Altered translation of GATA1 in Diamond-Blackfan anemia
Open accessAbstract
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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Functional follow-up showed that the more common ribosomal gene mutations impair the translation of GATA1 mRNA and thus result in impaired erythropoiesis.
“Inspired by this discovery and through functional follow up, it was shown that the more common ribosomal gene mutations impair the translation of GATA1 mRNA and thus result in impaired erythropoiesis (Khajuria et al., 2018; Ludwig et al., 2014).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Ludwig et al., 2014
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Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Self-citationHematopoiesis: An Evolving Paradigm for Stem Cell Biology
Orkin, S. H., & Zon, L. I. (2008) · Cell · doi:10.1016/j.cell.2008.01.025 · Cited by 2,570 · see citing works
TRANSFAC(R) and its module TRANSCompel(R): transcriptional gene regulation in eukaryotes
Matys, V. (2005) · Nucleic Acids Research · doi:10.1093/nar/gkj143 · Cited by 2,142 · see citing works
An analysis of vertebrate mRNA sequences: intimations of translational control.
Kozak, M. (1991) · The Journal of Cell Biology · doi:10.1083/jcb.115.4.887 · Cited by 1,623 · see citing works
Translational control of gene expression
Sonenberg, N., Hershey, J. W. B., & Mathews, M. B. (2000) · Cold Spring Harbor Laboratory eBooks · Cited by 1,379 · see citing works
Molecular mechanisms of translational control
Gebauer, F., & Hentze, M. W. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1488 · Cited by 991 · see citing works
Identification of RPS14 as a 5q- syndrome gene by RNA interference screen
Ebert, B. L., Pretz, J. L., Bosco, J., Chang, C. Y., Tamayo, P., Galili, N., Raza, A., Root, D. E., Attar, E. C., Ellis, S. R., et al. (2008) · Nature · doi:10.1038/nature06494 · Cited by 925 · see citing works
Sankaran, V. G., Menne, T. F., Xu, J., Akie, T. E., Lettre, G., Van Handel, B., Mikkola, H. K. A., Hirschhorn, J. N., Cantor, A. B., & Orkin, S. H. (2008) · Science · doi:10.1126/science.1165409 · Cited by 919 · see citing works
Self-citationDieterich, D. C., Link, A. J., Graumann, J., Tirrell, D. A., & Schuman, E. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601637103 · Cited by 874 · see citing works
Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome
Wechsler, J. B., Greene, M. E., McDevitt, M. A., Anastasi, J., Karp, J. E., Beau, M. M. L., & Crispino, J. D. (2002) · Nature Genetics · doi:10.1038/ng955 · Cited by 758 · see citing works
Specialized ribosomes: a new frontier in gene regulation and organismal biology
Xue, S., & Barna, M. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3359 · Cited by 687 · see citing works
Ribosome-Mediated Specificity in Hox mRNA Translation and Vertebrate Tissue Patterning
Kondrashov, N., Pusic, A. D., Stumpf, C. R., Shimizu, K., Hsieh, A. C., Xue, S., Ishijima, J., Shiroishi, T., & Barna, M. (2011) · Cell · doi:10.1016/j.cell.2011.03.028 · Cited by 581 · see citing works
Moerke, N., Aktas, H., Chen, H., Cantel, S., Reibarkh, M., Fahmy, A., Gross, J., Degterev, A., Yuan, J., Chorev, M., et al. (2007) · Cell · doi:10.1016/j.cell.2006.11.046 · Cited by 568 · see citing works
Autism-related deficits via dysregulated eIF4E-dependent translational control
Gkogkas, C. G., Khoutorsky, A., Ran, I., Rampakakis, E., Nevarko, T., Weatherill, D. B., Vasuta, C., Yee, S., Truitt, M., Dallaire, P., et al. (2013) · Nature · doi:10.1038/nature11628 · Cited by 522 · see citing works
Rate-Limiting Steps in Yeast Protein Translation
Shah, P., Ding, Y., Niemczyk, M., Kudla, G., & Plotkin, J. B. (2013) · Cell · doi:10.1016/j.cell.2013.05.049 · Cited by 463 · see citing works
Keersmaecker, K. D., Atak, Z. K., Li, N., Vicente, C., Patchett, S., Girardi, T., Gianfelici, V., Geerdens, E., Clappier, E., Porcu, M., et al. (2012) · Nature Genetics · doi:10.1038/ng.2508 · Cited by 426 · see citing works
