Chowdhury V, Mille B, Olds R J, Lane D A, Watton J, Barrowcliffe T W, Pabinger I, Woodcock B E, Thein S L
Institute of Molecular Medicine, Oxford, U.K.
Br J Haematol. 1995 Mar;89(3):602-9. doi: 10.1111/j.1365-2141.1995.tb08369.x.
We report the characterization of three variant antithrombins with reduced heparin binding as the primary abnormality. Two of these variants, antithrombin Southport (Leu 99 to Val, 2759 C to G) and antithrombin Vienna (Gln 118 to Pro, 5349 A to C) were novel, whereas the third, Pro 41 to Leu, has been previously described as antithrombin Basel. All three variants exhibited reduced binding for heparin on crossed immunoelectrophoresis and in a quantitative monoclonal antibody-based assay. The mutations were characterized by direct sequence analysis of enzymatically amplified genomic DNA and all affected individuals were heterozygous for the mutations. These three mutations do not occur at the sites of the basic amino acids directly involved in heparin binding nor do they result in a change in charge of the affected residue. It seems probable that they reduce heparin affinity either by perturbing the initial contact site involved in the heparin-binding domain (Arg 47, Arg 129 and possibly Arg 24), or by preventing the subsequent heparin-induced conformational change.
我们报告了三种主要异常为肝素结合能力降低的变异抗凝血酶的特征。其中两种变异体，抗凝血酶Southport（Leu 99突变为Val，2759 C突变为G）和抗凝血酶Vienna（Gln 118突变为Pro，5349 A突变为C）是新发现的，而第三种，Pro 41突变为Leu，先前已被描述为抗凝血酶巴塞尔型。在交叉免疫电泳和基于定量单克隆抗体的检测中，这三种变异体对肝素的结合能力均降低。通过对酶促扩增的基因组DNA进行直接序列分析对这些突变进行了表征，所有受影响个体均为这些突变的杂合子。这三种突变并非发生在直接参与肝素结合的碱性氨基酸位点，也未导致受影响残基的电荷变化。它们似乎很可能是通过干扰肝素结合结构域中涉及的初始接触位点（Arg 47、Arg 129以及可能的Arg 24），或通过阻止随后肝素诱导的构象变化来降低肝素亲和力。
