title: Altered translation of GATA1 in Diamond-Blackfan anemia.
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.
authors: 1] 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.
authors: Leif S
authors: LS
authors: Ludwig
authors: 1] 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.
authors: Hanna T
authors: HT
authors: Gazda
authors: 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Jennifer C
authors: JC
authors: Eng
authors: 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Stephen W
authors: SW
authors: Eichhorn
authors: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Prathapan
authors: P
authors: Thiru
authors: Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.
authors: Roxanne
authors: R
authors: Ghazvinian
authors: Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
authors: Tracy I
authors: TI
authors: George
authors: Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.
authors: Jason R
authors: JR
authors: Gotlib
authors: 1] 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.
authors: Alan H
authors: 0000000188180568
authors: AH
authors: Beggs
authors: 1] 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.
authors: Colin A
authors: CA
authors: Sieff
authors: 1] 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.
authors: Harvey F
authors: HF
authors: Lodish
authors: 1] 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.
authors: Eric S
authors: ES
authors: Lander
authors: 1] 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.
authors: Vijay G
authors: VG
authors: Sankaran
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics*; D050982:GATA1 Transcription Factor / Q000235:genetics*; D006801:Humans; D009154:Mutation; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D012333:RNA, Messenger; D012269:Ribosomal Proteins; C040343:ribosomal protein S19