Naturally occurring mutations in glycoprotein Ibα that result in defective ligand binding and synthesis of a truncated protein
Naturally occurring mutations in glycoprotein Ibα that result in defective ligand binding and synthesis of a truncated protein
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DOI：
10.1182/blood.v92.1.175.413a36_175_183
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发表时间：
1998-07-01
期刊：
影响因子：
20.3
通讯作者：
Montgomery, RR
中科院分区：
文献类型：
--
作者：
Kenny, D;Jónsson, OG;Montgomery, RR
血小板GPIb-V-IX复合物是介导血小板粘附的血管性血友病因子（vWF）的初始结合的受体，该复合物由四种跨膜糖蛋白（GP）组成：GPIb α、GPIb β、GPIX和GPV，Bernard-Soulier综合征由血小板膜GPIb-V-IX复合物的一种或多种组分的定性或定量缺陷引起，我们描述了一种新的Bernard-Soulier综合征变异的分子基础，在两个兄弟姐妹中，GPIb α在血小板表面未检测到，但在血浆中以可溶性形式存在。DNA序列分析表明，患病个体为两个突变的复合杂合子。一个是从母体等位基因遗传的，GPIb α中的T-777 --> C点突变，在第二个富含亮氨酸的重复序列内转换Cys（65）--> Arg，另一个是色氨酸密码子（TGG）的单核苷酸取代（G（2078）--> A），导致GPIb α跨膜区内残基498处的无义密码子（TGA），Bernard-Soulier表型在为这两种突变的复合杂合子的兄弟姐妹中观察到。尽管在患者的血小板表面上未检测到GPIb a，但可溶性GPIb a可从血浆中免疫沉淀。当将编码含有Cys（65）-> Arg突变的GPIb α的质粒瞬时转染到稳定表达GP β-IX复合物（CHO β IX）的中国仓鼠卵巢（CHO）细胞中时，GPIb α的表达与野生型（WT）GPIb α相似，但不结合vWF。当编码含有Trp（498）-->终止子的GPIb α的质粒瞬时转染到CHO β IX中时，与WT GPIb α相比，几乎检测不到GPIb α的表面表达。因此，这种新描述的复合杂合缺陷通过非功能性蛋白质和截短蛋白质的合成的组合产生Bernard-Soulier综合征，截短蛋白质未能插入血小板膜并在血浆中循环。(C)1998年，美国血液学会。
The platelet GPIb-V-IX complex is the receptor for the initial binding of von Willebrand factor (vWF) mediating platelet adhesion, The complex is composed of four membrane-spanning glycoproteins (GP): GPIb alpha, GPIb beta, GPIX, and GPV, Bernard-Soulier syndrome results from a qualitative or quantitative defect in one or more components of the platelet membrane GPIb-V-IX complex, We describe the molecular basis of a novel Bernard-Soulier syndrome variant in two siblings in whom GPIb alpha was not detected on the platelet surface but that was present in a soluble form in plasma. DNA sequence analysis showed that the affected individuals were compound heterozygotes for two mutations. One, inherited from a maternal allele, a T-777 --> C point mutation in GPIb alpha converting Cys(65) --> Arg within the second leucine rich repeat, the other, a single nucleotide substitution (G(2078) --> A) for the tryptophan codon (TGG) causing a nonsense codon (TGA) at residue 498 within the transmembrane region of GPIb alpha, inherited from a mutant paternal allele, The Bernard-Soulier phenotype was observed in siblings who were compound heterozygotes for these two mutations, Although GPlba was not detected on the surface of the patient's platelets, soluble GPIb alpha could be immunoprecipitated from plasma. When plasmids encoding GPIb alpha containing the Cys(65) --> Arg mutation were transiently transfected into Chinese hamster ovary (CHO) cells stably expressing the GP beta-IX complex (CHO beta IX), the expression of GPIb alpha was similar to the wild-type (WT) GPIb alpha, but did not bind vWF. When plasmids encoding GPIb alpha containing the Trp(498) --> stop were transiently transfected into CHO beta IX, the surface expression of GPIb alpha was barely detectable compared with the WT GPIb alpha. Thus, this newly described compound heterozygous defect produces Bernard-Soulier syndrome by a combination of synthesis of a nonfunctional protein and of a truncated protein that fails to insert into the platelet membrane and is found circulating in plasma. (C) 1998 by The American Society of Hematology.