|
|
 Previous Article | Table of Contents | Next Article 
Severe factor VII deficiency caused by mutations abolishing the cleavage
site for activation and altering binding to tissue factor
S Chaing, B Clarke, S Sridhara, K Chu, P Friedman, W VanDusen, HR Roberts, M Blajchman, DM Monroe and KA High
Department of Medicine, University of North Carolina at Chapel Hill.
Factor VII (F.VII) is a vitamin-K-dependent serine protease required in the
early stages of blood coagulation. We describe here a patient with severe
F.VII deficiency, with a normal plasma F.VII antigen level (452 ng/mL) and
F.VII activity less than 1%, who is homozygous for two defects: a G-->A
transition at nucleotide 6055 in exon 4, which results in an Arg-->Gln
change at amino acid 79 (R79Q); and a G-->A transition at nucleotide
8961 in exon 6, which results in an Arg-->Gln substitution at amino acid
152 (R152Q). The R79Q mutation occurs in the first epidermal growth factor
(EGF)-like domain, which has previously been implicated in binding to
tissue factor. The R152Q mutation occurs at a site (Arg 152-Ile 153) that
is normally cleaved to generate activated F.VII (F.VIIa). Analysis of
purified F.VII from patient plasma shows that the material cannot be
activated by F.Xa and cofactors. In addition, in an in vitro binding assay
using relipidated recombinant tissue factor, patient plasma showed markedly
reduced binding to tissue factor at all concentrations tested. In an effort
to separate the contributions of the two mutations, three recombinant
variants, wild-type, R79Q, and R152Q, were prepared and analyzed. The R152Q
variant had markedly reduced activity in a clotting assay, whereas R79Q
showed a milder, concentration-dependent reduction. The R152Q variant
exhibited nearly normal binding in the tissue factor binding assay, whereas
the R79Q variant had markedly reduced binding. The time course of
activation of the R79Q variant was slowed compared with wild-type. Our
results suggest that the first EGF-like domain is required for binding to
tissue factor and that the F.VII zymogen lacks activity and requires
activation for expression of biologic activity.
Volume 83,
Issue 12,
pp. 3524-3535,
06/15/1994
Copyright © 1994 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. Pinotti, D. Etro, D. Bindini, M. L. Papa, G. Rodorigo, A. Rocino, G. Mariani, N. Ciavarella, and F. Bernardi
Residual factor VII activity and different hemorrhagic phenotypes in CRM+ factor VII deficiencies (Gly331Ser and Gly283Ser)
Blood,
February 15, 2002;
99(4):
1495 - 1497.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Carew, E. S. Pollak, K. A. High, and K. A. Bauer
Severe Factor VII Deficiency Due to a Mutation Disrupting an Sp1 Binding Site in the Factor VII Promoter
Blood,
September 1, 1998;
92(5):
1639 - 1645.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Pinotti, R. Toso, R. Redaelli, M. Berrettini, G. Marchetti, and F. Bernardi
Molecular Mechanisms of FVII Deficiency: Expression of Mutations Clustered in the IVS7 Donor Splice Site of Factor VII Gene
Blood,
September 1, 1998;
92(5):
1646 - 1651.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Kemball-Cook, D. J. D. Johnson, O. Takamiya, D. W. Banner, J. H. McVey, and E. G. D. Tuddenham
Coagulation Factor VII Gln100 right-arrow Arg. AMINO ACID SUBSTITUTION AT THE EPIDERMAL GROWTH FACTOR 2-PROTEASE DOMAIN INTERFACE RESULTS IN SEVERELY REDUCED TISSUE FACTOR BINDING AND PROCOAGULANT FUNCTION
J. Biol. Chem.,
April 3, 1998;
273(14):
8516 - 8521.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Fan, P. J. Larson, J. Bognacki, P.N. Raghunath, J. E. Tomaszewski, A. Kuo, G. Canziani, I. Chaiken, D. B. Cines, and A. A.-R. Higazi
Tissue Factor Regulates Plasminogen Binding and Activation
Blood,
March 15, 1998;
91(6):
1987 - 1998.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. R. Stauffer, B. N. Chukwumezie, J. A. Wilberding, E. D. Rosen, and F. J. Castellino
Characterization of Transcriptional Regulatory Elements in the Promoter Region of the Murine Blood Coagulation Factor VII Gene
J. Biol. Chem.,
January 23, 1998;
273(4):
2277 - 2287.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Bharadwaj, M. Iino, M. Kontoyianni, K. J. Smith, D. C. Foster, and W. Kisiel
Factor VII Central. A NOVEL MUTATION IN THE CATALYTIC DOMAIN THAT REDUCES TISSUE FACTOR BINDING, IMPAIRS ACTIVATION BY FACTOR XA, AND ABOLISHES AMIDOLYTIC AND COAGULANT ACTIVITY
J. Biol. Chem.,
November 29, 1996;
271(48):
30685 - 30691.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
