Peyvandi F, Jenkins P V, Mannucci P M, Billio A, Zeinali S, Perkins S J, Perry D J
Department of Haematology, Royal Free and University College Medical School, London, UK.
Thromb Haemost. 2000 Aug;84(2):250-7.
Factor VII (FVII) is a four-domain glycoprotein that plays a critical role in the initiation of blood coagulation. Hereditary deficiencies of this plasma protein results in a bleeding diathesis that varies in severity amongst affected patients. We have analysed the FVII gene in 27 patients with FVII deficiency from 21 unrelated families predominantly of Middle-Eastern extraction. A total of 19 different mutations were identified, of which 12 were novel and 7 had been previously reported. Nine of the 12 novel mutations were missense mutations located in the Gla domain (Ser23Pro), the second epidermal growth factor domain (Cys135Arg) and the catalytic serine protease domain (Arg247Cys, Arg277Cys, Ser282Arg, Pro303Thr, Ser363Ile, Trp364Cys, Trp364Phe), of which five are homozygous. Three novel splice mutations were identified in intron 1a (IVS1a+5), intron 2 (IVS2+1) and intron 6 (IVS6+1). Of the seven previously reported mutations, five were missense mutations of which three are homozygous (Gln100Arg, Arg152Gln, Arg304Gln, Cys310Phe and Thr359Met), one was a 17 bp deletion (10585del117bp) and one was a splice site mutation within intron 7 (IVS7+7). This study has significantly extended the current database of FVII mutations, including the number of known homozygous mutations. Conformational analyses of crystal structures for FVIIa and the FVIIa-tissue factor complex provided likely explanations for the effect of the missense mutations on FVIIa secretion or function. In particular, since 23 missense mutations were located to the serine protease domain, mostly to the region between the catalytic triad and the contact surface with tissue factor, this showed that the orientation of the serine protease domain relative to bound tissue factor in the complex is crucial for functional activity.
凝血因子VII（FVII）是一种四结构域糖蛋白，在血液凝固起始过程中起关键作用。这种血浆蛋白的遗传性缺陷会导致出血素质，在受影响的患者中严重程度各不相同。我们分析了来自21个主要为中东血统的无关家庭的27例FVII缺乏患者的FVII基因。共鉴定出19种不同的突变，其中12种是新突变，7种先前已有报道。12种新突变中有9种是错义突变，分别位于Gla结构域（Ser23Pro）、第二个表皮生长因子结构域（Cys135Arg）和催化丝氨酸蛋白酶结构域（Arg247Cys、Arg277Cys、Ser282Arg、Pro303Thr、Ser363Ile、Trp364Cys、Trp364Phe），其中5种为纯合突变。在1a内含子（IVS1a + 5）、2内含子（IVS2 + 1）和6内含子（IVS6 + 1）中鉴定出3种新的剪接突变。在先前报道的7种突变中，5种是错义突变，其中3种为纯合突变（Gln100Arg、Arg152Gln、Arg304Gln、Cys310Phe和Thr359Met），1种是17 bp缺失（10585del117bp），1种是7内含子内的剪接位点突变（IVS7 + 7）。这项研究显著扩展了当前的FVII突变数据库，包括已知纯合突变的数量。对FVIIa和FVIIa - 组织因子复合物晶体结构的构象分析为错义突变对FVIIa分泌或功能的影响提供了可能的解释。特别是，由于23种错义突变位于丝氨酸蛋白酶结构域，主要位于催化三联体和与组织因子接触表面之间的区域，这表明复合物中丝氨酸蛋白酶结构域相对于结合的组织因子的取向对功能活性至关重要。
