To identify novel regulators of erythropoiesis, we performed independent forward 
genetic screens using the chemical mutagen ENU in mice. Among progeny displaying 
microcytic red-cell phenotypes, 7 independent mouse strains harboring mutations 
within the transferrin receptor gene Tfrc were identified. Six of the mutants, 
including the previously described red blood cell 6 (RBC6) strain, displayed 
reduced erythroblast CD71 expression and midgestation lethality of homozygotes 
(E12.5-E14.5), and 1 novel strain, RBC21, displayed a variable phenotype with 
sustained CD71 expression and late homozygous lethality (E18.5). Standard iron 
studies were normal in the RBC21 mutant, but intracellular ferritin was 
significantly reduced. The microcytic phenotype seen in the RBC21 strain was the 
result of impaired binding of transferrin to the receptor. Neither RBC6 nor 
RBC21 responded to iron replacement therapy. These studies describe how point 
mutations of the transferrin receptor can cause a microcytic anemia that does 
not respond to iron therapy and would not be detected by routine iron studies, 
such as serum ferritin.