Departments of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
J Thromb Haemost. 2013 Sep;11(9):1751-9. doi: 10.1111/jth.12334.
Glycoprotein VI (GPVI), 60-65 kDa, is a major collagen receptor on platelet membranes involved in adhesive and signaling responses. Mice lacking GPVI have impaired platelet response to collagen and defective primary adhesion and subsequent thrombus formation. Complete or partial deficiency of GPVI in humans is a rare condition presenting as a mild bleeding disorder. The defect in most of the reported patients is acquired and associated with other diseases. To date, only two patients have been characterized at the molecular level who carry different compound heterozygous mutations in the GP6 gene.
To report four unrelated patients from non-consanguineous families who presented with mucocutaneous bleeding. They had absent platelet aggregation and (14) C-5-HT secretion with collagen, convulxin and collagen-related peptide.
Flow cytometry and immunofluorescence-confocal microscopy showed an absence of GPVI in non-permeabilized platelets. All the patients had an adenine insertion in exon 6 (c.711_712insA), changing the reading frame and generating a premature 'stop codon' in site 242 of the protein. The mutation predicts the synthesis of the truncated protein before the trans-membrane domain, corresponding to a band of ≈49 kDa observed in western blots and in permeabilized platelets by immunofluorescence. Platelet mRNA from all the patients was sequenced and contained the corresponding adenine insertion. Heterozygous relatives had no pathological bleeding, normal response to collagen and convulxin and intermediate membrane expression of GPVI.
The identification of four unrelated homozygous patients with an identical defect suggests that inherited GPVI deficiency is more frequent than previously suspected, at least in Chile.
糖蛋白 VI（GPVI），60-65 kDa，是血小板膜上的主要胶原受体，参与黏附和信号转导反应。缺乏 GPVI 的小鼠对胶原的血小板反应受损，且原发性黏附和随后的血栓形成有缺陷。人类中 GPVI 的完全或部分缺失是一种罕见的疾病，表现为轻度出血障碍。大多数报道的患者的缺陷是获得性的，与其他疾病相关。迄今为止，只有两名患者在分子水平上得到了特征描述，他们在 GP6 基因中携带不同的复合杂合突变。
报告 4 名来自非近亲家庭的无关患者，他们表现为黏膜皮肤出血。他们的血小板聚集和（14）C-5-HT 分泌与胶原、凝血酶原酶和胶原相关肽缺失。
流式细胞术和免疫荧光共聚焦显微镜显示非透化血小板中缺乏 GPVI。所有患者在第 6 外显子（c.711_712insA）中均有腺嘌呤插入，改变了阅读框，并在蛋白的 242 位产生了一个过早的“终止密码子”。该突变预测在跨膜结构域之前合成截断蛋白，在 Western blot 和透化血小板的免疫荧光中观察到约 49 kDa 的条带。所有患者的血小板 mRNA 均进行了测序，并包含相应的腺嘌呤插入。杂合子亲属无病理性出血，对胶原和凝血酶原酶反应正常，GPVI 膜表达中等。
4 名无关的纯合子患者具有相同的缺陷，这表明遗传性 GPVI 缺乏症比以前认为的更为常见，至少在智利是这样。
