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Type 2M von Willebrand Disease: F606I and I662F Mutations in the
Glycoprotein Ib Binding Domain Selectively Impair Ristocetin- but not
Botrocetin-Mediated Binding of von Willebrand Factor to Platelets
Cheryl A. Hillery,
David J. Mancuso,
J. Evan Sadler,
Jay W. Ponder,
Mary A. Jozwiak,
Pamela A. Christopherson,
Joan Cox Gill,
J. Paul Scott, and
Robert R. Montgomery
From the Blood Research Institute, The Blood Center of Southeastern
Wisconsin, Milwaukee; the Department of Pediatrics, Medical College of
Wisconsin, Milwaukee, WI; and the Howard Hughes Medical Institute and
the Department of Biochemistry and Molecular Biophysics, Washington
University School of Medicine, St Louis, MO.
von Willebrand disease (vWD) is a common, autosomally inherited,
bleeding disorder caused by quantitative and/or qualitative deficiency of von Willebrand factor (vWF). We describe two families with a variant form of vWD where affected members of both families have
borderline or low vWF antigen levels, normal vWF multimer patterns,
disproportionately low ristocetin cofactor activity, and significant
bleeding symptoms. Whereas ristocetin-induced binding of plasma vWF
from affected members of both families to fixed platelets was reduced,
botrocetin-induced platelet binding was normal. The sequencing of
genomic DNA identified unique missense mutations in each family in the
vWF exon 28. In Family A, a missense mutation at nucleotide 4105T
 A resulted in a Phe606Ile amino acid substitution (F606I)
and in Family B, a missense mutation at nucleotide 4273A T
resulted in an Ile662Phe amino acid substitution (I662F). Both
mutations are within the large disulfide loop between Cys509 and Cys695
in the A1 domain that mediates vWF interaction with platelet
glycoprotein Ib. Expression of recombinant vWF containing either F606I
or I662F mutations resulted in mutant recombinant vWF with decreased
ristocetin-induced platelet binding, but normal multimer structure,
botrocetin-induced platelet binding, collagen binding, and binding to
the conformation-sensitive monoclonal antibody, AvW-3. Both mutations
are phenotypically distinct from the previously reported variant type
2MMilwaukee-1 because of the presence of normal
botrocetin-induced platelet binding, collagen binding, and AvW-3
binding, as well as the greater frequency and intensity of clinical
bleeding. When the reported type 2M mutations are mapped on the
predicted three-dimensional structure of the A1 loop of vWF, the
mutations cluster in one region that is distinct from the region in
which the type 2B mutations cluster.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1572-1581
© 1998 by The American Society of Hematology.
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