Ware J, Russell S, Ruggeri Z M
Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2803-8. doi: 10.1073/pnas.050582097.
The human Bernard-Soulier syndrome is an autosomal recessive disorder of platelet dysfunction presenting with mild thrombocytopenia, circulating "giant" platelets and a bleeding phenotype. The bleeding in patients with the Bernard-Soulier syndrome is disproportionately more severe than suggested by the reduced platelet count and is explained by a defect in primary hemostasis owing to the absence of the platelet glycoprotein (GP) Ib-IX-V membrane receptor. However, the molecular basis for the giant platelet phenotype and thrombocytopenia have remained unresolved but assumed to be linked to an absent receptor complex. We have disrupted the gene encoding the alpha-subunit of mouse GP Ib-IX-V (GP Ibalpha) and describe a murine model recapitulating the hallmark characteristics of the human Bernard-Soulier syndrome. The results demonstrate a direct link between expression of a GP Ib-IX-V complex and normal megakaryocytopoiesis and platelet morphogenesis. Moreover, using transgenic technology the murine Bernard-Soulier phenotype was rescued by expression of a human GP Ibalpha subunit on the surface of circulating mouse platelets. Thus, an in vivo model is defined for analysis of the human GP Ib-IX-V receptor and its role in the processes performed exclusively by megakaryocytes and platelets.
人类伯纳德-索利尔综合征是一种常染色体隐性血小板功能障碍疾病，表现为轻度血小板减少、循环“巨型”血小板和出血表型。伯纳德-索利尔综合征患者的出血比血小板计数降低所提示的更为严重，这是由于血小板糖蛋白（GP）Ib-IX-V膜受体缺失导致初级止血缺陷所致。然而，巨型血小板表型和血小板减少的分子基础仍未解决，但推测与受体复合物缺失有关。我们破坏了编码小鼠GP Ib-IX-Vα亚基（GP Ibalpha）的基因，并描述了一种重现人类伯纳德-索利尔综合征标志性特征的小鼠模型。结果表明，GP Ib-IX-V复合物的表达与正常巨核细胞生成和血小板形态发生之间存在直接联系。此外，利用转基因技术，通过在循环小鼠血小板表面表达人GP Ibalpha亚基，挽救了小鼠的伯纳德-索利尔表型。因此，定义了一种体内模型，用于分析人GP Ib-IX-V受体及其在巨核细胞和血小板特有的过程中的作用。
