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The mutation Arg (53)----Trp causes von Willebrand disease Normandy by
abolishing binding to factor VIII. Studies with recombinant von Willebrand
factor
S Jorieux, EA Tuley, C Gaucher, C Mazurier and JE Sadler
Howard Hughes Medical Institute, Department of Medicine, Washington
University School of Medicine, St Louis, MO 63110.
von Willebrand factor (vWF) and factor VIII (FVIII) circulate in plasma as
a noncovalently linked protein complex. The FVIII/vWF interaction is
required for the stabilization of procoagulant FVIII activity. Recently, we
reported a new variant of von Willebrand disease (vWD) tentatively named
"Normandy," characterized by plasma vWF that appears to be structurally and
functionally normal except that it does not bind FVIII. Three patients from
one family were found to be homozygous for a C----T transition at codon 816
converting Arg 53 to Trp in the mature vWF subunit. To firmly establish a
causal relationship between this missense mutation and vWD Normandy
phenotype, we have characterized the corresponding recombinant mutant
vWF(R53W). Expressed in COS-7 cells or CHO cell lines, normal vWF and
vWF(R53W) were processed and formed multimers with equal efficiency.
However, vWF(R53W) exhibited the same defect in FVIII binding as did plasma
vWF from patients with vWD Normandy, confirming that this mutation is
responsible for the vWD Normandy phenotype. These results illustrate the
importance of Arg 53 of the mature vWF subunit for the binding of FVIII to
vWF, and identify an amino acid residue within a disulfide loop not
previously known to be involved in this interaction.
Volume 79,
Issue 3,
pp. 563-567,
02/01/1992
Copyright © 1992 by The American Society of Hematology
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