The arginine-552-cysteine (R1315C) mutation within the Al loop of von Willebrand factor induces an abnormal folding with a loss of function resulting in type 2A-like phenotype of von Willebrand disease: study of 10 patients and mutated recombinant von Willebrand factor

被引:33
作者
Ribba, AS
Hilbert, L
Lavergne, JM
Fressinaud, E
Boyer-Neumann, C
Ternisien, C
Juhan-Vague, I
Goudemand, J
Girma, JP
Mazurier, C
Meyer, D
机构
[1] Hop Bicetre, INSERM U143, F-94276 Le Kremlin Bicetre, France
[2] CHU Lille, Hematol Lab, F-59037 Lille, France
[3] CHU Lille, Lab Francais Fractionnement & Biotechnol, F-59037 Lille, France
[4] CHU Lille, Hematol Lab, F-59037 Lille, France
[5] CHU Angers, Hemostase Lab, Angers, France
[6] CHU, Hematol Lab, Marseille, France
关键词
D O I
10.1182/blood.V97.4.952
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The study identified 10 patients from 6 families with prolonged bleeding time, decreased von Willebrand factor (vWF) ristocetin cofactor activity (RCoF) to vWF:Ag (antigen) ratio, and reduced ristocetin-induced platelet agglutination as well as ristocetin- or botrocetin-induced binding of plasma vWF to platelet glycoprotein Ib (GpIb), In addition, all patients showed a decrease of intermediate-molecular-weight (intermediate-MW) and high-molecular-weight (HMW) multimers of vWF, In the heterozygous state, a cysteine-to-threonine (C --> T) transversion was detected at nucleotide 4193 of the VWF gene of all patients and lead to the arginine (R)522C substitution in the Al loop of vWF mature subunit (R1315C in the preprovWF), By in vitro mutagenesis of full-length complementary DNA (cDNA) of vWF and transient expression in COS-7 cells, the mutated C552 recombinant vWF (C552rvWF) was found to exhibit decreased expression, abnormal folding, and lack of intermediate-MW and HMW multimers. In addition, direct binding of botrocetin to C552rvWF, as well as ristocetin- and botrocetin-induced binding of C552rvWF to GpIb, was markedly decreased. Although being localized in an area of the Al loop of vWF where most of the type 2B mutations that induce a gain-of-function have been identified, the R552C mutation induces a PA-like phenotype with a decrease of intermediate-MW and HMW multimers as well as a loss-of-function of vWF in the presence of either ristocetin or botrocetin. (C) 2001 by The American Society of Hematology.
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页码:952 / 959
页数:8
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