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Altered translation of GATA1 in Diamond-Blackfan anemia

Item Type:Article
Title:Altered translation of GATA1 in Diamond-Blackfan anemia
Creators Name:Ludwig, L.S. and Gazda, H.T. and Eng, J.C. and Eichhorn, S.W. and Thiru, P. and Ghazvinian, R. and George, T.I. and Gotlib, J.R. and Beggs, A.H. and Sieff, C.A. and Lodish, H.F. and Lander, E.S. and Sankaran, V.G.
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.
Keywords:Diamond-Blackfan Anemia, GATA1 Transcription Factor, Messenger RNA, Mutation, Protein Biosynthesis, Ribosomal Proteins
Source:Nature Medicine
Publisher:Nature Publishing Group
Page Range:748-753
Date:July 2014
Official Publication:https://doi.org/10.1038/nm.3557
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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