Ware J, Russell S R, Vicente V, Scharf R E, Tomer A, McMillan R, Ruggeri Z M
Roon Research Center for Cardiovascular Disease and Thrombosis, Department of Molecular and Experimental Medicine, Research Institute of Scripps Clinic, La Jolla, CA 92037.
Proc Natl Acad Sci U S A. 1990 Mar;87(5):2026-30. doi: 10.1073/pnas.87.5.2026.
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.
三种不同的基因产物，即糖蛋白（GP）Ib的α链和β链以及GP IX，构成了血小板膜GP Ib-IX复合物，它是血管性血友病因子和凝血酶的受体，参与血小板的黏附和聚集。GP Ib-IX复合物功能缺陷是一种罕见的先天性出血性疾病（伯纳德-索利尔综合征）的标志，其发病机制尚不清楚。我们分析了一名患者该疾病的分子基础，在该患者中，对溶解的血小板进行免疫印迹显示缺乏正常的GP Ibα，但存在一种较小的免疫反应性物质。截短的多肽与正常蛋白一起，也存在于患者母亲和他四个孩子中的两个孩子的血小板中。基因特征鉴定发现一个核苷酸转换，将Trp-343密码子（TGG）变为无义密码子（TGA）。这种突变解释了较小的GP Ibα的来源，由于其羧基末端一侧的序列缺失一半，包括跨膜结构域，无法正确插入血小板膜中。在患者中发现了正常和突变密码子，这表明他是一个复合杂合子，另一个GP Ibα等位基因存在尚未确定的缺陷。在三代中的四个人中发现无义突变和截短的GP Ibα多肽共分离，并且与伯纳德-索利尔综合征或携带者状态表型相关。该家族中显示的分子异常提供了证据，表明GP Ibα的合成缺陷改变了GP Ib-IX复合物的膜表达，可能是伯纳德-索利尔综合征的病因。
