title: The genetic basis of von Willebrand disease.
abstract: The common autosomally inherited mucocutaneous bleeding disorder, von Willebrand disease (VWD) results from quantitative or qualitative defects in plasma von Willebrand factor (VWF). Mutation can affect VWF quantity or its functions mediating platelet adhesion and aggregation at sites of vascular damage and carrying pro-coagulant factor VIII (FVIII). Phenotype and genotype analysis in patients with the three VWD types has aided understanding of VWF structure and function. Investigation of patients with specific disease types has identified mutations in up to 70% of type 1 and 100% of type 3 VWD cases. Missense mutations predominate in type 1 VWD and act through mechanisms including rapid clearance and intracellular retention. Many mutations are incompletely penetrant and attributing pathogenicity is challenging. Other factors including blood group O contribute to low VWF level. Missense mutations affecting platelet- or FVIII-binding through a number of mechanisms are responsible for the four type 2 subtypes; 2A, 2B, 2M and 2N. In contrast, mutations resulting in a lack of VWF expression predominate in recessive type 3 VWD. This review explores the genetic basis of each VWD type, relating mutations identified to disease mechanism. Additionally, utility of genetic analysis within the different disease types is explored.
authors.affiliation: Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, UK. a.goodeve@shef.ac.uk
authors.forename: Anne C
authors.initials: AC
authors.lastname: Goodeve
mesh_terms: D000017:ABO Blood-Group System / Q000235:genetics / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D010974:Platelet Aggregation / Q000235:genetics; D056725:von Willebrand Disease, Type 1 / Q000097:blood / Q000235:genetics*; D056728:von Willebrand Disease, Type 2 / Q000097:blood / Q000235:genetics*; D056729:von Willebrand Disease, Type 3 / Q000097:blood / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D000017:ABO Blood-Group System; D014841:von Willebrand Factor; C078147:F8 protein, human; D005169:Factor VIII