Kavlie A, Orning L, Grindflek A, Stormorken H, Prydz H
Biotechnology Centre of Oslo, University of Oslo, Norway.
Thromb Haemost. 1998 Jun;79(6):1136-43.
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.
在挪威21例严重因子VII（FVII）缺乏症患者中，有19例检测到第二表皮生长因子样结构域第100位密码子发生错义突变，导致谷氨酰胺100（Gln100）突变为精氨酸（Arg）。17例患者为纯合子，其余2例为复合杂合子。在纯合子患者中，FVII抗原检测为正常混合血浆的10%-28%，活性为0.6%-6.5%。含有该突变的重组FVII在CHO细胞中瞬时表达，平均抗原水平为野生型FVII蛋白的57%，比活性为野生型的6%。突变蛋白与组织因子（TF）的亲和力降低了14倍，而与FX的结合似乎未受影响。与实验数据一致，基于组织因子/FVIIa复合物坐标对该突变进行的分子建模显示，用精氨酸取代谷氨酰胺会破坏催化结构域与第二表皮生长因子样结构域之间的界面。
