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Translation of branched-chain aminotransferase-1 transcripts is impaired in cells haploinsufficient for ribosomal protein genes.

  • Pereboom, Tamara C1
  • Bondt, Albert1
  • Pallaki, Paschalina1
  • Klasson, Tim D1
  • Goos, Yvonne J1
  • Essers, Paul B1
  • Groot Koerkamp, Marian J A2
  • Gazda, Hanna T3
  • Holstege, Frank C P2
  • Costa, Lydie Da4
  • MacInnes, Alyson W5
  • 1 Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands. , (Netherlands)
  • 2 Molecular Cancer Research, UMC Utrecht, Utrecht, The Netherlands. , (Netherlands)
  • 3 Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA; Harvard Medical School, Boston, MA; Broad Institute, Cambridge, MA.
  • 4 AP-HP, Service d'Hématologie Biologique, Hôpital Robert Debré, Paris F-75019, France; Université Paris VII-Denis Diderot, Sorbonne Paris Cité, Paris F-75475, France; U773, CRB3, Paris F-75018, France. , (France)
  • 5 Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: [email protected] , (Netherlands)
Published Article
Experimental hematology
Publication Date
May 01, 2014
DOI: 10.1016/j.exphem.2013.12.010
PMID: 24463277


Diamond-Blackfan anemia (DBA) is a bone marrow failure syndrome linked to mutations in ribosomal protein (RP) genes that result in the impaired proliferation of hematopoietic progenitor cells. The etiology of DBA is not completely understood; however, the ribosomal nature of the genes involved has led to speculation that these mutations may alter the landscape of messenger RNA (mRNA) translation. Here, we performed comparative microarray analysis of polysomal mRNA transcripts isolated from lymphoblastoid cell lines derived from DBA patients carrying various haploinsufficient mutations in either RPS19 or RPL11. Different spectrums of changes were observed depending on the mutant gene, with large differences found in RPS19 cells and very few in RPL11 cells. However, we find that the small number of altered transcripts in RPL11 overlap for the most part with those altered in RPS19 cells. We show specifically that levels of branched-chain aminotransferase-1 (BCAT1) transcripts are significantly decreased on the polysomes of both RPS19 and RPL11 cells and that translation of BCAT1 protein is especially impaired in cells with small RP gene mutations, and we provide evidence that this effect may be due in part to the unusually long 5'UTR of the BCAT1 transcript. The BCAT1 enzyme carries out the final step in the biosynthesis and the first step of degradation of the branched-chain amino acids leucine, isoleucine, and valine. Interestingly, several animal models of DBA have reported that leucine ameliorates the anemia phenotypes generated by RPS19 loss. Our study suggests that RP mutations affect the synthesis of specific proteins involved in regulating amino acid levels that are important for maintaining the normal proliferative capacity of hematopoietic cells.

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