Title
A cluster of mutations in the D3 domain of von Willebrand factor correlates with a distinct subgroup of von Willebrand disease: type 2A/IIE A cluster of mutations in the D3 domain of von Willebrand factor correlates with a distinct subgroup of von Willebrand disease: type 2A/IIE
Author
Faculty/Department
University Hospital Antwerp
Publication type
article
Publication
New York, N.Y. ,
Subject
Human medicine
Source (journal)
Blood / American Society of Hematology. - New York, N.Y.
Volume/pages
115() :23 , p. 4894-4901
ISSN
0006-4971
ISI
000278635900038
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Among the different phenotypes of von Willebrand disease (VWD) type 2A, we identified a particular subgroup with a high frequency of 29%, characterized by a relative decrease of large von Willebrand factor (VWF) multimers and decreased A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motifs, member 13 (ADAMTS13)-mediated proteolysis previously described in a single family as VWD type IIE (VWD2A/IIE). Phenotype and genotype of 57 patients from 38 unrelated families displaying a particular multimer pattern resembling the original VWD2A/IIE were studied. Pathogenicity of candidate mutations was confirmed by expression studies and phenotypic characterization of recombinant mutants. Specific mutations were identified in all patients. Twenty-two different mutations, most of them affecting cysteine residues, 17 of them being novel, are clustering mainly in the VWF D3 domain and correlate with the VWD2A/IIE phenotype. An intracellular retention of most mutants and/or a defect of multimerization seem to be the main pathogenic molecular mechanisms. ADAMTS13 proteolysis of mutant VWF was not different from wild-type VWF in a static assay, suggesting that reduced in vivo proteolysis is not an intrinsic property of mutant VWF. Our study identified a distinct VWD subtype with a common molecular background which contributes significantly to the heterogeneous spectrum of VWD. (Blood. 2010;115(23):4894-4901)
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