von Willebrand factor (vWF) is a central protein in blood coagulation. It serves as the carrier in plasma for factor VIII and as a major adhesive link between platelets and the blood vessel wall at sites of vascular injury. Abnormalities in vWF result in von Willebrand disease (vWD), the most common inherited bleeding disorder in humans. During the initial finding period for this project, we have made considerable progress toward understanding the molecular basis of vWD and the structure and function of vWF. Four point mutations, accounting for approximately 90% of type IIB vWD, have been identified within a 35 amino acid segment of the vWF A2 domain. A panel of seven mutations within the vWF Al domain similarly accounts for the majority of type IIA vWD patients. Transfection analysis of the latter mutations has identified two functional subgroups of type IIA vWD, associated with distinct molecular mechanisms. Structure/function studies, along with analysis of a new class of vWD patient mutations, has begun to define the critical region of vWF responsible for interaction with factor VIII. Comparative DNA and platelet RNA polymorphism analysis has been applied to the study of type I and type III vWD. Initial observations suggest that distinct molecular mechanisms may be responsible for these two disorders. Preliminary molecular genetic studies of type I vWD in the RIIIS/J mouse suggest that this animal model may be due to a defect at a novel genetic locus, distinct from the vWF gene.
The specific aims of the current proposal will extend our previous observations, with particular emphasis on the molecular basis of type I and type Ill vWD. Additional vWD patients will be studied to assemble diagnostically useful mutation screening panels and to further correlate genotype with phenotype. Additional vWF structure/function studies will further define the vWF binding domains for factor VIII and specific vWF receptors on the platelet surface and the blood vessel wall. Genetic linkage studies will address the questions of locus heterogeneity and potential modifying genetic factors in human vWD. In addition, positional cloning methods will be employed to identify the novel type I vWD gene in the RIIIS/J mouse. Taken together, the results of these studies should advance our understanding of vWD pathogenesis and should also provide new tools for the diagnosis and classification of this common disorder. In addition, these studies may lead to the development of new therapeutic approaches for the treatment of vWD as well as other genetic and acquired thrombotic and hemorrhagic disorders.
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