Model for the regulation of mRNA translation applied to haemoglobin synthesis
Lodish, H. F. (1974) · Nature · doi:10.1038/251385a0 · Cited by 423 · see citing works
Self-citationDutt, S., Narla, A., Lin, K. I., Mullally, A., Abayasekara, N., Megerdichian, C., Wilson, F. H., Currie, T., Khanna‐Gupta, A., Berliner, N., et al. (2010) · Blood · doi:10.1182/blood-2010-07-295238 · Cited by 410 · see citing works
Global regulation of erythroid gene expression by transcription factor GATA-1
Welch, J. J. (2004) · Blood · doi:10.1182/blood-2004-04-1603 · Cited by 408 · see citing works
Rousseau, D. L., Kaspar, R. L., Rosenwald, I. B., Gehrke, L., & Sonenberg, N. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.3.1065 · Cited by 401 · see citing works
Hu, J., Liu, J., Xue, F., Halverson, G. R., Reid, M. E., Guo, A., Chen, L., Raza, A., Galili, N., Jaffray, J., et al. (2013) · Blood · doi:10.1182/blood-2013-01-476390 · Cited by 389 · see citing works
Exaggerated translation causes synaptic and behavioural aberrations associated with autism
Santini, E., Huynh, T. N., MacAskill, A. F., Carter, A. G., Pierre, P., Ruggero, D., Kaphzan, H., & Klann, E. (2012) · Nature · doi:10.1038/nature11782 · Cited by 376 · see citing works
Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia
Sankaran, V. G., Ghazvinian, R., Do, R., Thiru, P., Vergilio, J.-A., Beggs, A. H., Sieff, C. A., Orkin, S. H., Nathan, D. G., Lander, E. S., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63597 · Cited by 342 · see citing works
Control of mammalian translation by mRNA structure near caps
Babendure, J. R., Babendure, J. L., Ding, J.-H., & Tsien, R. Y. (2006) · RNA · doi:10.1261/rna.2309906 · Cited by 339 · see citing works
Lansdorp, P., & Dragowska, W. H. (1992) · The Journal of Experimental Medicine · doi:10.1084/jem.175.6.1501 · Cited by 223 · see citing works
MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13
Sankaran, V. G., Menne, T., Šćepanović, D., Vergilio, J., Ji, P., Kim, J., Thiru, P., Orkin, S. H., Lander, E. S., & Lodish, H. F. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1018384108 · Cited by 214 · see citing works
Self-citationDiamond-Blackfan Anemia: Diagnosis, Treatment, and Molecular Pathogenesis
Lipton, J. M. M., & Ellis, S. R. (2009) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2009.01.004 · Cited by 208 · see citing works
Ribosomal Protein SA Haploinsufficiency in Humans with Isolated Congenital Asplenia
Bolze, A., Mahlaoui, N., Byun, M., Turner, B., Trede, N. S., Ellis, S. R., Abhyankar, A., Itan, Y., Patin, É., Brebner, S., et al. (2013) · Science · doi:10.1126/science.1234864 · Cited by 189 · see citing works
Horos, R., IJspeert, H., Pospı́šilová, D., Sendtner, R., Andrieu‐Soler, C., Taskesen, E., Nieradka, A., Čmejla, R., Sendtner, M., Touw, I. P., et al. (2011) · Blood · doi:10.1182/blood-2011-06-358200 · Cited by 186 · see citing works
Erythroid Precursors in Congenital Hypoplastic (Diamond-Blackfan) Anemia
Nathan, D. G., Clarke, B. J., Hillman, D. G., Alter, B. P., & Housman, D. E. (1978) · Journal of Clinical Investigation · doi:10.1172/jci108960 · Cited by 154 · see citing works
Gazda, H. T., Preti, M., Sheen, M. R., et al. (2012) · Human Mutation · doi:10.1002/humu.22081 · Cited by 153 · see citing works
Self-citationJaako, P., Flygare, J., Olsson, K., Quéré, R., Ehinger, M., Henson, A. L., Ellis, S. R., Schambach, A., Baum, C., Richter, J., et al. (2011) · Blood · doi:10.1182/blood-2011-08-371963 · Cited by 146 · see citing works
Garçon, L., Ge, J., Manjunath, S. H., Mills, J. A., Apicella, M., Parikh, S. P., Sullivan, L. M., Podsakoff, G. M., Gadue, P. J., French, D. L., et al. (2013) · Blood · doi:10.1182/blood-2013-01-478321 · Cited by 92 · see citing works
Translation initiation at an ACG triplet in mammalian cells.
