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Fibrinogen Kyoto III: a congenital dysfibrinogen with a gamma aspartic
acid-330 to tyrosine substitution manifesting impaired fibrin monomer
polymerization
S Terukina, K Yamazumi, K Okamoto, H Yamashita, Y Ito and M Matsuda
Institute of Hematology, Jichi Medical School, Tochigi-Ken, Japan.
A congenital dysfibrinogen characterized by impaired fibrin monomer
polymerization was found in an asymptomatic 50-year-old woman and her two
sons. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis
(SDS-PAGE) run according to the method of Laemmli, we noticed two gamma
chain species in fibrinogen and its plasmic fragments D1 and D2, consisting
of a normal species and an apparently lower molecular weight (mol wt)
variant in respective fractions. However, in fragment D3 only a single
gamma chain remnant was observed. By chromatofocusing of the plasmic-CaCl2
digests of the abnormal fibrinogen, we separately isolated the normal and
abnormal D1 species, the latter having been eluted in a slightly higher pH
range. As expected, the abnormal D1 species failed to interfere with
thrombin clotting of normal fibrinogen and normal fibrin monomer
polymerization, whereas the normal D1 species inhibited them markedly. By
analyzing the lysyl endopeptidase digests of the isolated gamma chain, we
identified a replacement of aspartic acid by tyrosine at position 330 of
the mutant gamma chain. The point mutation from an aspartic acid (pK for
the beta-carboxyl = 3.86) to a tyrosine (pK for the aromatic hydroxyl =
10.07) may have perturbed the folding gamma chain structure in the D domain
of fibrinogen specifically required for polymerization.
Volume 74,
Issue 8,
pp. 2681-2687,
12/01/1989
Copyright © 1989 by The American Society of Hematology
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