错义突变
C2域
血管性血友病因子
因子IX
化学
突变
突变体
结合位点
表位
因子X
因子IXa
同源建模
凝血因子
抗体
遗传学
生物
生物化学
血小板
免疫学
医学
基因
凝血酶
膜
内科学
酶
作者
Miao‐Liang Liu,Betty Shen,Shelley Nakaya,Kathleen P. Pratt,Kazuo Fujikawa,Earl W. Davie,Barry Stoddard,Arthur R. Thompson
出处
期刊:Blood
[American Society of Hematology]
日期:2000-08-01
卷期号:96 (3): 979-987
被引量:109
标识
DOI:10.1182/blood.v96.3.979.015k42a_979_987
摘要
Factor VIII C domains contain key binding sites for von Willebrand factor (vWF) and phospholipid membranes. Hemophilic patients were screened for factor VIII C-domain mutations to provide a well-characterized series. Mutated residues were localized to the high-resolution C2 structure and to a homology model of C1. Of 30 families found with mutations in the C domains, there were 14 missense changes, and 9 of these were novel. Of the missense mutations, 10 were associated with reduced vWF binding and 8 were at residues with surface-exposed side chains. Six of the 10 mutants had nearly equivalent factor VIII clotting activity and antigen level, suggesting that reduced vWF binding could cause hemophilia by reducing factor VIII stability in circulation. When the present series was combined with previously described mutations from an online international database, 11 C1 and C2 mutations in patients with mild or moderately severe hemophilia A were associated with antibody-inhibitor development in at least one affected individual. Of these substitutions, 6 occurred at surface-exposed residues. As further details of the C1 structure and its interface with C2 become available, and as binding studies are performed on the plasma of more patients with hemophilic C-domain mutations, prediction of surface binding sites should improve, allowing confirmation by site-specific mutagenesis of surface-exposed residues.
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