Factor X Stockton: a mild bleeding diathesis associated with an active site mutation in factor X
Factor X Stockton: a mild bleeding diathesis associated with an active site mutation in factor X
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DOI：
10.1097/00001721-199601000-00001
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发表时间：
1996-01
影响因子：
1.1
通讯作者：
T. Messier;C. Y. Wong;E. Bovill;G. Long;W. Church
中科院分区：
文献类型：
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作者：
T. Messier;C. Y. Wong;E. Bovill;G. Long;W. Church
在一个有出血史的家族中发现了一种独特的凝血因子 X 变异。受影响家庭成员的血浆凝血酶原时间和活化的部分凝血活酶时间延长，X 因子凝血活性低至低于正常，X 因子抗原水平正常。对产前 DNA 进行测序显示，因子 X 的一个等位基因在碱基 964 处有一个 G 到 A 的替换，导致残基 282 处的 Asn 氨基酸替换为 Asp。该残基对应于胰凝乳蛋白酶的活性位点 Asp102。该取代消除了 TaqI 限制性位点，并为检测聚合酶链式反应 (PCR) 扩增的 X 因子外显子 VIII DNA 中突变的筛选测定提供了基础。另外 14 个家族成员被鉴定为在碱基 964 处具有突变。使用抗因子 X 单克隆抗体免疫吸附剂从原代纯化的血浆因子 X 与以类似方式从正常个体纯化的因子 X 相比，表现出比活性降低约 50%。携带突变（称为因子 X Stockton）的家庭成员中的出血似乎是由于血浆中循环异常因子 X 的存在破坏了正常止血。因子 X Stockton 是丝氨酸蛋白酶活性位点 Asp 上第一个自然发生的替代，强调了该氨基酸残基在因子 Xa 凝血活性中的重要性。
A unique blood coagulation factor X variant has been identified in a family with a history of bleeding. Plasma from affected family members had prolonged prothrombin times and activated partial thromboplastin times, low to below normal factor X coagulant activity, and normal factor X antigen levels. Sequencing of DNA from the propositus revealed a single G to A substitution in one allele of factor X at base 964 resulting in an amino acid substitution of Asn for Asp at residue 282. This residue corresponds with the active site Asp102 of chymotrypsin. The substitution eliminates a TaqI restriction site and provided the basis for a screening assay to detect the mutation in polymerase chain reaction (PCR) amplified factor X exon VIII DNA. Fourteen additional family members were identified as having the mutation at base 964. Plasma factor X purified from the proposita using an anti-factor X monoclonal antibody immunoadsorbent exhibited an approximately 50% decrease in specific activity compared with factor X purified from a normal individual in a similar manner. Bleeding in family members with the mutation, termed factor X Stockton, appears to be due to disruption of normal hemostasis by the presence in plasma of circulating abnormal factor X. Factor X Stockton is the first naturally occurring substitution at the active site Asp of a serine protease and underscores the importance of this amino acid residue in factor Xa coagulant activity.