Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor by Anne F. Riddell,

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Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor by Anne F. Riddell, Keith Gomez, Carolyn M. Millar, Gillian Mellars, Saher Gill, Simon A. Brown, Megan Sutherland, Mike A. Laffan, and Thomas A. J. McKinnon Blood Volume 114(16):3489-3496 October 15, 2009 ©2009 by American Society of Hematology

Phenotypic data for patients and family members. Phenotypic data for patients and family members. (A) Table showing laboratory results. Reference values are given for each assay. Ratios of antigen to activity are shown alongside activity columns. VWF indicates von Willebrand factor; Ag, antigen; RCo, ristocetin cofactor activity; CB, collagen-binding activity; and WT, wild type. Bleeding scores were calculated using the condensed MCMDM-1VWD questionnaire. (B) Gels showing VWF multimer pattern from plasma samples. Gray bars are placed to maintain patient confidentiality. Patient ID or type of control is shown at the bottom of each lane. A sample from 3J was not available for electrophoresis. Anne F. Riddell et al. Blood 2009;114:3489-3496 ©2009 by American Society of Hematology

Ribbon diagram of the VWF A3 domain (gray) complexed with the RU5 antibody (green) that inhibits collagen binding (PDB Id: 1FE8). Ribbon diagram of the VWF A3 domain (gray) complexed with the RU5 antibody (green) that inhibits collagen binding (PDB Id: 1FE8). The putative collagen-binding surface is toward the lower left of the A3 domain in this view. The 3 naturally mutated residues are shown as blue sticks. H1786 is shown as a yellow stick. Anne F. Riddell et al. Blood 2009;114:3489-3496 ©2009 by American Society of Hematology

Expression of recombinant VWF mutants. Expression of recombinant VWF mutants. Recombinant wt and mutant VWF were transiently expressed in HEK293T cells, and VWF ELISA was used to determine the concentration of secreted VWF (A) and VWF retained within the cell lysate (B). Error bars represent mean ± SD of 3 separate experiments each performed in duplicate. (C) The multimer composition of recombinant VWF was analyzed in 1.3% agarose gels and visualized with HRP-conjugated anti-VWF polyclonal antibodies. RP indicates reference plasma. Lane 1 indicates wt-rVWF; lane 2, S1731T; lane 3, W1745C; lane 4, W1745A; lane 5, wt/W1745C; lane 6, S1783A. All mutants are expressed at similar levels to wild-type rVWF, with similar supernatant to lysate ratios and normal multimer distribution. Anne F. Riddell et al. Blood 2009;114:3489-3496 ©2009 by American Society of Hematology

CB:Ag ratio of recombinant VWF mutants. CB:Ag ratio of recombinant VWF mutants. Collagen-binding assays to (A) type I collagen and (B) type III collagen were performed in parallel with VWF:Ag ELISA. Error bars represent mean ± SD of 3 separate experiments performed in duplicate. Wild-type recombinant VWF and H1786A (a mutation previously shown to abolish collagen binding) are shown as controls. Only S1731T shows significant binding, which is greater with collagen type III. Coexpression of wild-type VWF with W1745C significantly improved binding to type III collagen. Anne F. Riddell et al. Blood 2009;114:3489-3496 ©2009 by American Society of Hematology

Binding isotherms of the collagen-VWF interactions. Binding isotherms of the collagen-VWF interactions. Microtiter plates were coated with either type I (A) or type III (B) human collagen at a final concentration of 5 μg/mL and incubated with decreasing concentrations of wild-type or mutant recombinant VWF. As previously reported, H1786A shows no binding to either collagen type and only S1731T binds significantly to type 1 collagen. Anne F. Riddell et al. Blood 2009;114:3489-3496 ©2009 by American Society of Hematology