Molecular characterization of a unique von Willebrand disease variant. A novel mutation affecting von Willebrand factor/factor VIII interaction

von Willebrand factor (vWF) plays a central role in blood coagulation, mediating the adhesion of the initial platelet plug to the subendothelium, and serving as the carrier for factor VIII (FVIII) in the circulation. In previous studies, we have mapped the epitope for an anti-vWF monoclonal antibody...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 1991-07, Vol.266 (21), p.13499-13502
Main Authors: CACHERIS, P. M, NICHOLS, W. C, GINSBURG, D
Format: Article
Language:English
Subjects:
Adult
Base Sequence
Binding Sites
Biological and medical sciences
Blood coagulation. Blood cells
Coagulation factors
Factor VIII - metabolism
Female
Fundamental and applied biological sciences. Psychology
Humans
Molecular and cellular biology
Molecular Sequence Data
Mutation
Oligonucleotides - chemistry
Polymerase Chain Reaction
von Willebrand Diseases - genetics
von Willebrand Factor - genetics
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:von Willebrand factor (vWF) plays a central role in blood coagulation, mediating the adhesion of the initial platelet plug to the subendothelium, and serving as the carrier for factor VIII (FVIII) in the circulation. In previous studies, we have mapped the epitope for an anti-vWF monoclonal antibody which inhibits the interaction between FVIII and vWF to a region spanning Thr78 to Thr96 of the mature protein (Bahou, W.F., Ginsburg, D., Sikkink, R., Litwiller, R., and Fass, D. N. (1989) J. Clin. Invest. 84, 56-61). We now report the identification of a mutation within this region of vWF that results in decreased FVIII binding. Sequence analysis of polymerase chain reaction amplified platelet vWF mRNA from a von Willebrand disease (vWD) patient with a disproportionately low FVIII level identified a single nucleotide substitution (G---A), resulting in the conversion of Arg91---Gln. Recombinant vWF carrying this substitution showed decreased binding to FVIII compared with wild-type vWF or vWF carrying a polymorphic substitution in the same region (Arg89---Gln). These observations suggest a critical role for Arg91 in the interaction of vWF with FVIII and identify the molecular mechanism for a variant of vWD associated with unusually low FVIII levels.
ISSN:0021-9258
1083-351X
DOI:10.1016/S0021-9258(18)92725-0