Critical von Willebrand factor A1 domain residues influence type VI collagen binding

V H Flood; J C Gill; P A Christopherson; D B Bellissimo; K D Friedman; S L Haberichter; S R Lentz; R R Montgomery

doi:10.1111/j.1538-7836.2012.04746.x

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Critical von Willebrand factor A1 domain residues influence type VI collagen binding

Journal article

Open access

Peer reviewed

Critical von Willebrand factor A1 domain residues influence type VI collagen binding

V H Flood, J C Gill, P A Christopherson, D B Bellissimo, K D Friedman, S L Haberichter, S R Lentz and R R Montgomery

Journal of thrombosis and haemostasis, Vol.10(7), pp.1417-1424

07/2012

DOI: 10.1111/j.1538-7836.2012.04746.x

PMCID: PMC3809952

PMID: 22507569

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Abstract

von Willebrand factor (VWF) binds to subendothelial collagen at sites of vascular injury. Laboratory testing for von Willebrand disease (VWD), however, does not always include collagen binding assays (VWF:CB) and standard VWF:CB assays use type I and/or type III collagen rather than type VI collagen. We report here on several mutations that exclusively alter binding to type VI collagen. Healthy controls and index cases from the Zimmerman Program for the Molecular and Clinical Biology of VWD were analyzed for VWF antigen (VWF:Ag), VWF ristocetin cofactor activity and VWF:CB with types I, III and VI collagen. VWF gene sequencing was performed for all subjects. Two healthy controls and one type 1 VWD subject were heterozygous for an A1 domain sequence variation, R1399H, and displayed a selective decreased binding to type VI collagen but not types I and III. Expression of recombinant 1399H VWF resulted in absent binding to type VI collagen. Two other VWF A1 domain mutations, S1387I and Q1402P, displayed diminished binding to type VI collagen. An 11 amino acid deletion in the A1 domain also abrogated binding to type VI collagen. VWF:CB may be useful in diagnosis of VWD, as a decreased VWF:CB/VWF:Ag ratio may reflect specific loss of collagen binding ability. Mutations that exclusively affect type VI collagen binding may be associated with bleeding, yet missed by current VWF testing.

Mutation

Recombinant Proteins - metabolism

Humans

Collagen Type VI - metabolism

Models, Molecular

Recombinant Proteins - chemistry

Male

Recombinant Proteins - genetics

von Willebrand Factor - genetics

Case-Control Studies

Pedigree

von Willebrand Factor - chemistry

Protein Binding

Female

von Willebrand Factor - metabolism

Details

Title: Subtitle: Critical von Willebrand factor A1 domain residues influence type VI collagen binding
Creators: V H Flood - Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53201-2178, USA. vflood@mcw.edu
J C Gill
P A Christopherson
D B Bellissimo
K D Friedman
S L Haberichter
S R Lentz
R R Montgomery
Resource Type: Journal article
Publication Details: Journal of thrombosis and haemostasis, Vol.10(7), pp.1417-1424
DOI: 10.1111/j.1538-7836.2012.04746.x
PMID: 22507569
PMCID: PMC3809952
ISSN: 1538-7933
eISSN: 1538-7836
Grant note: R01 HL033721 / NHLBI NIH HHS UL1 RR031973 / NCRR NIH HHS R01 HL112614 / NHLBI NIH HHS HL081588 / NHLBI NIH HHS NIH UL1RR031973 / NCRR NIH HHS K08 HL102260 / NHLBI NIH HHS P01 HL044612 / NHLBI NIH HHS P01 HL081588 / NHLBI NIH HHS HL33721 / NHLBI NIH HHS R01 HL139847 / NHLBI NIH HHS HL044612 / NHLBI NIH HHS
Language: English
Date published: 07/2012
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094331702771

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