INHERITED DISORDERS OF COPPER TRANSPORT

遗传性铜转运障碍

• 批准号: 2146534
• 负责人: JANE M GITSCHIER
• 金额: $ 25.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2146534
• 关键词: Menkes' syndrome; adenosinetriphosphatase; alleles; atomic absorption spectrometry; biological transport; copper; cutis laxa; gene expression; gene mutation; genetic disorder; human genetic material tag; human subject; immunocytochemistry; in situ hybridization; laboratory mouse; molecular pathology; northern blottings; nucleic acid probes; nucleic acid sequence; pathologic process; phenotype; polymerase chain reaction; protein structure function; southern blotting

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.

这项调查的长期目标是了解机制 痕量金属的传输，尤其是与 继承的疾病。拟议的研究集中于Menkes疾病， X连锁的铜运输障碍及其鼠类对应物， 斑驳的鼠标。我们最近发现的Menkes基因编码铜 - 现在，运输ATPase使我们能够解决特定的生化和 铜运输的生理问题并阐明分子 Menkes疾病和相关疾病的基础。这项工作应该有 对遗传预测的影响，建立临床预后， 最终，用于制定治疗策略。这 具体施舍是以下内容： l。表征在铜传输ATPase基因中的突变 经典Menkes疾病，轻度和非典型Menkes病的患者， 和X连锁的Cutis laxa。这些突变的定义应该导致我们进入 了解法规，结构或 运输蛋白的定位会导致如此多样化 临床表型。 2。要在铜的鼠同源物中表征突变 运输几个表型不同等位基因的ATPase基因 斑驳的鼠标。这些突变的定义将增加我们的 了解人类疾病，并将提供研究模型 他们的病理生理学更详细。 3。确定menkes铜的亚细胞位置 通过免疫细胞化学运输ATPase。这项研究应该帮助我们 了解铜通常分泌的路线，并且 病理隔离，将提供一个确定的框架 某些人类还是鼠突变是否导致误导 特定细胞器的蛋白质。 4。确定表达的组织分布和 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对 人类Menkes疾病中表现形式的发展，将是有价值的 用于评估产前或预症状疗法的策略。 5。隔离铜运输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 来自人类和小鼠研究。