Phenotypic heterogeneity in the Gray platelet syndrome extends to the expression of TREM family member, TLT-1.
Phenotypic heterogeneity in the Gray platelet syndrome extends to the expression of TREM family member, TLT-1.
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DOI：
10.1160/th08-02-0067
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发表时间：
2008-07
影响因子：
6.7
通讯作者：
Washington AV
中科院分区：
文献类型：
--
作者：
Nurden AT;Nurden P;Bermejo E;Combrié R;McVicar DW;Washington AV
格雷血小板综合征 (GPS) 是一种罕见的遗传性疾病，与阻止 α 颗粒形成和成熟的未定义的分子异常有关。在这里，我们报告了对两名来自无关家庭的患者的研究，证实了该疾病的表型异质性。首先，我们使用免疫电子显微镜（I-EM）确认TREM样转录物-1（TLT-1）主要定位于正常血小板的α颗粒膜。然后，我们用透化血小板进行蛋白质印迹 (WB) 和流式细胞术，结果显示患者 1 的血小板中 TLT-1 选择性减少，此前患者 1 的血小板缺乏糖蛋白 (GP)VI (Nurden 等人，Blood 2004；104:107−114)。然而，TLT-1 和 GPVI 在患者 2 的血小板中均正常表达。在两名患者的血小板中均检测到了正常水平的 JAM-C 和 Claudin-5（也是免疫球蛋白受体家族的成员）。相反，患者 1 的 P-选择素显着下降，但患者 2 则没有。两种金属蛋白酶 MMP-2 和 MMP-9 正常存在。正如预测的那样，患者 1 的血小板在 I-EM 中几乎没有显示 TLT-1 标记，而在小囊泡结构和 P-选择素衬里的空泡或通道（可能是表面连接的小管系统的元件）中看到了残留的 Fg。我们的结果确定 TLT-1 是 GPS 患者血小板中可能靶向的一种糖蛋白，而至少三种膜糖蛋白的减少表明，一种未识别的蛋白水解活性可能有助于某些患有这种罕见疾病的患者的表型。
The Gray platelet syndrome (GPS) is a rare inherited disorder linked to undefined molecular abnormalities that prevent the formation and maturation of α-granules. Here, we report studies on two patients from unrelated families that confirm phenotypic heterogeneity in the disease. First we used immunoelectron microscopy (I-EM) to confirm that TREM-like transcript-1 (TLT-1) is mostly localized to α-granule membranes of normal platelets. Then we performed Western blotting (WB) and flow cytometry with permeabilized platelets to show that TLT-1 is selectively reduced in the platelets of patient 1, previously noted to be deficient in glycoprotein (GP)VI (Nurden et al, Blood 2004; 104:107−114). Yet both TLT-1 and GPVI were normally expressed in platelets of patient 2. Usual levels of JAM-C and claudin-5, also members of the immunoglobulin receptor family, were detected in platelets of both patients. In contrast, P-selectin was markedly decreased for patient 1 but not patient 2. Two metalloproteases, MMP-2 and MMP-9 were normally present. As predicted, platelets of patient 1 showed little labelling for TLT-1 in I-EM, whereas residual Fg was seen in small vesicular structures and P-selectin lining vacuoles or channels of what may be elements of the surface-connected canalicular system. Our results identify TLT-1 as a glycoprotein potentially targeted in platelets of GPS patients, while decreases in at least three membrane glycoproteins suggest that an unidentified proteolytic activity may contribute to the phenotype in some patients with this rare disease.