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Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure

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 内科学
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]
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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