The characterization of spontaneous and induced mutants has proven invaluable in understanding mammalian iron metabolism. In particular, positional cloning of genes mutated in mouse, rat, human, and zebrafish iron deficiency and iron overload phenotypes has led to the discovery of multiple proteins that directly participate in or modify iron transport in mammals, many of which are directly relevant to understanding the pathophysiology of human diseases. Over the past several years, the generation of dense genetic and physical maps and near-complete genome sequences of mice and humans has greatly facilitated positional cloning and the rapidity in which mutants can be cloned. Here, we describe the initial phenotypic characterization of a new murine autosomal recessive hypochromic, microcytic anemia mutation, nm1054 (Dew mutation 1054). The phenotype of these animals strongly suggests an underlying defect in erythroid intracellular iron metabolism. Genetic mapping localizes the trait to mouse chromosome 1, and demonstrates that the mutant phenotype is due to a large genomic deletion that includes at least 5 genes. In this grant, we propose to evaluate the hypothesis that nm1054 is a defect in intraerythroid iron metabolism using bone marrow transplantation studies and in vitro iron uptake assays. Furthermore, we will clone the nm1054 anemia gene using bacterial artificial chromosome (BAC) and cDNA transgenic complementation. We expect that determining which of the deleted genes is responsible for the anemia will provide insight into the pathway of iron delivery and utilization in mammalian cells.
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