3 NOVEL MUTATIONS OF ANTITHROMBIN INDUCING HIGH-MOLECULAR-MASS COMPOUNDS
3 NOVEL MUTATIONS OF ANTITHROMBIN INDUCING HIGH-MOLECULAR-MASS COMPOUNDS
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DOI：
10.1161/01.atv.14.12.1958
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发表时间：
1994-12-01
期刊：
影响因子：
--
通讯作者：
AIACH, M
中科院分区：
文献类型：
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作者：
EMMERICH, J;VIDAUD, D;AIACH, M
我们在血栓性并发症患者中发现了三种新的抗凝血酶（AT）基因突变：Cys 128 -> Tyr突变，外显子5 5'的插入序列4（IVS 4）14个核苷酸中的G -> A突变，以及外显子6 3'端的9 bp缺失，导致Arg 425后的短异常序列。后一种突变与两个复合杂合子兄弟中的Arg 47 -> His突变相关。这三种突变导致免疫印迹分析中少量高分子量的无活性分子在循环中表达。在还原条件下，这些变体分子具有正常的分子量，这使我们假设这些突变阻止了一个分子内二硫键的形成，并允许形成分子间二硫键。将来自携带Cys 128 --> Tyr突变的杂合患者和来自携带Arg 47 --> His突变和外显子6中9 bp缺失的复合杂合子的血浆通过肝素-琼脂糖柱。在这两种情况下，一个人口的高分子量AT分子没有结合亲和力和AT的活性，从一个人口的正常分子在第一个病人，连同人口的分子与肝素的结合亲和力降低，由于取代精氨酸47，在复合杂合子。这三种突变的共同特征是它们导致部分错误折叠并与其他血浆组分形成分子间二硫键，诱导观察到的多效性表型。
We have identified three novel mutations of the antithrombin (AT) gene in patients with thrombotic complications: a Cys 128 --> Tyr mutation, a G --> A mutation in the intervening sequence 4 (IVS4) 14 nucleotide 5' to exon 5, and a 9 bp deletion in the 3' end of exon 6 resulting in a short aberrant sequence after Arg 425. The latter mutation was associated with an Arg 47 --> His mutation in two compound heterozygous brothers. These three mutations led to the expression in the circulation of small amounts of inactive molecules with a high molecular mass in immunoblot analysis. In reducing conditions, these variant molecules had a normal molecular mass, which led us to postulate that these mutations prevent the formation of one intramolecular disulfide bond and allow the formation of intermolecular disulfide bonds. Plasma from a heterozygous patient bearing the Cys 128 --> Tyr mutation and from a compound heterozygote bearing the Arg 47 --> His mutation and the 9 bp deletion in exon 6 were passed through a heparin-sepharose column. In both cases a population of high-molecular-weight AT molecules with no binding affinity and no AT activity was separated from a population of normal molecules in the first patient, together with a population of molecules with a reduced binding affinity for heparin due to the substitution of Arg 47, in the compound heterozygote. The common feature of these three mutations is that they lead to partial misfolding and to the formation of intermolecular disulfide bonds with other plasma components, inducing the pleiotropic phenotypes observed.