Molecular genetics of von Willebrand disease

Von Willebrand disease (vWD), the most common congenital bleeding disorder in man, is related to quantitative and/or qualitative abnormalities of von Willebrand factor (vWF). This multimeric glycoprotein serves as carrier protein of factor VIII, an essential cofactor of coagulation in plasma, and promotes platelet adhesion to the damaged vessel and platelet aggregation. Distinct abnormalities of vWF are responsible for the three types of vWD. Types 1 and 3 are characterized by a quantitative defect of vWF whereas type 2, comprising subtypes 2A, 2B, 2M and 2N, refers to molecular variants with a qualitative defect of vWF. The knowledge of the structure of the vWF gene and the use of Polymerase Chain Reaction (PCR) have led to the identification of the molecular basis of vWD in a significant number of patients. Type 2A is characterized by a decreased platelet-dependent function of vWF associated with the absence of high molecular weight (HMW) multimers of vWF. Most of the type 2A mutations have been identified in the A2 domain of vWF which contains a proteolytic site, while a few others have been found within the propeptide and the C-terminal part of vWF which are involved in its multimerization and dimerization, respectively. In type 2B, defined by an increased affinity of vWF to platelet glycoprotein Ib (GPIb), various amino-acid (aa) substitutions or insertion have been localized within the A1 domain containing the GPIb binding site. In the latter domain have been also identified the few molecular abnormalities described in type 2M which is defined by a decreased platelet-dependent function not caused by the absence of HMW multimers. In type 2N, characterized by a defective binding of vWF to factor VIII, several aa substitutions have been identified within the factor VIII-binding domain in the N-terminal part of vWF. The identification of gene defects remains difficult in types 1 and 3. Whereas various abnormalities (total, partial or point deletions, point insertions, nonsense mutations) have already been identified in type 3, the molecular basis of type 1 is still unresolved in most cases. The characterization of the molecular basis of vWD is of fundamental interest in providing further insight into the structure-function relationship and the biosynthesis of vWF.