Hemoglobin Synthesis in Siderocytes of Flexed-tailed Mutant (f/f) Fetal Mice

Abstract

Mice carrying two mutant genes at the f locus on chromosome 13 have severe anemia during fetal development, characterized by hypochromic and microcytic red blood cells laden with many iron granules. Ultrastructural studies reveal that the excessive nonheme iron accumulated in mutant (f/f) fetal erythrocytes is present within mitochondria, similar to those seen in human sideroblastic anemia. The level of free erythrocyte protoporphyrin in f/f fetal red cells is similar to that in normal (+/+) fetal red cells. Furthermore, in f/f fetal reticulocytes β-chain synthesis is decreased compared with α-chain synthesis. Exogenous hemin fails to alter significantly globin synthesis in f/f cells, while it preferentially stimulates α-chain synthesis in +/+ cells. Protein synthesis in mutant reticulocytes is also more resistant than that in normal reticulocytes to the inhibitory effect of three heme synthesis inhibitors, i.e., isoniazid, 2,2'-bipyridine, and ethanol. These results are consistent with the hypothesis that in fetal mutant f/f red cells there is diminished globinchain production, leading to hypochromic and microcytic anemia. In addition, there is a relative excess of intracellular free heme pool due to decreased utilization. Iron accumulation in these erythroid cells may be secondary to the hemoglobin synthetic derangement. The present study also demonstrates that sideroblastic anemia recognized by identical morphologic criteria is a heterogeneous group of disorders with different basic biochemical abnormalities.