title: Ribosomal deficiencies in Diamond-Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts.
abstract: Diamond-Blackfan anemia (DBA) is associated with developmental defects and profound anemia. Mutations in genes encoding a ribosomal protein of the small (e.g., RPS19) or large (e.g., RPL11) ribosomal subunit are found in more than half of these patients. The mutations cause ribosomal haploinsufficiency, which reduces overall translation efficiency of cellular mRNAs. We reduced the expression of Rps19 or Rpl11 in mouse erythroblasts and investigated mRNA polyribosome association, which revealed deregulated translation initiation of specific transcripts. Among these were Bag1, encoding a Hsp70 cochaperone, and Csde1, encoding an RNA-binding protein, and both were expressed at increased levels in erythroblasts. Their translation initiation is cap independent and starts from an internal ribosomal entry site, which appeared sensitive to knockdown of Rps19 or Rpl11. Mouse embryos lacking Bag1 die at embryonic day 13.5, with reduced erythroid colony forming cells in the fetal liver, and low Bag1 expression impairs erythroid differentiation in vitro. Reduced expression of Csde1 impairs the proliferation and differentiation of erythroid blasts. Protein but not mRNA expression of BAG1 and CSDE1 was reduced in erythroblasts cultured from DBA patients. Our data suggest that impaired internal ribosomal entry site-mediated translation of mRNAs expressed at increased levels in erythroblasts contributes to the erythroid phenotype of DBA.
authors: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Rastislav
authors: R
authors: Horos
authors: Hanna
authors: H
authors: Ijspeert
authors: Dagmar
authors: D
authors: Pospisilova
authors: Regine
authors: R
authors: Sendtner
authors: Charlotte
authors: C
authors: Andrieu-Soler
authors: Erdogan
authors: E
authors: Taskesen
authors: Andrzej
authors: A
authors: Nieradka
authors: Radek
authors: R
authors: Cmejla
authors: Michael
authors: M
authors: Sendtner
authors: Ivo P
authors: IP
authors: Touw
authors: Marieke
authors: M
authors: von Lindern
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004900:Erythroblasts / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011132:Polyribosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: C091732:BCL2-associated athanogene 1 protein; D015415:Biomarkers; C079950:CSDE1 protein, human; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; C531064:Rps19 protein, mouse; D014157:Transcription Factors; C027624:ribosomal protein L11; C040343:ribosomal protein S19