BACKGROUND: The Ribosomal protein S19 gene locus (RPS19) has been linked to two 
kinds of red cell aplasia, Diamond-Blackfan Anemia (DBA) and Transient 
Erythroblastopenia in Childhood (TEC). Mutations in RPS19 coding sequences have 
been found in 25% of DBA patients, but not in TEC patients. It has been 
suggested that non-coding RPS19 sequence variants contribute to the considerable 
clinical variability in red cell aplasia. We therefore aimed at identifying 
non-coding variations associated with DBA or TEC phenotypes.
METHODOLOGY/PRINCIPAL FINDINGS: We targeted a region of 19'980 bp encompassing 
the RPS19 gene in a cohort of 89 DBA and TEC patients for resequencing. We 
provide here a catalog of the considerable, previously unrecognized degree of 
variation in this region. We identified 73 variations (65 SNPs, 8 indels) that 
all are located outside of the RPS19 open reading frame, and of which 67.1% are 
classified as novel. We hypothesize that specific alleles in non-coding regions 
of RPS19 could alter the binding of regulatory proteins or transcription 
factors. Therefore, we carried out an extensive analysis to identify 
transcription factor binding sites (TFBS). A series of putative interaction 
sites coincide with detected variants. Sixteen of the corresponding 
transcription factors are of particular interest, as they are housekeeping genes 
or show a direct link to hematopoiesis, tumorigenesis or leukemia (e.g. 
GATA-1/2, PU.1, MZF-1).
CONCLUSIONS: Specific alleles at predicted TFBSs may alter the expression of 
RPS19, modify an important interaction between transcription factors with 
overlapping TFBS or remove an important stimulus for hematopoiesis. We suggest 
that the detected interactions are of importance for hematopoiesis and could 
provide new insights into individual response to treatment.