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.
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