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Understanding iron metabolism has been enhanced by identification of genes for iron deficiency mouse mutants. We characterized the genetics and iron metabolism of the severe anemia mutant hea (hereditary erythroblastic anemia), which is lethal at 5 to 7 days. The hea mutation results in reduced red blood cell number, hematocrit, and hemoglobin. The hea mice also have elevated Zn protoporphyrin and serum iron. Blood smears from hea mice are abnormal with elevated numbers of smudge cells. Aspects of the hea anemia can be transferred by hematopoietic stem cell transplantation. Neonatal hea mice show a similar hematologic phenotype to the flaky skin (fsn) mutant. We mapped the hea gene near the fsn locus on mouse chromosome 17 and show that the mutants are allelic. Both tissue iron overloading and elevated serum iron are also found in hea and fsn neonates. There is a shift from iron overloading to iron deficiency as fsn mice age. The fsn anemia is cured by an iron-supplemented diet, suggesting an iron utilization defect. When this diet is removed there is reversion to anemia with concomitant loss of overloaded iron stores. We speculate that the hea/fsn gene is required for iron uptake into erythropoietic cells and for kidney iron reabsorption. IntroductionThe genes involved in absorbing iron from the gut and transporting it to the bone marrow have been uncovered from studying defects of iron metabolism in human beings, mice, and zebrafish. [1][2][3][4][5][6][7][8][9] Divalent metal transporter-1 (DMT1) is the iron transporter on the apical surface of intestinal epithelial cells that facilitates the transport of iron from the intestinal lumen into enterocytes in cooperation with the ferric reductase encoded by the gene Dcytb1 (duodenal cytochrome b). 2,[10][11][12] The transport of iron through the basolateral surface of intestinal enterocytes into the circulation is carried out by a protein called ferroportin (gene symbol Fpn-1), which requires the ceruloplasmin-like ferroxidase hephaestin (gene symbol Heph). 3,4 Genes playing essential roles in iron homeostasis have yet to be identified. These include the gene responsible for reducing iron to the ferrous state for its transport by DMT1 in cells other than the intestinal epithelium. A novel gene affecting iron metabolism may be identified by studying 2 additional anemia mouse mutants: hea (hereditary erythroblastic anemia) and fsn (flaky skin).The hea mouse mutant arose spontaneously on the CFO strain in Japan and is inherited in an autosomal recessive manner. 13 Affected homozygous hea/hea mice are identified by their pale color at birth. These mice suffer from severe anemia in the homozygous state (hea/hea) and die at 1 week of age. The hea mice exhibit elevated numbers of nucleated red blood cells (erythroblasts) in the peripheral circulation.In this paper we report that C57BL/6J-hea mutant is allelic to another anemia mutant, the flaky skin mouse. 14 The fsn mouse is an autosomal recessive mutant with severe anemia that is lethal at 3 months of age. The fsn ane...