The molecular characterization of von Willebrand disease: good in parts

Abstract

Since the cloning of the gene that encodes von Willebrand factor (VWF), 27 years ago, significant progress has been made in our understanding of the molecular basis of the most common inherited bleeding disorder, von Willebrand disease (VWD). The molecular pathology of this condition represents a range of genetic mechanisms, some of which are now very well characterized, and others that are still under investigation. In general, our knowledge of the molecular basis of type 2 and 3 VWD is now well advanced, and in some instances this information is being used to enhance clinical management. In contrast, our understanding of the molecular pathogenesis of the most common form of VWD, type 1 disease, is still at an early stage, with preliminary evidence that this phenotype involves a complex interplay between environmental factors and the influence of genetic variability both within and outside of the VWF locus.

Figure 1

Primary structure of the von WiIlebrand factor (VWF) pre-pro-polypeptide and its ligands. There is a typical 22 amino acid (AA) hydrophobic signal peptide, a large 741 AA propeptide responsible for facilitating N-terminally aligned multimer formation, and a 2050 AA secreted mature VWF subunit containing the binding sites for FVIII, platelets and the subendothelium. CK=cysteine knot domain.

Figure 2

Location of mutations resulting in Type 2 von Willebrand disease. Almost all of these mutations are missense variants. Type 2A substitutions affect predominantly the A2 domain, with some additional substitutions in the propeptide, D’ domain and the cysteine knot region. Almost all type 2B and 2M substitutions are located in the A1 domain, and the loss-of-function FVIII binding mutations in type 2N disease are in the D’/D3 domains.

Figure 3

Proposal for the molecular pathogenesis of the phenotype in type 1 VWD. There is growing evidence that many (most) cases of mild/moderately severe type 1 VWD are due to a combination of genetic variables both within and outside the VWF locus. Some of these sequence variances may involve distinct polymorphic haplotypes within VWF, some may be located adjacent to, but outside of the VWF gene, and additional modifiers may involve other genes involved in VWF biosynthesis, secretion and clearance. SNP, single nucleotide polymorphism.

Figure 4

Potential sites of pathogenic variants resulting in quantitative von Willebrand factor (VWF) traits (type 1 and 3 von Willebrand disease). Genetic variables anywhere along the VWF life cycle from the regulation of gene expression to protein clearance may result in quantitative phenotypes. In some instances, single variables may produce a dominant effect but in mild/moderate quantitative phenotypes combinations of variables may be more prevalent.