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Nat Med. 2014 Jul;20(7):748-53. doi: 10.1038/nm.3557. Epub 2014 Jun 22.

Altered translation of GATA1 in Diamond-Blackfan anemia.

Author information

  • 11] Division of Hematology and Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. [4] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [5] Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany. [6] Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • 21] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
  • 31] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • 41] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 5Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
  • 6Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.
  • 7Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
  • 8Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.
  • 91] Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
  • 101] Division of Hematology and Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
  • 111] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 121] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [3] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
  • 131] Division of Hematology and Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. [4] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [5] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA), congenital asplenia and T cell leukemia. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type- and tissue-specific defects remains unknown. Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA-binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease.

PMID:
24952648
[PubMed - indexed for MEDLINE]
PMCID:
PMC4087046
Free PMC Article
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