A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome
A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome
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DOI：
10.1182/blood-2004-05-2056
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发表时间：
2005-07-15
期刊：
影响因子：
20.3
通讯作者：
Higgins, CF
中科院分区：
文献类型：
--
作者：
Albrecht, C;McVey, JH;Higgins, CF
斯科特综合征（SS）是一种出血性疾病，其特征是磷脂酰丝氨酸（PS）未能暴露于血小板质膜的外叶。由于三磷酸腺苷（ATP）结合盒转运蛋白A1（ABCA1）涉及PS的外表面易位，我们评估了其在SS患者的病理生理学中的作用。与对照组相比，在患者的白细胞中发现ABCA 1 mRNA水平显著降低。SS患者是一种新的错义突变c.6064G>A（ABCA 1 R19250）的杂合子，未受影响的家庭成员和对照组中不存在。突变型和野生型等位基因的mRNA表达均降低，ABCA1基因或其近端启动子中未发现导致这种现象的突变，这表明反式作用调节基因中的假定第二突变也可能参与该患者的疾病。体外表达研究显示ABCA1 R1925Q向质膜的运输受损。SS淋巴细胞中野生型ABCA 1的过表达补充了细胞表面的Ca 2+依赖性PS暴露。这些数据确定了ABCA1的突变，导致我们的SS患者PS易位表型缺陷。
Scott syndrome (SS) is a bleeding disorder characterized by a failure to expose phosphatidylserine (PS) to the outer leaflet of the platelet plasma membrane. Because the adenosine triphosphate (ATP)binding cassette transporter A1 (ABCA1) is implicated in the exofacial translocation of PS, we assessed its role in the pathophysiology of a patient with SS. Substantially reduced levels of ABCA1 mRNA were found in the patient's leukocytes, compared with controls. The SS patient was heterozygous for a novel missense mutation c.6064G>A (ABCA1 R19250), absent from unaffected family members and controls. Both mutant and wild-type alleles were reduced in mRNA expression, and no causative mutation for this phenomenon was identified in the ABCA1 gene or its proximal promoter, suggesting a putative second mutation in a trans-acting regulatory gene may also be involved in the disorder in this patient. In vitro expression studies showed impaired trafficking of ABCA1 R1925Q to the plasma membrane. Overexpression of wild-type ABCA1 in SS lymphocytes complemented the Ca2+-dependent PS exposure at the cell surface. These data identify a mutation in ABCA1 that contributes to the defective PS translocation phenotype in our patient with SS.