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The defective interaction between von Willebrand factor and factor VIII in
a patient with type 1 von Willebrand disease is caused by substitution of
Arg19 and His54 in mature von Willebrand factor
PA Kroner, PA Foster, SA Fahs and RR Montgomery
Blood Research Institute. The Blood Center of Southeastern Wisconsin,
Milwaukee 53201-2178, USA.
In this report we describe the further investigation of the von Willebrand
factor (vWF)/FVIII interaction in a type 1 von Willebrand disease patient
characterized by discrepant VIII:C levels as determined by one-stage and
two-stage VIII:C assays. A solid-phase binding assay shows that this
patient's plasma vWF is moderately defective in capturing recombinant
FVIII. Sequence analysis of the FVIII-binding domain encoded by the vWF
mRNA of the affected individual identified mutations in both vWF alleles.
In allele A, the mutations C2344T and T2451A result in the substitution of
Trp for Arg19 (R19W) and of G1n for His54 (H54Q) in mature vWF,
respectively. This allele also contains a reported polymorphism (A2365G,
Thr26Ala). Allele B, which is underexpressed at the RNA level, contains a
one-nucleotide deletion in the FVIII-binding domain (delta G2515) that
results in the premature termination of translation. Analysis of the
binding of FVIII by full- length vWF transiently expressed in COS-7 cells
confirms that the combined R19W and H54Q substitutions are the cause of the
defective vWF/FVIII interaction in this patient. The FVIII-binding defect
of vWF containing either mutation alone is approximately half that of the
double mutant, which suggests that the effect of these mutations is
additive. The mutant proteins are recognized equally well by vWF monoclonal
antibodies MBC105.4, 32B12, and 31H3, which block the binding of FVIII by
vWF, indicating that amino acids Arg19, Thr26, and His54 are not critical
residues in the epitopes of these antibodies.
Volume 87,
Issue 3,
pp. 1013-1021,
02/01/1996
Copyright © 1996 by The American Society of Hematology
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