Translational Read-through of a Nonsense Mutation in ATP7A Impacts Treatment Outcome in Menkes Disease
Translational Read-through of a Nonsense Mutation in ATP7A Impacts Treatment Outcome in Menkes Disease
复制标题
DOI：
10.1002/ana.21576
复制
发表时间：
2009-01-01
影响因子：
11.2
通讯作者：
Kaneski, Christine R.
中科院分区：
文献类型：
--
作者：
Kaler, Stephen G.;Tang, Jingrong;Kaneski, Christine R.
当基因信使 RNA 转录本中的终止密码子进入核糖体 A 位点时，蛋白质翻译结束。产生过早终止密码子的突变（无义突变）通常会导致翻译过早终止。另一种结果，即通读翻译（或无义抑制），在原核、病毒和酵母基因中众所周知，但除了药理学操作外，在人类中尚未得到明确记录。在这里，我们识别并表征了人类铜转运基因 ATP7A 中无义突变 (R201X) 的本机通读。使用来自经典门克斯病患者的培养成纤维细胞进行的蛋白质印迹、体外表达分析、免疫组织化学和酵母互补测定均表明存在少量天然 ATP7A(R201X)，通读并与早期铜治疗的显着临床反应相关。
Protein translation ends when a stop codon in a gene's messenger RNA transcript enters the ribosomal A site. Mutations that create premature stop codons (nonsense mutations) typically cause premature translation termination. An alternative outcome, read-through translation (or nonsense suppression), is well known in prokaryotic, viral, and yeast genes but has not been clearly documented in humans except in the context of pharmacological manipulations. Here, we identify and characterize native read-through of a nonsense mutation (R201X) in the human copper transport gene, ATP7A. Western blotting, in vitro expression analyses, immunohistochemistry, and yeast complementation assays using cultured fibroblasts from a classic Menkes disease patient all indicated small amounts of native ATP7A(R201X), read-through and were associated with a dramatic clinical response to early copper treatment.