Ribosomal deficiencies in Diamond-Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts

TitleRibosomal deficiencies in Diamond-Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts
Publication TypeJournal Article
Year of Publication2012
AuthorsHoros, R, IJspeert, H, Pospisilova, D, Sendtner, R, Andrieu-Soler, C, Taskesen, E, Nieradka, A, Cmejla, R, Sendtner, M, Touw, IP, von Lindern, M
JournalBlood
Volume119
Issue1
Pagination262-72
Date Published2012 Jan 5
ISSN1528-0020
KeywordsAnemia, Diamond-Blackfan, Animals, Biological Markers, Blotting, Western, Cell Differentiation, Cell Proliferation, DNA-Binding Proteins, Embryo, Mammalian, Erythroblasts, Female, Flow Cytometry, Gene Expression Profiling, Humans, Mice, Mice, Knockout, Mutation, Oligonucleotide Array Sequence Analysis, Phenotype, Polyribosomes, Protein Biosynthesis, Real-Time Polymerase Chain Reaction, Ribosomal Proteins, RNA, Messenger, RNA, Small Interfering, RNA-Binding Proteins, Transcription Factors
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.

DOI10.1182/blood-2011-06-358200
Custom 1

http://www.ncbi.nlm.nih.gov/pubmed/22058113?dopt=Abstract

Alternate JournalBlood
PubMed ID22058113