Altered translation of GATA1 in Diamond-Blackfan anemia
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-ty...
| Main Authors: | , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2015
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| Online Access: | http://hdl.handle.net/1721.1/96702 https://orcid.org/0000-0002-6410-4699 https://orcid.org/0000-0002-7029-7415 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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 |
| author_sort | Ludwig, Leif S. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:14:49Z |
| format | Article |
| id | mit-1721.1/96702 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:14:49Z |
| publishDate | 2015 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/967022022-09-30T19:51:16Z Altered translation of GATA1 in Diamond-Blackfan anemia 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 Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Eichhorn, Stephen William Lodish, Harvey F. Lander, Eric S. 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. National Institutes of Health (U.S.) (Grant P01 HL32262) National Institutes of Health (U.S.) (Grant U54 HG003067-09) 2015-04-22T17:37:31Z 2015-04-22T17:37:31Z 2014-06 2013-12 Article http://purl.org/eprint/type/JournalArticle 1078-8956 1546-170X 1744-7933 http://hdl.handle.net/1721.1/96702 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. https://orcid.org/0000-0002-6410-4699 https://orcid.org/0000-0002-7029-7415 en_US http://dx.doi.org/10.1038/nm.3557 Nature Medicine Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Nature Publishing Group PMC |
| spellingShingle | 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 Altered translation of GATA1 in Diamond-Blackfan anemia |
| title | Altered translation of GATA1 in Diamond-Blackfan anemia |
| title_full | Altered translation of GATA1 in Diamond-Blackfan anemia |
| title_fullStr | Altered translation of GATA1 in Diamond-Blackfan anemia |
| title_full_unstemmed | Altered translation of GATA1 in Diamond-Blackfan anemia |
| title_short | Altered translation of GATA1 in Diamond-Blackfan anemia |
| title_sort | altered translation of gata1 in diamond blackfan anemia |
| url | http://hdl.handle.net/1721.1/96702 https://orcid.org/0000-0002-6410-4699 https://orcid.org/0000-0002-7029-7415 |
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