BACKGROUND AND OBJECTIVES: Diamond-Blackfan anemia (DBA) is a rare congenital 
pure red cell aplasia characterized by normochromic macrocytic anemia, 
reticulocytopenia, and normocellular bone marrow with a selective deficiency of 
erythroid precursors. Ribosomal protein S19 (RPS19), currently the only gene 
associated with DBA, is mutated in 25% of DBA patients, but its role in 
erythropoiesis is unknown. We attempted to elucidate the importance of RPS19 in 
translation in relation to the pathogenesis of DBA.
DESIGN AND METHODS: We measured translation and proliferation rates in 
unstimulated and phytohemagglutinin (PHA)-stimulated lymphocytes isolated from 
DBA patients, as well as in K562 cells expressing several RPS19 mutants to 
directly test the effect of RPS19 mutations on translation. The effect of 
leucine on overall translation was also studied.
RESULTS: We found that the level of translation was on average 48-73% of 
controls in both unstimulated and PHA-activated DBA lymphocytes irrespective of 
mutations in RPS19. The addition of leucine increased the translational level in 
RPS19-non-mutated DBA cells, but not in cells with an RPS19 mutation. In 
unstimulated DBA cells, proliferation was significantly impaired in both 
RPS19-mutated and non-mutated cells, but in both groups could be efficiently 
activated by PHA. Studies on K562 cells showed that RPS19 mutations affecting 
RPS19 conserved arginines R56Q and R62Q could significantly inhibit the rate of 
protein synthesis, indicating the importance of RPS19 in translation.
INTERPRETATION AND CONCLUSIONS: Our results indicate that inefficient 
translation may be the main cause of DBA, and administration of leucine may be 
beneficial for at least some DBA patients.