The Belgrade Rat - An Intracellular Defect in the Transferrin Cycle
Laura Garrick Principal Investigator
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The Belgrade rat has a microcytic, hypochromic anemia inherited as an autosomal recessive (gene symbol b), which is due to a transferrin cycle defect, resulting in defective intracellular iron metabolism. Iron-loaded transferrin enters b/b reticulocytes via endocytosis, but is released from the cells still bound to iron. The defect can be partially alleviated when ferric-salicylaldehyde isonicotinoyl hydrazone delivers iron, bypassing the transferrin cycle. When succinylacetone inhibits iron incorporation into heme, b/b reticulocytes lack the typical buildup of nonheme iron in mitochondria, and less iron than usual reaches a putative cytosolic iron carrier. These observations suggest that iron is unable to exit normally from Belgrade endosomes. This difficulty could be caused by: (1) poor endosomal acidification; (2) transferrin receptors that fail to aid release of iron from transferrin; (3) a mutant vesicular component that normally transports iron out of the endosome; or (4) a functional or quantitative decrease in the putative cytosolic iron carrier. Whichever is the case, studies of the cells of this mutant rat would provide new insight into the problem of how cells utilize transferrin iron. This mutant also has great value for testing in vivo the validity of recent concepts in cellular iron metabolism and defining previously unknown or poorly understood steps. %%% The Belgrade rat has an inborn error of iron metabolism which is due to a cellular dysfunction in utilization of iron from endocytosed transferrin. Thus, it is a valuable model system for studying various aspects of cellular endocytosis as it relates to transferrin and iron metabolism, both at the cellular and whole- organism levels. Belgrade rats are not commercially available, and in fact the world's supply of breeding stock of these rats is in jeopardy. This award is to support the maintenance of a breeding colony of the mutant rat.