Cloning and characterization of human ORNT2: a second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder
Cloning and characterization of human ORNT2: a second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder
复制标题
DOI：
10.1016/s1096-7192(03)00105-7
复制
发表时间：
2003-08-01
影响因子：
3.8
通讯作者：
Kong, J
中科院分区：
文献类型：
--
作者：
Camacho, JA;Rioseco-Camacho, N;Kong, J
我们最近的特点是线粒体鸟氨酸转运蛋白（ORNT 1），基因缺陷的高鸟氨酸血症-高氨血症-高瓜氨酸尿症（HHH）综合征，尿素循环障碍。尽管在10个具有ORNT 1-F188 Delta等位基因的法裔加拿大先证者中ORNT 1的明显功能性消融，但与其他尿素循环障碍如鸟氨酸转氨甲酰酶缺乏症患者相比，这些患者受到轻度影响。考虑到线粒体内膜对溶质是不可渗透的，我们假设其他未鉴定的载体与ORNT 1具有一定程度的功能冗余。使用哺乳动物和真菌线粒体鸟氨酸转运蛋白的保守序列，我们筛选了表达序列标签数据库中属于ORNT亚家族的其他转运蛋白。在这里，我们确定了一个新的无内含子基因，ORNT 2。位于5号染色体上ORNT 2的基因产物与ORNT 1具有88%的同一性，靶向线粒体，并在人肝脏、胰腺、肾脏和来自对照和HHH患者的培养成纤维细胞中表达。当ORNT 2在来自HHH患者的培养的成纤维细胞中瞬时过表达时，它挽救了这些细胞中缺乏的鸟氨酸代谢。我们的研究结果表明，ORNT 2可能部分负责HHH患者继发于基因冗余效应的温和表型。我们认为ORNT 2是由反转录转座事件引起的。据我们所知，这是第一个报告的功能性逆转录酶（ORNT 2），可以拯救疾病的表型的基因，它所产生的，ORNT 1。因此，ORNT 2最终可能成为基于药理学的方法来纠正尿素循环障碍的候选者。(C)2003 Elsevier Science（美国）。All rights reserved.
We recently characterized the mitochondrial ornithine transporter (ORNT1), the gene defective in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, a urea cycle disorder. Despite the apparent functional ablation of ORNT1 in 10 French-Canadian probands with the ORNT1-F188Delta allele, these patients are mildly affected when compared to patients with other urea cycle disorders such as deficiency of ornithine transcarbamylase. Given that the inner mitochondrial membrane is impermeable to Solutes, we hypothesize that other unidentified carriers have some degree of functional redundancy with ORNT1 Using conserved sequences of mammalian and fungal mitochondrial ornithine transporters, we screened the Expressed Sequence Tag database for additional transporters belonging to the ORNT subfamily. Here we identify a new intronless gene, ORNT2. located on chromosome 5. The gene product of ORNT2 is 88%,, identical to ORNT1, targets to the mitochondria and is expressed in human liver, pancreas, kidney, and cultured fibroblasts from control and HHH patients. When ORNT2 is overexpressed transiently in cultured fibroblasts from HHH patients, it rescues the deficient ornithine metabolism in these cells. Our results suggest that ORNT2 may in part be responsible for the milder phenotype in HHH patients secondary to a gene redundancy effect. We believe ORNT2 arose from a retrotransposition event. To our knowledge, this is the first report of a functional retroposon (ORNT2) that can rescue the disease phenotype of the gene it arose from, ORNT1. As such, ORNT2 may eventually become a candidate for pharmacological-based approaches to correct a urea cycle disorder. (C) 2003 Elsevier Science (USA). All rights reserved.