Genetic aspects of von Willebrand disease

Abstract

Introduction. Von Willebrand disease (VWD), the most common inherited bleeding disorder in humans, is a heterogeneous disorder caused by a partial quantitative (type 1 VWD), qualitative (type 2 VWD) or severe quantitative (type 3 VWD) deficiency of von Willebrand factor protein (VWF). It is characterised clinically by mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. VWF is a large, multimeric protein that plays a role in platelet adhesion and serves as a carrier for the thrombotic protein factor VIII. The VWF gene is located at the short arm of chromosome 12 (12p13.31). Depending on its type, VWD can either have an autosomal dominant inheritance pattern (type 1, type 2A, 2B, 2M) or an autosomal recessive inheritance pattern (type 2N and type 3). Aim of the study. Expanding the understanding of the genetic basis of different types of VWD. Materials and methods. This study is based on a review of different articles from the open access data bases: PubMed, OMIM, SpringerLink. Results. In type 1 VWD mutations are located throughout the VWF gene from the promoter region to exon 52 and the majority are missense mutations (75%), whereas splice, deletion, nonsense, insertion, duplication, and large in-frame deletions mutations comprise minor proportions. The most common locations for mutations in type 2A WVD are: the A2 domain (p.Arg1315Cys, p.Arg1374Cys and p.Arg1374His) , D3 domain (missense mutations are located in ex22 and 25 to 28, many introducing/substituting cysteine residues; replacement of p.Cys1130 is the most common change), D2 domain (mutations are recessively inherited and are located in ex11 to 16), and CK domains (mutations affect ex51 to 52). Mutations in type 2B and 2M are located in the A1 domain (ex 28). Type 2N VWD is caused by mutations in ex 17-20 and 24-25 (missense mutations or null allele). The most frequent mutation in the European populations is p.Arg854Gln, for which ∼1% of individuals are heterozygous. In type 3 VWD the mutation location is 5′ VWF-Ex52 (missense mutations or null allele). Conclusions. VWF mutations are located throughout the VWF gene, resulting in a wide range of mutation types that cause quantitative and qualitative disorders. VWF protein is involved in several processes that can be damaged by mutation, and the varying phenotypes in VWD illustrate the processes that are impaired.