title: Targeted resequencing and analysis of the Diamond-Blackfan anemia disease locus RPS19.
abstract: 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.
  
  
  RESULTS
  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.
authors: The Linnaeus Centre for Bioinformatics Uppsala University/Swedish University of Agricultural Sciences, Uppsala University, Uppsala, Sweden.
authors: Alvaro
authors: A
authors: Martinez Barrio
authors: Oskar
authors: O
authors: Eriksson
authors: Jitendra
authors: J
authors: Badhai
authors: Anne-Sophie
authors: AS
authors: Fröjmark
authors: Erik
authors: E
authors: Bongcam-Rudloff
authors: Niklas
authors: N
authors: Dahl
authors: Jens
authors: J
authors: Schuster
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D002887:Chromosomes, Human, Pair 18; D015331:Cohort Studies; D004247:DNA; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012269:Ribosomal Proteins / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D012269:Ribosomal Proteins; D014157:Transcription Factors; C040343:ribosomal protein S19; D004247:DNA