The histidin-loop is essential for transport activity of human MDR3. A novel mutation of MDR3 in a patient with progressive familial intrahepatic cholestasis type 3
The histidin-loop is essential for transport activity of human MDR3. A novel mutation of MDR3 in a patient with progressive familial intrahepatic cholestasis type 3
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DOI：
10.1016/j.gene.2012.06.029
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发表时间：
2012-09-10
期刊：
影响因子：
3.5
通讯作者：
Kubitz, Ralf
中科院分区：
文献类型：
--
作者：
Dzagania, Tamar;Engelmann, Guido;Kubitz, Ralf
实验证据表明，ABC 转运蛋白核苷酸结合域内的组氨酸环对于此类转运蛋白的有效功能至关重要。在这里，我们报告了第一例人类 ABC 转运蛋白组氨酸环（多药耐药蛋白 3 (MDR3)）发生突变的患者。该患者于 4 岁时就诊，多年来有严重瘙痒病史、血清 γ-谷氨酰转移酶和胆汁酸水平升高，提示诊断为 MDR3 缺陷导致的进行性家族性肝内胆汁淤积 3 型 (PFIC-3)。肝活检显示 MDR3 表达明显正常，然而，遗传分析显示患者的 ABCB4 基因 (c.3691C>T) 存在新的纯合突变。该突变与 MDR3 (p.H1231Y) 氨基酸位置 1231 处的组氨酸变为酪氨酸有关。如序列比对所示，该氨基酸对应于“H 环”的高度保守的组氨酸，其对于 ATP 水解至关重要，表明人 MDR3 的组氨酸 1231 具有重要作用。 (C) 2012 Elsevier B.V. 保留所有权利。
Experimental evidence has been provided that a histidine-loop within the nucleotide binding domain of ABC transporter is essential for efficient function of this class of transporter proteins. Here we report the first patient with a mutation of the putative histidine-loop of a human ABC transporter, the multi drug resistance protein 3 (MDR3). The patient presented at the age of 4 years with a history of severe pruritus, elevated serum gamma-glutamyltransferase and bile acid levels since several years suggesting the diagnosis of progressive familial intrahepatic cholestasis type 3 (PFIC-3) due to defects in MDR3. Liver biopsy demonstrated an apparently normal MDR3 expression, however, genetic analysis revealed a novel homozygous mutation in the ABCB4 gene (c.3691C>T) in the patient. This mutation was associated with a change of histidine to tyrosine at amino acid position 1231 of MDR3 (p.H1231Y). As shown by sequence alignment, this amino acid corresponds to the highly conserved histidine of the "H-loop", which is critical for ATP-hydrolysis, suggesting an essential role of histidine 1231 of human MDR3. (C) 2012 Elsevier B.V. All rights reserved.