Peabody, D. S. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)60891-9 · Cited by 88 · see citing works
Moniz, H., Gastou, M., Leblanc, T. M., Hurtaud, C., Crétien, A., Lécluse, Y., Raslová, H., Larghero, J., Croisille, L., Faubladier, M., et al. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.88 · Cited by 84 · see citing works
Gazda, H. T., Kho, A. T., Sanoudou, D., Zaucha, J. M., Kohane, I. S., Sieff, C. A., & Beggs, A. H. (2006) · Stem Cells · doi:10.1634/stemcells.2005-0554 · Cited by 82 · see citing works
Self-citationTranslational efficiency in patients with Diamond-Blackfan anemia.
Čmejlová, J., Dolezalova, L., Pospı́šilová, D., et al. (2006) · PubMed · Cited by 77 · see citing works
Torihara, H., Uechi, T., Chakraborty, A., et al. (2011) · British Journal of Haematology · doi:10.1111/j.1365-2141.2010.08535.x · Cited by 72 · see citing works
GATA-1 associates with and inhibits p53
Trainor, C. D., Mas, C., Archambault, P., Di Lello, P., & Omichinski, J. G. (2009) · Blood · doi:10.1182/blood-2008-10-180489 · Cited by 51 · see citing works
p53-mediated differentiation of the erythroleukemia cell line K562.
Chylicki, K., Ehinger, M., Svedberg, H., et al. (2000) · PubMed · Cited by 30 · see citing works
Weiss, M. J., Mason, P. J., & Bessler, M. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63989 · Cited by 17 · see citing works
Kobayashi, E. H., Shimizu, R., Kikuchi, Y., Takahashi, S., & Yamamoto, M. P. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.030726 · Cited by 15 · see citing works
Flagged first, then by citations
Research works printed but not linked: 6
- [42]Sankaran VG MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13 Proc Natl Acad Sci U S A 108 1519 1524 2011 21205891 PMC3029749
- [43]Hu J Isolation and functional characterization of human erythroblasts at distinct stages: implications for understanding of normal and disordered erythropoiesis in vivo Blood 121 3246 3253 2013 23422750 PMC3630836
- [44]Kondrashov N Ribosome-mediated specificity in Hox mRNA translation and vertebrate tissue patterning Cell 145 383 397 2011 21529712 PMC4445650
- [45]Sankaran VG Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia J Clin Invest 122 2439 2443 2012 22706301 PMC3386831
- [46]Lansdorp PM Dragowska W Long-term erythropoiesis from constant numbers of CD34+ cells in serum-free cultures initiated with highly purified progenitor cells from human bone marrow J Exp Med 175 1501 1509 1992 1375263 PMC2119250
- [49]Subramanian A Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles Proc Natl Acad Sci U S A 102 15545 15550 2005 16199517 PMC1239896
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Self-citation
- Authors
- Ludwig, L. S., Gazda, H. T., Eng, J. C., Eichhorn, S. W., Thiru, P., Ghazvinian, R., George, T. I., Gotlib, J. R., Beggs, A. H., Sieff, C. A., Lodish, H. F., Lander, E. S., & Sankaran, V. G.
- Affiliations
- Broad Institute (US)
- Whitehead Institute for Biomedical Research (US)
- Boston Children's Hospital (US)
- Stanford Medicine (US)
- Corresponding author
- Sankaran, Vijay G
- ORCID
- Venue
- Nature Medicine
- Published
- 2014-06-22
- Volume
- 20
- Issue
- 7
- Pages
- 748-753
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4087046
- OpenAlex
- W1572977798
- Cited by
- 302
- References
- 43
- Citations by year
- 2026: 21 · 2025: 15 · 2024: 25 · 2023: 15 · 2022: 24 · 2021: 35 · 2020: 28 · 2019: 29 · 2018: 29 · 2017: 27 · 2016: 22 · 2015: 24 · 2014: 8
- FWCI
- 17.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- March of Dimes Foundation
- Diamond Blackfan Anemia Foundation
- Studienstiftung des Deutschen Volkes
- National Institutes of Health (HL32262)
- National Heart, Lung, and Blood Institute (K02HL111156, P01HL032262, P01 HL32262, R01 HL120791-01, R21HL120791, R01HL107558)
- National Human Genome Research Institute (U54HG003067)
- National Institute of General Medical Sciences (T32GM007287)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103794)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- Diamond-Blackfan anemia, GATA-1, ribosomal protein haploinsufficiency, RPS19, translation initiation, hematopoietic transcription factors, hematopoiesis, ribosomal protein mutations
- MeSH terms
- Humans, Mutation, Ribosomal Proteins, RNA, Messenger, Protein Biosynthesis, Anemia, Diamond-Blackfan, GATA1 Transcription Factor
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