The gene encoding the ribosomal protein S19 (RPS19) is frequently mutated in 
Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia. The consequence 
of these mutations on the onset of the disease remains obscure. Here, we show 
that RPS19 plays an essential role in biogenesis of the 40S small ribosomal 
subunit in human cells. Knockdown of RPS19 expression by siRNAs impairs 18S rRNA 
synthesis and formation of 40S subunits and induces apoptosis in HeLa cells. 
Pre-rRNA processing is altered, which leads to an arrest in the maturation of 
precursors to the 18S rRNA. Under these conditions, pre-40S particles are not 
exported to the cytoplasm and accumulate in the nucleoplasm of the cells in 
perinuclear dots. Consistently, we find that ribosome biogenesis and nucleolar 
organization is altered in skin fibroblasts from DBA patients bearing mutations 
in the RPS19 gene. In addition, maturation of the 18S rRNA is also perturbed in 
cells from a patient bearing no RPS19-related mutation. These results support 
the hypothesis that DBA is directly related to a defect in ribosome biogenesis 
and indicate that yet to be discovered DBA-related genes may be involved in the 
synthesis of the ribosomal subunits.