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We have used succinylacetone (4,6-dioxoheptanoic acid), a specific inhibitor of δ-aminolevulinic acid dehydrase, to gain insight into the defect in iron metabolism in the Belgrade anemia. The Belgrade rat has an inherited microcytic, hypochromic anemia associated with poor iron uptake into developing erythroid cells. Succinylacetone inhibits heme synthesis, leading to nonheme iron accumulation in mitochondria and cytosol of normal reticulocytes. When succinylacetone is used to inhibit Belgrade heme synthesis, iron from diferric transferrin does not accumulate in the stromal fraction that contains mitochondria, nor does 59Fe accumulate in the nonheme cytosolic fraction. Hence, the defect in the Belgrade rat reticulocyte occurs in the endocytic vesicle or in a step subsequent to iron transit from the vesicle but before the nonheme cytosolic or mitochondrial iron fractions. Therefore, the mutation affects either the release of iron from transferrin or iron transport from the vesicle to the mitochondrion.

Mice with hemoglobin deficit (hbd) have a hypochromic, microcytic anemia inherited as an autosomal recessive. The mice also exhibit reticulocytosis, hyperferremia and elevated free protoporphyrin in red cells (Bannerman et al 1986 Proc Soc Exp Biol Med 182:52). The spontaneous mutation has been mapped to chromosome 19 (Bloom et al 1998 Mamm Genome 9:666), making it ripe for identification of the gene, given the power of mouse genetics. Until the actual locus is determined, however, some mice must be identified as +/? as dominant inheritance obscures the second allele. Prior studies established that hbd/hbdreticulocytes take up 125I-labelled transferrin as well as +/? controls, but are less effective at incorporating 59Fe from transferrin (Garrick et al 1987 Exp Hemato 15:671). Scatchard analysis showed the affinity of transferrin receptors for transferrin was similar in hbd/hbdversus +/? reticulocytes; slightly more receptors were present, however, on the surface of hbd/hbdreticulocytes.