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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4663-4670
A Novel Mutation in the D3 Domain of von Willebrand Factor Markedly
Decreases Its Ability to Bind Factor VIII and Affects Its
Multimerization
S. Jorieux,
C. Gaucher,
J. Goudemand, and
C. Mazurier
From the Laboratoire de Recherche sur l'Hémostase, Laboratoire
Français du Fractionnement et des Biotechnologies, Lille, France;
and the Laboratoire d'Hématologie, Centre Hospitalier
Régional Universitaire de Lille, Lille, France.
In type 2N von Willebrand disease (vWD), von Willebrand factor (vWF)
is characterized by normal multimeric pattern, normal platelet-dependent function, but a markedly decreased affinity for
factor VIII (FVIII). In this report, we describe the case of a vWD
patient who has an abnormal vWF multimers distribution associated with
a markedly decreased vWF ability to bind FVIII. Sequencing analysis of
patient's vWF gene showed, at heterozygous state, a G A
transition resulting in the substitution of Asn for Asp at position 116 of the mature vWF subunit and a CT transition, changing the
codon for Arg 896 into a stop codon. His sister who has a subnormal vWF
level, but a normal FVIII/vWF interaction, was found to be heterozygous
for the Arg896ter mutation only. Recombinant vWF (rvWF) containing the
candidate (Asn116) missense mutation was expressed in COS-7 cells. The
expression level of Asn116rvWF was significantly decreased compared
with wild-type rvWF. The multimeric pattern of Asn116rvWF was greatly
impaired as shown by the decrease in high molecular weight forms. The
FVIII binding ability of Asn116rvWF was dramatically decreased. These data show that the Asp116Asn substitution is the cause of both the
defective FVIII/vWF interaction and the impaired multimeric pattern
observed in the patient's vWF. The monoclonal antibody 31H3 against
D' domain of vWF (epitope aa 66-76) that partially inhibits the FVIII
binding and recognizes only nonreduced vWF, showed a decreased ability
to bind Asn116rvWF when used as capture-antibody in enzyme-linked
immunosorbent assay (ELISA). This result suggests that a potential
conformation change in the D' domain is induced by the Asp116Asn
substitution, which is localized in the D3 domain.
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