Disorders of iron metabolism are among the most prevalent causes of human morbidity and mortality. Iron deficiency affects up to 1 billion individuals worldwide, primarily women and children. The severe deficiency state presents with anemia, because most of the body's iron is used to make red blood cells, and normal red cell development depends on the availability of adequate amounts of iron. Red blood cells appropriate almost three quarters of the body's iron endowment to produce the oxygen-carrying protein hemoglobin. They require mechanisms to transport iron efficiently and to coordinate its acquisition with other aspects of differentiation. Erythroid iron is taken up through receptor-mediated endocytosis of iron-loaded transferrin (Tf), termed the Tf cycle. In the last funding period we showed that the Tf cycle plays a unique and essential role in normal erythropoiesis. In the experiments described here we will study hbd mice, a strain with a spontaneous mutation resulting in impaired erythroid iron assimilation, to better understand this process. We have mapped the hbd mutation to a small segment of mouse chromosome 19, which contains 4 possible candidate genes.
The aims of the work described in this proposal are to characterize the biology of the hbd defect in mutant reticulocytes, to identify the molecular nature of the hbd defect, and to determine the role of the hbd gene product in erythropoiesis. This will be accomplished through detailed comparison of steps of the Tf cycle in hbd versus wild type reticulocytes, identification of all possible mutations within the hbd candidate region, transgenic rescue of the hbd phenotype, and determination of the subcellular localization and function of the hbd gene product. We anticipate that information derived from these experiments will be relevant to disorders of erythropoiesis and iron balance.
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