The genetic basis of von Willebrand disease

被引:130
作者
Goodeve, Anne C. [1 ,2 ]
机构
[1] Univ Sheffield, Dept Cardiovasc Sci, Haemostasis Res Grp, Fac Med Dent & Hlth, Sheffield S10 2RX, S Yorkshire, England
[2] Sheffield Childrens NHS Fdn Trust, Sheffield Diagnost Genet Serv, Sheffield, S Yorkshire, England
关键词
Genetic analysis; Genotype; Mutation; Polymorphism; von Willebrand factor; von Willebrand disease; FACTOR-VIII BINDING; VONWILLEBRAND-FACTOR; CLINICAL MARKERS; MOLECULAR ANALYSIS; FACTOR SURVIVAL; CLEAVAGE SITE; HEMOPHILIA-A; IN-VIVO; MUTATION; DIAGNOSIS;
D O I
10.1016/j.blre.2010.03.003
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The common autosomally inherited mucocutaneous bleeding disorder, von Willebrand disease (VWD) results from quantitative or qualitative defects in plasma von Willebrand factor (VWF). Mutation can affect VWF quantity or its functions mediating platelet adhesion and aggregation at sites of vascular damage and carrying pro-coagulant factor VIII (FVIII). Phenotype and genotype analysis in patients with the three VWD types has aided understanding of VWF structure and function. Investigation of patients with specific disease types has identified mutations in up to 70% of type 1 and 100% of type 3 VWD cases. Missense mutations predominate in type 1 VWD and act through mechanisms including rapid clearance and intracellular retention. Many mutations are incompletely penetrant and attributing pathogenicity is challenging. Other factors including blood group 0 contribute to low VWF level. Missense mutations affecting platelet- or FVIII-binding through a number of mechanisms are responsible for the four type 2 subtypes; 2A, 2B, 2M and 2N. In contrast, mutations resulting in a lack of VWF expression predominate in recessive type 3 VWD. This review explores the genetic basis of each VWD type, relating mutations identified to disease mechanism. Additionally, utility of genetic analysis within the different disease types is explored. (C) 2010 Elsevier Ltd. All rights reserved.
引用
收藏
页码:123 / 134
页数:12
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