Jenkins, Peter Vincent; (1999) A molecular analysis of Von Willebrand disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Von Willebrand disease (VWD), the most common inherited bleeding disorder, is caused by either qualitative or quantitative abnormalities of the circulating glycoprotein Von Willebrand Factor (VWF). This thesis describes an approach to the study of mutations causing VWD by analysis of the essential coding region of VWF. This was performed by the amplification of regions of VWF derived from mRNA and genomic DNA. By use of this approach mutations were identified in a series of patients with VWD, and the inheritance of causative mutations demonstrated in affected families. Molecular analysis demonstrated that a number of the patients have qualitative rather than the quantitative abnormalities of VWF originally diagnosed. In addition to the identification of causative mutations in VWD, this thesis describes the modelling of the three VWF-A domains and the location of known mutation sites within the models. This provided an explanation for the various effects of the mutations on VWF structure and function. Important residues involved in ligand binding to the VWF-A1 domains were identified and a mechanism proposed for the action of mutations causing an upregulation in binding of VWF to platelets, and other mutations causing downregulation. VWF is a large protein that interacts with a variety of ligands and exhibits multiple functions. In many cases of VWD the action of mutations cannot be simply explained by knowledge of the sequence alteration. This thesis demonstrates that a variety of approaches are required for integrated molecular understanding of VWD and VWF.

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