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

Tamara C Pereboom, Albert Bondt, Paschalina Pallaki, Tim D Klasson, Yvonne J Goos, Paul B Essers, Marian J A Groot Koerkamp, Hanna T Gazda, Frank C P Holstege, Lydie Da Costa, Alyson W MacInnes

Research output: Contribution to journal/periodicalArticleScientificpeer-review


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.

Original languageEnglish
Pages (from-to)394-403.e4
JournalExperimental Hematology
Issue number5
Publication statusPublished - May 2014


  • 5' Untranslated Regions
  • Anemia, Diamond-Blackfan
  • Haploinsufficiency
  • Humans
  • Polyribosomes
  • Protein Biosynthesis
  • Ribosomal Proteins
  • Transaminases
  • Transcription, Genetic


Dive into the research topics of 'Translation of branched-chain aminotransferase-1 transcripts is impaired in cells haploinsufficient for ribosomal protein genes'. Together they form a unique fingerprint.

Cite this