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Molecular pathology of novel two variants of antithrombin III

抗凝血酶 III 的两种新型变体的分子病理学

基本信息

批准号：
04671529
负责人：
OKAJIMA Kenji
金额：
$ 1.34万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671529/
关键词：
Antithrombin III Congenital prethrombotic state Thrombosis Heparin Gene analysis

项目摘要

To know the molecular mechanism by which antitrhombin III (AT III) regulates the coagulation cascade, we analyzed the fnction and structure of two novel variant antithrombin III molecules found in patients with thrombosis. A variant AT III found in the first case bound heaprin normally, but it did not inhibit thrombin as the normal AT III.Analysis of the whole base sequence of the propositus' AT III gene revealed a Arg393-His conversion and that the propsitus was a heterozygote for the abnormality. Purified abnormal AT III did not inhibit thrombin and the affinity for heparin was increased, suggesting that Arg393-His conversion might affect the affnity for heparin. A variant AT III found in the second case did not bind heaprin, but it inhibited thrombin normally. Whole base sequence analysis of the AT III gene disclosed a Ser116-Pro conversion. Alle-specific oligonucleotide hybridization demonstrated that the propositus was a heterozygote and the same mutation was found in his father's AT III gene. Such a substitution was first demonstrated among variants AT III so far reported. Although thrombosis was not associated with a heterozygous state for heparin binding defect in most cases, the propositus suffered from recurrent arterial thrombosis probably due to his heavy smoking habit. Thus, a heterozygous state for heparin binding defect would lead to a predisposition to thrombosis when associated with risk factors for thrombosis.

为了了解抗凝血酶III （AT III）调控凝血级联的分子机制，我们分析了在血栓患者中发现的两种新型变异抗凝血酶III分子的功能和结构。在第一个病例中发现的atiii变体正常结合肝素，但它不像正常的atiii那样抑制凝血酶。对拟子AT III基因全碱基序列的分析表明，该拟子发生Arg393-His转换，为杂合子。纯化的异常AT III不抑制凝血酶，对肝素的亲和力增强，提示Arg393-His转化可能影响肝素的亲和力。在第二例中发现的atiii变体不与肝素结合，但它能正常抑制凝血酶。atiii基因的全碱基序列分析揭示了Ser116-Pro转换。等位基因特异性寡核苷酸杂交表明，该子为杂合子，在其父亲的AT III基因中发现了相同的突变。这种替代首先在atiii变体中得到证实。虽然血栓形成在大多数情况下与肝素结合缺陷的杂合状态无关，但可能由于其重度吸烟习惯，其动脉血栓复发。因此，肝素结合缺陷的杂合状态与血栓形成的危险因素相关时，会导致血栓形成的易感性。