Pleiotropic effects of the Belgrade mutation on erythroid differentiation in rats

The Belgrade rat (b/b) has a microcytic, hypochromic anemia. This radiation-induced mutation is inherited as an autosomal recessive trait. Iron is incorporated into b/b erythroid cells at 25% of normal levels, while globin synthesis is ~50% (Edwards et al. 1978 Blood 51:347). Seven distinct globin structural genes are expressed in both normal and Belgrade adult rats. We analyzed the basis of diminished globin synthesis by preparing and fractionating RNA from b/b and normal reticulocytes. Messenger RNA activity of b/b reticulocytes is half the normal level but the seven mRNAs are translated in the same proportions as for normal mRNAs. We found a similar deficiency in mRNA sequences by hybridization to cDNA complementary to the seven globin mRNAs. Exogenous hemin increases incorporation into globin by b/b, but not by normal, reticulocytes. Although hemin prolongs globin synthesis in cell-free extracts of normal rat reticulocytes, unusual conditions are required to obtain a response to hemin by b/b lysates. Our data suggest that there is a chronic heme deficit during erythroid differentiation in Belgrade rats and that the deficiency is accompanied by decreased accumulation of seven globin mRNAs.