Zhou Q, Sims P J, Wiedmer T
Blood Research Institute of The Blood Center of Southeastern Wisconsin, Milwaukee, WI, USA.
Blood. 1998 Sep 1;92(5):1707-12.
Scott syndrome is a rare inherited bleeding disorder in which platelets and other blood cells fail to promote normal assembly of the membrane-stabilized proteases of the plasma coagulation system. The defect in Scott blood cells is known to reflect inability to mobilize phosphatidylserine from inner plasma membrane leaflet to the cell surface in response to an elevation of Ca2+ at the endofacial surface. To gain insight into the molecular basis of this membrane defect, we examined the expression in Scott cells of plasma membrane proteins that have been implicated to participate in the accelerated transbilayer movement of plasma membrane PL. By both reverse transcriptase-polymerase chain reaction (RT-PCR) and functional assay, the level of expression of the multidrug resistance (MDR)1 and MDR3 P-glycoproteins in immortalized B-lymphoblast cell lines from the patient with Scott syndrome were indistinguishable from matched cell lines derived from normal controls. Whereas the plasma membrane of Scott cells are insensitive to activation of the plasma membrane PL scramblase pathway, it had been shown that PL scramblase protein isolated from detergent-solubilized Scott erythrocytes exhibits normal function when incorporated into proteoliposomes (Stout JG, Basse F, Luhm RA, Weiss HJ, Wiedmer T, Sims PJ: J Clin Invest 99:2232, 1997). Consistent with this finding in Scott erythrocytes, we found that Scott lymphoblasts expressed normal levels of PL scramblase mRNA and protein, and that the deduced sequence of PL scramblase in Scott cells is identical to that of normal controls. These data suggest that the defect in Scott syndrome is related either to aberrant posttranslational processing of the PL scramblase polypeptide or to a defect or deficiency in an unknown cofactor that is required for normal expression of plasma membrane PL scramblase function in situ, or alternatively, reflects the presence of a detergent-dissociable inhibitor of this pathway.
斯科特综合征是一种罕见的遗传性出血性疾病，其中血小板和其他血细胞无法促进血浆凝固系统中膜稳定蛋白酶的正常组装。已知斯科特血细胞中的缺陷反映了在膜内表面Ca2+升高时，无法将磷脂酰丝氨酸从质膜内小叶转运到细胞表面。为了深入了解这种膜缺陷的分子基础，我们检测了质膜蛋白在斯科特细胞中的表达情况，这些蛋白被认为参与了质膜磷脂的加速跨双层运动。通过逆转录聚合酶链反应（RT-PCR）和功能分析，来自斯科特综合征患者的永生化B淋巴母细胞系中多药耐药（MDR）1和MDR3 P-糖蛋白的表达水平与来自正常对照的匹配细胞系没有区别。虽然斯科特细胞的质膜对质膜磷脂翻转酶途径的激活不敏感，但已表明从去污剂溶解的斯科特红细胞中分离出的磷脂翻转酶蛋白在掺入蛋白脂质体时表现出正常功能（Stout JG，Basse F，Luhm RA，Weiss HJ，Wiedmer T，Sims PJ：J Clin Invest 99：2232，1997）。与斯科特红细胞中的这一发现一致，我们发现斯科特淋巴母细胞表达正常水平的磷脂翻转酶mRNA和蛋白，并且斯科特细胞中磷脂翻转酶的推导序列与正常对照相同。这些数据表明，斯科特综合征中的缺陷要么与磷脂翻转酶多肽的异常翻译后加工有关，要么与原位质膜磷脂翻转酶功能正常表达所需的未知辅因子的缺陷或缺乏有关，或者反映了该途径中一种可被去污剂解离的抑制剂的存在。
