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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 958-965
A novel cause of mild/moderate hemophilia A: mutations scattered
in the factor VIII C1 domain reduce factor VIII binding to von
Willebrand factor
Marc Jacquemin,
Renaud Lavend'homme,
Abdellah Benhida,
Beatrijs Vanzieleghem,
Roseline d'Oiron,
Jean-Maurice Lavergne,
Hans H. Brackmann,
Rainer Schwaab,
Thierry VandenDriessche,
Marinee K. L. Chuah,
Marc Hoylaerts,
Jean Guy G. Gilles,
Kathelijne Peerlinck,
Jos Vermylen, and
Jean-Marie R. Saint-Remy
From the Center for Molecular and Vascular Biology, University of
Leuven, Leuven, Belgium; Hôpital Bicêtre, le
Kremlin-Bicêtre, AP-HP, France; Institut für Experimentelle
Hämatologie und Transfusionsmedizin, Bonn, Germany; and the
Center for Transgene Technology and Gene Therapy, Flanders
Interuniversity Institute for Biotechnology, University of Leuven,
Leuven, Belgium.
The mechanisms responsible for the low factor VIII (fVIII) activity
in the plasma of patients with mild/moderate hemophilia A are poorly
understood. In such patients, we have identified a series of fVIII
mutations (Ile2098Ser, Ser2119Tyr, Asn2129Ser, Arg2150His, and
Pro2153Gln) clustered in the C1 domain and associated with reduced
binding of fVIII to von Willebrand factor (vWf). For each patient
plasma, the specific activity of mutated fVIII was close to
that of normal fVIII. Scatchard analysis showed that the affinity for
vWf of recombinant Ile2098Ser, Ser2119Tyr, and Arg2150His
fVIII mutants was reduced 8-fold, 80-fold, and 3-fold, respectively,
when compared with normal fVIII. Given the importance of vWf for the
stability of fVIII in plasma, these findings suggested that the
reduction of fVIII binding to vWf resulting from the above-mentioned
mutations could contribute to patients' low fVIII plasma levels. We,
therefore, analyzed the effect of vWf on fVIII production by Chinese
hamster ovary (CHO) cells transfected with expression vectors for
recombinant B domain-deleted normal, Ile2098Ser, Ser2119Tyr, and
Arg2150His fVIII. These 3 mutations impaired the vWf-dependent
accumulation of functional fVIII in culture medium. Analysis of fVIII
production by transiently transfected CHO cells indicated that, in
addition to the impaired stabilization by vWf, the secretion of
functional Ile2098Ser and Arg2150His fVIII was reduced about 2-fold and
6-fold, respectively, by comparison to Ser2119Tyr and normal fVIII.
These findings indicate that C1-domain mutations resulting in reduced
fVIII binding to vWf are an important cause of mild/moderate hemophilia A.
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