CHARACTERIZATION OF THE WILSON-DISEASE GENE ENCODING A P-TYPE COPPER TRANSPORTING ATPASE - GENOMIC ORGANIZATION, ALTERNATIVE SPLICING, AND STRUCTURE/FUNCTION PREDICTIONS
CHARACTERIZATION OF THE WILSON-DISEASE GENE ENCODING A P-TYPE COPPER TRANSPORTING ATPASE - GENOMIC ORGANIZATION, ALTERNATIVE SPLICING, AND STRUCTURE/FUNCTION PREDICTIONS
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DOI：
10.1093/hmg/3.9.1647
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发表时间：
1994-09-01
影响因子：
3.5
通讯作者：
GILLIAM, TC
中科院分区：
文献类型：
--
作者：
PETRUKHIN, K;LUTSENKO, S;GILLIAM, TC
Wilson病是一种常染色体隐性遗传的铜转运障碍。铜的毒性积聚主要在肝脏中，随后在脑、肾、角膜和其他组织中形成疾病症状。WD的候选基因（ATP 7 B）最近已经基于明显的疾病特异性突变和与负责另一种人类铜转运障碍X连锁门克斯病（MNK）的基因（ATP 7A）的惊人的氨基酸同源性而被鉴定。WD和MNK基因的克隆为研究人体铜稳态提供了第一个机会。本文对WD基因进行了初步分析，包括：WD基因5 '端的分离和鉴定、基因组限制性内切酶图谱的构建、全部21个外显子/内含子边界的鉴定、脑内广泛的选择性剪接的鉴定、WD和MNK蛋白的结构/功能特征的预测，以及WD和MNK蛋白在重金属转运P型ATP酶亚类中的独特性。并对六个金属结合域进行了比较分析。分析表明，WD和MNK蛋白属于一个子集的运输ATP酶的几个独特的功能，大概反映了他们的具体调控和功能。似乎选择性剪接的机制用于调节脑、肾、胎盘和可能的肝中产生的功能性WD蛋白的量。
Wilson disease is an autosomal recessive disorder of copper transport. Disease symptoms develop from the toxic build-up of copper primarily in the liver, and subsequently in the brain, kidney, cornea and other tissues. A candidate gene for WD (ATP7B) has recently been identified based upon apparent disease-specific mutations and a striking amino acid homology to the gene (ATP7A) responsible for another human copper transport disorder, X-linked Menkes disease (MNK). The cloning of WD and MNK genes provides the first opportunity to study copper homeostasis in humans. A preliminary analysis of the WD gene is presented which includes: isolation and characterization of the 5'-end of the gene; construction of a genomic restriction map; identification of all 21 exon/intron boundaries; characterization of extensive alternative splicing in brain; prediction of structure/function features of the WD and MNK proteins which are unique to the subset of heavy metal-transporting P-type ATPases; and comparative analysis of the six metal-binding domains. The analysis indicates that WD and MNK proteins belong to a subset of transporting ATPases with several unique features presumably reflecting their specific regulation and function. It appears that the mechanism of alternative splicing serves to regulate the amount of functional WD protein produced in brain, kidney, placenta, and possibly in liver.