Altered translation of GATA1 in Diamond-Blackfan anemia
Author(s)Ludwig, Leif S.; Gazda, Hanna T.; Eng, Jennifer Christina; Thiru, Prathapan; Ghazvinian, Roxanne; George, Tracy I.; Gotlib, Jason R.; Beggs, Alan H.; Sieff, Colin A.; Sankaran, Vijay G.; Eichhorn, Stephen William; Lodish, Harvey F; Lander, Eric Steven; ... Show more Show less
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Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA)[superscript 1, 2], congenital asplenia[superscript 3] and T cell leukemia[superscript 4]. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type– and tissue-specific defects remains unknown[superscript 5]. 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.
DepartmentMassachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research
Nature Publishing Group
Ludwig, Leif S, Hanna T Gazda, Jennifer C Eng, Stephen W Eichhorn, Prathapan Thiru, Roxanne Ghazvinian, Tracy I George, et al. “Altered Translation of GATA1 in Diamond-Blackfan Anemia.” Nature Medicine 20, no. 7 (June 22, 2014): 748–753.
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