Hypotheses linking 40S deficiency to anemia. (A) The erythroblast normally produces exceptionally high amounts of ribosomes. Erythroid development may come to a halt at the erythroblast stage in 40S-deficient cells, because they will have difficulties to meet the high demand of ribosome biogenesis. The relative 40S deficiency is expected to be most severe at this arrested stage of erythroid development. (B) Several transcription factors can be translated from alternative translation initiation sites in the 5′ untranslated region. A 40S subunit deficiency may cause translation from alternative translation initiation sites and produce protein isoforms with unwanted characteristics.