Evidence for and consequences of chronic heme deficiency in Belgrade rat reticulocytes

The Belgrade rat has a microcytic, hypochromic anemia inherited as an autos omal recessive trait (gene symbol b). Transferrin-dependent iron uptake is defective because of a mutation in Nramp2 (now DMT1, also called DCT1), the protein responsible for endosomal iron efflux. Hence, Belgrade reticulocyt es are iron deficient. We show that a chromatographic method is able to mea sure the amount of 'free' heme in reticulocytes, Most of the 'free' heme is the result of biosynthesis. Succinylacetone, an inhibitor of heme synthesi s, decreases the level of 'free' heme and cycloheximide, an inhibitor of gl obin synthesis, increases the 'free' heme level. In a pulse-chase experimen t with Fe-59-transferrin, the 'free' heme pool behaves as an intermediate, with a half-life of just over 2 h. Belgrade reticulocytes contain about 40% as much 'free' heme as do heterozygous or homozygous reticulocytes, This d eficiency of 'free' heme slows initiation of translation in Belgrade reticu locytes by increasing the level of an inhibitor of initiation. Thus the Bel grade rat makes a whole animal model available with chronic heme deficiency . (C) 1999 Elsevier Science B.V. All rights reserved.