Novel heterozygous missense mutation in the platelet glycoprotein Ibβ gene associated with isolated giant platelet disorder
Novel heterozygous missense mutation in the platelet glycoprotein Ibβ gene associated with isolated giant platelet disorder
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DOI：
10.1002/ajh.10000
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发表时间：
2001-12-01
影响因子：
12.8
通讯作者：
Saito, H
中科院分区：
文献类型：
--
作者：
Kunishima, S;Naoe, T;Saito, H
糖蛋白（GP）Ib/IX/V复合物作为血管性血友病因子（vWF）的血小板受体，在原发性止血中发挥重要作用。最近的研究表明，由GPIb/IX复合物亚基突变引起的表型跨越了很宽的范围;从正常表型到孤立的巨血小板疾病（GPD），再到全面的出血性疾病，Bernard-Soulier综合征（BSS）。我们在这里描述了一个新的错义突变的GPIb β基因与孤立的GPD。在患者的血小板中，GPIb/IX复合物的表达水平与GPIb/IIIa复合物的表达水平相比适度降低，而后者的表达水平高于正常对照。免疫印迹分析显示GPIb α、GPIb β和GPIX的电泳迁移率正常。然而，GPIb β的量约为正常值的66%。DNA测序分析揭示了GPIb β基因中一种新的杂合错义突变，该突变在残基17处将Arg（CGC）转化为Cys（TGC）。瞬时转染研究表明，在转染的293 T细胞中未检测到突变GPIb β蛋白。这些发现表明，异常GPIb β的无效表达导致复合物的表达降低，并导致患者的GPD表型，并表明突变的纯合性可能导致体内BSS表型。(C)2001 Wiley-Liss，Inc.
The glycoprotein (GP) Ib/IX/V complex plays an important role in primary hemostasis, serving as the platelet receptor for von Willebrand factor (vWF). Recent studies have shown that the phenotype caused by mutations in the subunits of the GPIb/IX complex spans a wide spectrum; from the normal phenotype, to isolated giant platelet disorders (GPD), and to the full-blown bleeding disorder, the Bernard-Soulier syndrome (BSS). We characterize here a novel missense mutation of the GPIb beta gene associated with isolated GPD. In the patient's platelets, the expression level of the GPIb/IX complex was moderately reduced compared with that of the GPIIb/IIIa complex, whereas the latter was expressed at higher levels than in a normal control. Immunoblot analysis showed normal electrophoretic mobility of GPIb alpha, GPIb beta, and GPIX. However, the amount of GPIb beta was approximately 66% of the normal value. DNA sequencing analysis revealed a novel heterozygous missense mutation in the GPIb beta gene that converts Arg (CGC) to Cys (TGC) at residue 17. Transient transfection studies demonstrated that mutant GPIb beta protein was not detected in transfected 293T cells. These findings indicated that null expression of the abnormal GPIb beta causes decreased expression of the complex and results in the GPD phenotype in the patient, and suggested that homozygosity of the mutation may lead to a BSS phenotype in vivo. (C) 2001 Wiley-Liss, Inc.