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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 979-987
Hemophilic factor VIII C1- and C2-domain missense mutations and
their modeling to the 1.5-angstrom human C2-domain
crystal structure
Miao-Liang Liu,
Betty W. Shen,
Shelley Nakaya,
Kathleen P. Pratt,
Kazuo Fujikawa,
Earl W. Davie,
Barry L. Stoddard, and
Arthur R. Thompson
From the Department of Medicine, University of Washington, Puget
Sound Blood Center; Fred Hutchinson Cancer Research Center; and
Department of Biochemistry, University of Washington, Seattle, WA.
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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