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.
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.
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. schneppenheim@uke.de
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schneppenheim
authors.forename: Jan Jacques
authors.initials: JJ
authors.lastname: Michiels
authors.forename: Tobias
authors.initials: T
authors.lastname: Obser
authors.forename: Florian
authors.initials: F
authors.lastname: Oyen
authors.forename: Antje
authors.initials: A
authors.lastname: Pieconka
authors.forename: Sonja
authors.initials: S
authors.lastname: Schneppenheim
authors.forename: Kerstin
authors.initials: K
authors.lastname: Will
authors.forename: Barbara
authors.initials: B
authors.lastname: Zieger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Budde
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071120:ADAMTS13 Protein; D020816:Amino Acid Motifs; D016022:Case-Control Studies; D019483:Disintegrins / Q000235:genetics / Q000378:metabolism; D005190:Family; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D055503:Protein Multimerization / Q000235:genetics*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D056728:von Willebrand Disease, Type 2 / Q000235:genetics* / Q000378:metabolism*; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism*
chemical_list: D019483:Disintegrins; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human