A NEW VARIANT OF GLANZMANN THROMBASTHENIA (STRASBOURG-I) - PLATELETS WITH FUNCTIONALLY DEFECTIVE GLYCOPROTEIN IIB-IIIA COMPLEXES AND A GLYCOPROTEIN-IIIA (214)ARG-](214)TRP MUTATION
A NEW VARIANT OF GLANZMANN THROMBASTHENIA (STRASBOURG-I) - PLATELETS WITH FUNCTIONALLY DEFECTIVE GLYCOPROTEIN IIB-IIIA COMPLEXES AND A GLYCOPROTEIN-IIIA (214)ARG-](214)TRP MUTATION
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DOI：
10.1172/jci115808
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发表时间：
1992-06-01
影响因子：
15.9
通讯作者：
CAZENAVE, JP
中科院分区：
文献类型：
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作者：
LANZA, F;STIERLE, A;CAZENAVE, JP
我们描述了一种新的变异格兰兹曼血栓症（变异Strasbourg I）。患者（ms）表现为ADP、凝血酶和胶原蛋白缺乏血小板聚集，凝块收缩减少。血小板纤维蛋白原约为正常水平的20%。adp刺激的血小板结合可显著降低可溶性纤维蛋白原的含量，血小板与表面结合的纤维蛋白原的粘附存在缺陷。通过SDS-PAGE、交叉免疫电泳和抗体结合，检测到血小板纤维蛋白原受体糖蛋白（GP） IIb- iiia （α (IIb) β -3）复合物的正常量和亚正常量。然而，配合物在室温下对EDTA解离异常敏感。此外，流式细胞术显示，刺激后血小板不能结合活化依赖性单克隆抗体PAC-1。相比之下，含有RGD的肽诱导抗配体诱导的结合位点抗体D3GP3的显著结合，表明患者的GPIIb-IIIa复合物上存在功能性RGD结合域。对选定患者的GPIIIa外显子和患者的血小板GPIIb和GPIIIa mrna进行聚合酶链反应扩增后进行序列分析。GPIIIa的外显子D （iv）发生点突变（C到T），导致214Arg到214Trp氨基酸取代。这一缺陷遗传自具有相同突变的杂合子父母。这种替换指向GPIIIa区域的一个必需氨基酸，该氨基酸参与纤维蛋白原的结合并影响GPIIb-IIIa复合物的Ca2+依赖性稳定性。
We describe a new variant of Glanzmann's thrombasthenia (variant Strasbourg I). The patient (M.S.) showed an absence of platelet aggregation to ADP, thrombin, and collagen, and a decreased clot retraction. Platelet fibrinogen was approximately 20% of normal levels. ADP-stimulated platelets bound markedly reduced amounts of soluble fibrinogen and platelet adhesion to surface-bound fibrinogen was defective. Normal to subnormal amounts of glycoprotein (GP) IIb-IIIa (alpha(IIb)beta-3) complexes, the platelet fibrinogen receptor, were revealed by SDS-PAGE, crossed immunoelectrophoresis, and antibody binding. However, the complexes were unusually sensitive to dissociation with EDTA at room temperature. Furthermore, flow cytometry showed that the platelets failed to bind the activation-dependent monoclonal antibody, PAC-1, after stimulation. In contrast, an RGDS-containing peptide induced significant binding of the anti-ligand-induced binding site antibody, D3GP3, suggesting the presence of a functional RGD binding domain on the patient's GPIIb-IIIa complex. Sequence analysis was performed after polymerase chain reaction amplification of selected patient's GPIIIa exons, and of the patient's platelet GPIIb and GPIIIa mRNAs. A Point mutation (C to T) was localized in exon D (iv) of GPIIIa that resulted in an 214Arg to 214Trp amino acid substitution. The defect has been inherited from the parents who are heterozygous for the same mutation. This substitution points to an essential amino acid in a region of GPIIIa involved in the binding of fibrinogen and influencing the Ca2+-dependent stability of the GPIIb-IIIa complex.