|
|
 Previous Article | Table of Contents | Next Article 
Type 2M:Milwaukee-1 von Willebrand disease: an in-frame deletion in the
Cys509-Cys695 loop of the von Willebrand factor A1 domain causes deficient
binding of von Willebrand factor to platelets
DJ Mancuso, PA Kroner, PA Christopherson, EA Vokac, JC Gill and RR Montgomery
Blood Center of Southeastern Wisconsin, Milwaukee 53201-2178, USA.
This report examines the genetic basis of a variant form of moderately
severe von Willebrand disease (vWD) characterized by low plasma von
Willebrand factor antigen (vWF:Ag) levels and normal multimerization,
typical of type 1 vWD, but disproportionately-low agonist-mediated
platelet-binding activity. We identified an in-frame deletion in vWF exon
28 in three generations of affected family members, who are heterozygous
for this mutation. The deletion of nucleotides 4,173-4,205 results in the
loss of amino acids Arg629-Gln639 in the Cys509-Cys695 loop of the A1
domain in mature vWF. The secreted mutant vWF showed a normal multimeric
profile but did not bind to platelets in the presence of optimal
concentrations of either ristocetin or botrocetin. The mutant vWF also
failed to interact with heparin, and with vWF monoclonal antibody AvW3,
which blocks the binding of vWF to GPlb. In addition, mutant vWF showed
reduced secretion from transfected cells concomitant with increased
intracellular levels. These results confirm that the deletion is the
genetic defect responsible for the reduced interaction of vWF with
platelets. We have designated this new variant type 2M:Milwaukee-1 vWD. Our
analysis suggests that the potential frequency of this phenotype in
individuals diagnosed with type 1 vWD is about 0.5%.
Volume 88,
Issue 7,
pp. 2559-2568,
10/01/1996
Copyright © 1996 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:
|
|
|
|
 
J. J. Michiels, Z. Berneman, A. Gadisseur, M. van der Planken, W. Schroyens, A. van de Velde, and H. van Vliet
Classification and Characterization of Hereditary Types 2A, 2B, 2C, 2D, 2E, 2M, 2N, and 2U (Unclassifiable) von Willebrand Disease
Clinical and Applied Thrombosis/Hemostasis,
October 1, 2006;
12(4):
397 - 420.
[Abstract]
[PDF]
|
|
|
|
|
|
|
V. Rathore, M. A. Stapleton, C. A. Hillery, R. R. Montgomery, T. C. Nichols, E. P. Merricks, D. K. Newman, and P. J. Newman
PECAM-1 negatively regulates GPIb/V/IX signaling in murine platelets
Blood,
November 15, 2003;
102(10):
3658 - 3664.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A.-S. Ribba, L. Hilbert, J.-M. Lavergne, E. Fressinaud, C. Boyer-Neumann, C. Ternisien, I. Juhan-Vague, J. Goudemand, J.-P. Girma, C. Mazurier, et al.
The arginine-552-cysteine (R1315C) mutation within the A1 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
Blood,
February 15, 2001;
97(4):
952 - 959.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Ajzenberg, A.-S. Ribba, G. Rastegar-Lari, D. Meyer, and D. Baruch
Effect of recombinant von Willebrand factor reproducing type 2B or type 2M mutations on shear-induced platelet aggregation
Blood,
June 15, 2000;
95(12):
3796 - 3803.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. V. Jenkins, K. J. Pasi, and S. J. Perkins
Molecular Modeling of Ligand and Mutation Sites of the Type A Domains of Human von Willebrand Factor and Their Relevance to von Willebrand's Disease
Blood,
March 15, 1998;
91(6):
2032 - 2044.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
