Nonsense mutation in the glycoprotein Ib alpha coding sequence associated with Bernard-Soulier syndrome.
Nonsense mutation in the glycoprotein Ib alpha coding sequence associated with Bernard-Soulier syndrome.
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与 Bernard-Soulier 综合征相关的糖蛋白 Ib α 编码序列中的无义突变。
DOI：
10.1073/pnas.87.5.2026
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发表时间：
1990
影响因子：
11.1
通讯作者：
Ruggeri,ZM
中科院分区：
文献类型：
--
作者：
Ware,J;Russell,SR;Vicente,V;Scharf,RE;Tomer,A;McMillan,R;Ruggeri,ZM
三种不同的基因产物，即糖蛋白(GP)Ib和GP Ix的α和β链，构成了血小板膜GP Ib-Ix复合体，它是参与血小板黏附和聚集的von Willebrand因子和凝血酶的受体。GP Ib-IX复合体功能缺陷是一种罕见的先天性出血性疾病的标志，其发病机制仍未确定，即Bernard-Soulier综合征。我们在一位患者身上分析了这种疾病的分子基础，其中溶解的血小板免疫印迹显示没有正常的GP Ibα，但存在较小的免疫活性物种。在患者母亲和他四个孩子中的两个孩子的血小板中，也存在截短的多肽，以及正常的蛋白质。基因特征确定了将Trp-343密码子(TGG)改变为无意义密码子(TGA)的核苷酸转换。这种突变解释了较小的GP Ibα的起源，由于缺少羧基末端的一半序列，包括跨膜结构域，不能正确地插入血小板膜。在患者中发现了正常密码子和突变密码子，这表明他是一个复合杂合子，在另一个GP Ibα等位基因上存在未知的缺陷。无义突变和截短的GP Ibα多肽在3代中发现4个个体共分离，并与Bernard-Soulier综合征或携带者状态表型相关。这个家族的分子异常提供了证据，即GP Ibα合成缺陷改变了GP Ib-IX复合体的膜表达，可能是Bernard-Soulier综合征的原因。
Three distinct gene products, the alpha and beta chains of glycoprotein (GP) Ib and GP IX, constitute the platelet membrane GP Ib-IX complex, a receptor for von Willebrand factor and thrombin involved in platelet adhesion and aggregation. Defective function of the GP Ib-IX complex is the hallmark of a rare congenital bleeding disorder of still undefined pathogenesis, the Bernard-Soulier syndrome. We have analyzed the molecular basis of this disease in one patient in whom immunoblotting of solubilized platelets demonstrated absence of normal GP Ib alpha but presence of a smaller immunoreactive species. The truncated polypeptide was also present, along with normal protein, in platelets from the patient's mother and two of his four children. Genetic characterization identified a nucleotide transition changing the Trp-343 codon (TGG) to a nonsense codon (TGA). Such a mutation explains the origin of the smaller GP Ib alpha, which by lacking half of the sequence on the carboxyl-terminal side, including the trans-membrane domain, cannot be properly inserted in the platelet membrane. Both normal and mutant codons were found in the patient, suggesting that he is a compound heterozygote with a still unidentified defect in the other GP Ib alpha allele. Nonsense mutation and truncated GP Ib alpha polypeptide were found to cosegregate in four individuals through three generations and were associated with either Bernard-Soulier syndrome or carrier state phenotype. The molecular abnormality demonstrated in this family provides evidence that defective synthesis of GP Ib alpha alters the membrane expression of the GP Ib-IX complex and may be responsible for Bernard-Soulier syndrome.