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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Altered translation of GATA1 in Diamond-Blackfan anemia
Nature medicine, v 20(7), pp 748-753
01 Jul 2014
PMID: 24952648
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Altered translation of GATA1 in Diamond-Blackfan anemia
- Creators
- Leif S Ludwig - Dana-Farber/Boston Children's Cancer and Blood Disorders CenterHanna T Gazda - Broad InstituteJennifer C Eng - Whitehead Institute for Biomedical ResearchStephen W Eichhorn - Whitehead Institute for Biomedical ResearchPrathapan Thiru - Whitehead Institute for Biomedical ResearchRoxanne Ghazvinian - Dana-Farber/Boston Children's Cancer and Blood Disorders CenterTracy I George - Stanford UniversityJason R Gotlib - Stanford UniversityAlan H Beggs - Dana-Farber/Boston Children's Cancer and Blood Disorders CenterColin A Sieff - Dana-Farber Cancer InstituteHarvey F Lodish - Whitehead Institute for Biomedical ResearchEric S Lander - Broad InstituteVijay G Sankaran - Broad Institute
- Publication Details
- Nature medicine, v 20(7), pp 748-753
- Publisher
- Springer Nature
- Grant note
- P01 HL32262 / NHLBI NIH HHS R01 DK103794 / NIDDK NIH HHS T32 GM007287 / NIGMS NIH HHS R21 HL120791 / NHLBI NIH HHS P01 HL032262 / NHLBI NIH HHS R01 HL107558 / NHLBI NIH HHS K02 HL111156 / NHLBI NIH HHS R01 HL120791-01 / NHLBI NIH HHS U54 HG003067 / NHGRI NIH HHS U54 HG003067-09 / NHGRI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics
- Web of Science ID
- WOS:000338689500017
- Scopus ID
- 2-s2.0-84904021040
- Other Identifier
- 991021838576104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Medicine, Research & Experimental