The gene encoding the small subunit ribosomal protein 19 (RPS19) is mutated in 
about 25% of cases of the bone marrow failure syndrome Diamond Blackfan Anemia 
(DBA), a childhood disease characterized by failure of red cell production. In 
these cases DBA is inherited as an autosomal dominant trait and RPS19 
haploinsufficiency is thought to cause the disease. To study the molecular 
pathogenesis of DBA we used siRNA to decrease the level of RPS19 in two human 
cell lines, HeLa cells and U-2 OS osteosarcoma cells. Cells with reduced RPS19 
levels showed a dramatic reduction in the amounts of small 40S ribosome subunits 
and mature 80S ribosomes and an excess of large 60S subunits. These cells were 
defective in 18S rRNA production and accumulated 21S and 20S nuclear pre-rRNA 
molecules, suggesting that RPS19 is required for specific steps in rRNA 
processing. RPS19 depletion produced a reduction in steady-state levels of RPS6 
and RPS16 via a post-transcriptional mechanism while the levels of RPL7 and 
RPL26 were unaltered, indicating that levels of ribosomal proteins are 
determined by subunit assembly. This has interesting implications for the 
pathogenesis of DBA suggesting that deficiency of any of the RPS proteins might 
have a similar effect and thus may be responsible for causing DBA. Finally in 
cell lines from DBA patients with mutations we find increased levels of 21S rRNA 
precursors but no abnormality in the ribosome profile on sucrose gradients or in 
the steady-state levels of RPS19 suggesting that some cells can partially 
compensate for the loss of one allele of RPS19. We conclude that defects in 
ribosome biogenesis may underlie the pathology of Diamond Blackfan Anemia.