of factor VII 304-Gln: a variant molecule
with reduced activity isolated from a clinically unaffected male
DP O'Brien, KM Gale, JS Anderson, JH McVey, GJ Miller, TW Meade and EG Tuddenham
Haemostasis Research Group, MRC Clinical Research Centre, Harrow,
Middlesex, UK.
Factor VII (FVII) is the plasma serine protease zymogen which, on binding
to its cellular receptor tissue factor (TF), initiates blood coagulation. A
47-year-old man with no clinical bleeding tendency was found to have
undetectable plasma FVII activity when tested in a one- stage assay using
rabbit brain TF, but 0.3 U/mL using recombinant human TF and 1.04 U/mL FVII
antigen. Variant FVII purified from his plasma showed an identical
migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis to
wild-type zymogen. By enzyme kinetic analysis the Km of the variant using
FX as a substrate was 12-fold higher than that of normal FVII. Also, the
variant FVII was unable to compete with wild-type FVII for limited rabbit
TF binding sites. A ligand blot procedure was used to directly demonstrate
reduced binding of recombinant human TF to the variant FVII compared with
normal FVII. Genetic analysis of leukocyte DNA showed a G to A mutation in
the propositus' gene at codon 304 that results in the substitution of a
glutamine for an arginine residue in the catalytic domain of the protease.
We conclude that this region of the FVII molecule is important for its
function.
Volume 78,
Issue 1,
pp. 132-140,
07/01/1991
Copyright © 1991 by The American Society of Hematology
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