INHERITED DISORDERS OF COPPER TRANSPORT

这项调查的长期目标是了解这些机制 特别是当它们与糖尿病的发病机制有关时。 遗传性疾病。拟议的研究集中在门克斯病上， 一种X连锁的铜运输障碍，以及它的小鼠对应的 斑驳的老鼠。我们最近发现门克斯基因编码一种铜- 运输ATPase现在允许我们解决特定的生化和 铜转运的生理问题和阐明分子 孟克斯病及相关疾病的基础。这部作品应该有 对遗传预测、建立临床预后的影响， 最终，用于治疗策略的发展。这个 具体施舍如下： L对铜离子转运酶基因突变的研究 典型门克斯病，轻度和非典型门克斯病， 和X连锁皮肤松弛。对这些突变的定义应该会引导我们 了解法规、结构或规则中的特定缺陷 运输蛋白的本地化可以导致这种多样性 临床表型。 2.鉴定小鼠铜同源基因的突变 几种表型不同等位基因的ATPase基因转运 斑驳的老鼠。对这些突变的定义将增强我们的 了解人类疾病，并将为研究提供模型 他们的病理生理学更详细。 3.为了确定门克斯铜的亚细胞位置- 通过免疫细胞化学转运ATPase。这项研究应该有助于我们 了解铜的正常分泌途径和 病理上被隔离，并将提供一个框架来确定 无论是某些人类或小鼠突变导致错误定位 特定细胞器的蛋白质。 4.确定表达的组织分布和时间 正常和突变小鼠铜转运的产前表达 ATPase基因。这项工作将有助于我们理解 人类门克斯病的临床表现及其临床应用价值 用于评估产前或症状前治疗的策略。 5.分离铜转运ATPase的酵母同源物 未来的遗传和功能研究。酵母模型将使我们能够 快速测试得出的一些结构和功能预测 来自人类和老鼠的研究。

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.