Gene Defects in 150 Unrelated French Cases with Type 2 von Willebrand Disease: from the Patient to the Gene

Abstract

von Willebrand disease (vWD) is a frequent and heterogeneous bleeding disorder which is characterized by quantitative and/or qualitative abnormalities of von Willebrand factor (vwF). vwF is a high molecular weight (HMw), multimeric glycoprotein, which carries factor VIII (FVIII) and mediates platelet adhesion and aggregation ar high shear rates (l,Z). The vwF gene, of 178 kb, contains 52 exons. A precursor protein, pre-pro-vWF, containing four types of repeating domains (A to D), is synthesized in endothelial cells and megakaryocytes (Fig. 1). Disulphide bridges involved in the dimerization and multim erization of vWF are located in the C-terminal part and D3 domain, respectively. vWF multimers are composed of mature vWF subunits of 270 kDa corresponding to the 2050 C-terminal aa of pre-pro-vWF. These subunits contain two remarkable disulphide loops of l g5 aa in Al and ,{3 domains, an important proteolytic site within ,{2 domain, between aa 842 and 843, and an RGD sequence in Cl domain. The functions of vWF are related to the presence along the 270 kDa subunit of a series of binding sites for FVIII, collagen, platelet glycoproteins (GP) GPIb and GPIIb/IIIa (Fig.1). The multimerization of vWF is also essential for its role in platelet adhesion and aggregation.

Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease

“…38 Twentyeight reported mutations in the VWF gene involve cysteine residues that result in different types of VWD. 10,[42][43][44][45] In contrast, only 1 reported "polymorphism" in the VWF gene involves a substitution to cysteine (Tyr1584Cys), and we have provided evidence demonstrating that this sequence variation is a common mutation in Canadian families with type 1 VWD.…”

C1272S: A new candidate mutation in type 2A von Willebrand disease that disrupts the disulfide loop responsible for the interaction of VWF with platelet GP lb‐IX

“…However, two other changes affecting the same codon, C1272G [11] and C1272R [12], were reported. Expression studies of these two mutants showed a VWF with an absence of intermediate and high molecular weight multimers.…”

Investigation of von Willebrand Factor Gene Mutations in Korean von Willebrand Disease Patients

“…Methods : In 40 known vWD patients mutations of vWF gene were sought by direct sequencing of PCR products targeting exons 18,19,20,26,28 and 52 frequently implicated as the locations of mutation. For factors other than VWF gene contributing to VWD phenotype, we tested ABO blood group and measured ADAMTS13 activity in VWD patients.…”