Characterization of a Factor VII Molecule Carrying a Mutation in the Second Epidermal Growth Factor-like Domain

Anita Kavlie; Lars Örning; Anne Grindflek; Helge Stormorken; Hans Prydz

doi:10.1055/s-0037-1615030

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1998; 79(06): 1136-1143
DOI: 10.1055/s-0037-1615030

Rapid Communication

Schattauer GmbH

Characterization of a Factor VII Molecule Carrying a Mutation in the Second Epidermal Growth Factor-like Domain

Anita Kavlie

¹From the Biotechnology Centre of Oslo, University of Oslo

,

Lars Örning

²Nycomed Pharma A/S, Oslo, Norway

,

Anne Grindflek

¹From the Biotechnology Centre of Oslo, University of Oslo

,

Helge Stormorken

³Research Institute for Internal Medicine, University of Oslo, Oslo, Norway

,

Hans Prydz

¹From the Biotechnology Centre of Oslo, University of Oslo

› Institutsangaben

Abstract

Summary

A missense mutation at codon 100 in the second epidermal growth factor-like domain, resulting in Gln100→Arg, was detected in 19 out of 21 available severely factor VII (FVII) deficient patients in Norway. Seventeen patients were homozygous, and the two remaining were compound heterozygotes. In the homozygous patients, FVII antigen was measured to 10-28%, and activity to 0.6-6.5% of that in normal pooled plasma. Recombinant FVII containing the mutation was expressed transiently in CHO cells to a mean antigen level of 57% of the wild type FVII protein, and with a specific activity of 6% of wild type. The mutant protein had a 14-fold reduction in affinity for tissue factor (TF), whereas binding of FX seemed unaffected. In line with the experimental data, molecular modelling of the mutation based on the coordinates of the tissue factor/FVIIa complex showed that substituting arginine for glutamine disrupts the interface between the catalytic and second epidermal growth factor-like domains.

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