MOLECULAR-GENETICS OF VONWILLEBRAND-DISEASE

Von Willebrand disease (vWD), the most common congenital bleeding diso rder in man, is related to quantitative and/or qualitative abnormaliti es of von Willebrand factor (vWF). This multimeric glycoprotein serves as carrier protein of factor VIII, an essential cofactor of coagulati on in plasma, and promotes platelet adhesion to the damaged vessel and platelet aggregation. Distinct abnormalities of vWF are responsible f or the three types of vWD. Types 1 and 3 are characterized by a quanti tative defect of vWF whereas type 2, comprising subtypes 2A, 2B, 2M an d 2N, refers to molecular variants with a qualitative defect of vWF. T he knowledge of the structure of the vWF gene and the use of Polymeras e Chain Reaction (PCR) have led to the identification of the molecular basis of vWD in a significant number of patients. Type 2A is characte rized by a decreased platelet-dependent function of vWF associated wit h the absence of high. molecular weight (HMV) multimers of vWF. Most o f the type 2A mutations have been identified in the A2 domain of vWF w hich contains a proteolytic site, while a few others have been found w ithin the propeptide and the C-terminal part of vWF which are involved in its multimerization and dimerization, respectively. Fn type 2B, de fined by an increased affinity of vWF to platelet glycoprotein Ib (GPI b), various amino-acid (aa) substitutions or insertion have been local ized within the A1 domain containing the GPIb binding site. In the lat ter domain have been also identified the few molecular abnormalities d escribed in type 2M which is defined by a decreased platelet-dependent function not caused by the absence of HMW multimers. In type 2N, char acterized by a defective binding of vWF to factor VIII, several aa sub stitutions have been identified within the factor VIII-binding domain in the N-terminal part of vWF. The identification of gene defects rema ins 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 molevular basis of type 1 is s till unresolved in most cases. The characterization of the molecular b asis of vWD is of fundamental interest in providing further insight in to the structure-function relationship and the biosynthesis of vWF.