INHERITED DISORDERS OF COPPER TRANSPORT

这项研究的长期目标是了解 微量金属运输，特别是因为它们涉及的发病机制， 遗传性疾病拟议的研究集中在门克斯病， 一种X染色体连锁的铜转运障碍， 斑点鼠我们最近发现门克斯基因编码一种铜- 转运ATP酶现在允许我们解决特定的生化和 铜转运的生理问题，并澄清分子 Menkes病和相关疾病的基础。这项工作应该有 对遗传预测、临床预后的建立、 并最终用于治疗策略的发展。的 具体的救济措施如下： L.目的：研究中国汉族人群铜转运ATP酶基因突变的特点， 典型Menkes病、轻度和非典型Menkes病患者， 和X连锁皮肤松弛拉克萨。这些突变的定义应该会引导我们 了解监管、结构或 转运蛋白的定位可以引起这种多样性， 临床表型 2.为了表征铜的小鼠同源物中的突变， 转运ATP酶基因的几个表型不同的等位基因 斑点鼠的照片这些突变的定义将增强我们的 了解人类疾病，并将提供研究模型 他们的病理生理学。 3.为了确定门克斯铜的亚细胞位置- 免疫细胞化学法检测ATP酶的表达。这项研究将帮助我们 了解铜通常分泌的途径， 病理隔离，并将提供一个框架， 一些人类或鼠突变是否会导致 蛋白质到特定的细胞器。 4.为了确定表达的组织分布和表达的时间， 正常和突变小鼠铜转运蛋白的产前表达 ATP酶基因这项工作将有助于我们了解 在人类Menkes病的表现发展，将是有价值的 用于评估产前或症状前治疗的策略。 5.分离酵母铜转运ATP酶同源物， 未来的基因和功能研究。酵母模型可以让我们 快速测试一些结构和功能的预测， 从人类和老鼠的研究中。

The long-term goal of this investigation is to understand the mechanisms of trace metal transport, especially as they relate to the pathogenesis of inherited disorders. The proposed studies are centered on Menkes disease, an X-linked disorder of copper transport, and its murine counterpart, the mottled mouse. Our recent discovery that the Menkes gene encodes a copper- transporting ATPase now allows us to address specific biochemical and physiological issues of copper transport and to clarify the molecular bases of Menkes disease and related disorders. This work should have implications for genetic prediction, establishment of clinical prognosis, and, ultimately, for the development of therapeutic strategies. The specific alms are the following: l. To characterize mutations in the copper-transporting ATPase gene of patients with classic Menkes disease, mild and atypical Menkes disease, and X-linked cutis laxa. Definition of these mutations should lead us to understand how particular defects in the regulation, structure, or localization of the transport protein can give rise to such diverse clinical phenotypes. 2. To characterize mutations in the murine homolog of the copper transporting ATPase gene for the several phenotypically disparate alleles of the mottled mouse. Definition of these mutations will augment our understanding of the human diseases, and will provide models for studying their pathophysiology in more detail. 3. To determine the sub-cellular location of the Menkes copper- transporting ATPase by immunocytochemistry. This study should help us to understand the route through which copper is normally secreted and pathologically sequestered, and will provide a framework for determining whether some human or murine mutations result in mistargeting of the protein to particular organelles. 4. To determine the tissue distribution of expression and the timing of prenatal expression of the normal and mutant mouse copper-transporting ATPase gene. This work will contribute to our understanding of the development of manifestations in human Menkes disease and will be valuable for assessing strategies for prenatal or presymptomatic therapies. 5. To isolate the yeast homolog of the copper-transporting ATPase for future genetic and functional studies. A yeast model would allow us to rapidly test some of the structural and functional predictions derived from the human and mouse studies.