Mazurier C, Ribba A S, Gaucher C, Meyer D
Laboratoire Français du Fractionnement et des Biotechnologies, Lille, France.
Ann Genet. 1998;41(1):34-43.
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.
血管性血友病（vWD）是人类最常见的先天性出血性疾病，与血管性血友病因子（vWF）的数量和/或质量异常有关。这种多聚体糖蛋白作为血浆中凝血必需辅因子因子VIII的载体蛋白，并促进血小板黏附于受损血管及血小板聚集。vWF的不同异常导致了三种类型的vWD。1型和3型的特征是vWF的数量缺陷，而2型包括2A、2B、2M和2N亚型，指的是vWF存在质量缺陷的分子变异体。vWF基因结构的知识以及聚合酶链反应（PCR）的应用，已使大量患者中vWD的分子基础得以鉴定。2A型的特征是vWF的血小板依赖性功能降低，伴有vWF高分子量（HMW）多聚体缺失。大多数2A型突变已在vWF的A₂结构域中被鉴定出来，该结构域含有一个蛋白水解位点，而其他一些突变则在vWF的前肽和C末端部分被发现，它们分别参与vWF的多聚化和二聚化。在2B型中，其定义为vWF与血小板糖蛋白Ib（GPIb）的亲和力增加，已在含有GPIb结合位点的A₁结构域内定位了各种氨基酸（aa）替代或插入。在该结构域中也鉴定出了2M型中描述的少数分子异常，2M型的定义是血小板依赖性功能降低，但不是由HMW多聚体缺失引起的。在2N型中，其特征是vWF与因子VIII的结合缺陷，已在vWF N末端的因子VIII结合结构域内鉴定出几个aa替代。在1型和3型中，基因缺陷的鉴定仍然困难。虽然在3型中已经鉴定出各种异常（完全、部分或点缺失、点插入、无义突变），但在大多数情况下，1型的分子基础仍未解决。vWD分子基础的表征对于进一步深入了解vWF的结构-功能关系和生物合成具有重要意义。
