The wide spectrum of multidrug resistance 3 deficiency: From neonatal cholestasis to cirrhosis of adulthood
The wide spectrum of multidrug resistance 3 deficiency: From neonatal cholestasis to cirrhosis of adulthood
复制标题
DOI：
10.1053/gast.2001.23984
复制
发表时间：
2001-05-01
期刊：
影响因子：
29.4
通讯作者：
Elferink, RPJO
中科院分区：
文献类型：
--
作者：
Jacquemin, E;de Vree, JML;Elferink, RPJO
背景和目标：我们已经详细说明了进行性家族性肝内胆汁淤积症3型的特点，并在31例患者中研究了这种表型是否存在多药耐药3基因（MDR3）缺陷。研究方法：结果：肝组织学显示胆汁性肝硬化，胆汁树通畅。发病年龄从新生儿期到成年早期不等。序列分析显示17例患者中有16种不同的突变。12例患者在两个等位基因上鉴定出突变，5例仅在1个等位基因上鉴定出突变，4个突变导致移码，2个是无义突变，10个是错义突变，在5例患者中发现可能代表多态性的额外错义突变，MDR3突变与异常MDRB小管染色和低比例胆汁磷脂相关，在患者或父母中发现胆结石或妊娠期胆汁淤积症。错义突变儿童的疾病不太严重，熊去氧胆酸治疗的有益效果更常见。结论：至少有三分之一的进行性家族性肝内胆汁淤积症3型患者存在MDR3基因缺陷，这种基因缺陷在成人肝脏疾病中也应考虑。
Background & Aims: We have specified the features of progressive familial intrahepatic cholestasis type 3 and investigated in 31 patients whether a defect of the multidrug resistance 3 gene (MDR3) underlies this phenotype. Methods: MDR3 sequencing liver MDR3 immunohistochemistry, and biliary phospholipid dosage were performed, Results: Liver histology showed a pattern of biliary cirrhosis with patency of the biliary tree. Age at presentation ranged from the neonatal period to early adulthood. Sequence analysis revealed 16 different mutations in 17 patients. Mutations were identified on both alleles in 12 patients and only on 1 allele in 5, Four mutations lead to a frame shift, 2 are nonsense, and 10 are missense, An additional missense mutation probably representing a polymorphism was found in 5 patients, MDR3 mutations were associated with abnormal MDRB canalicular staining and a low proportion of biliary phospholipids, Gallstones or episodes of cholestasis of pregnancy were found in patients or parents. Children with missense mutations had a less severe disease and more often a beneficial effect of ursodeoxycholic acid therapy. Conclusions: At least one third of the patients with a progressive familial intrahepatic cholestasis type 3 phenotype have a proven defect of MDR3, This gene defect should also be considered in adult liver diseases.