Altered translation of GATA1 in Diamond-Blackfan anemia
Ludwig, Leif S.
Eng, Jennifer C.
Eichhorn, Stephen W.
George, Tracy I.
Gotlib, Jason R.
Lodish, Harvey F.
MetadataShow full item record
CitationLudwig, L. S., H. T. Gazda, J. C. Eng, S. W. Eichhorn, P. Thiru, R. Ghazvinian, T. I. George, et al. 2014. “Altered translation of GATA1 in Diamond-Blackfan anemia.” Nature medicine 20 (7): 748-753. doi:10.1038/nm.3557. http://dx.doi.org/10.1038/nm.3557.
AbstractRibosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA),1,2 congenital asplenia,3 and T-cell leukemia.4 Yet how mutations in such ubiquitously expressed proteins result in cell-type and tissue specific defects remains a mystery.5 Here, we show that GATA1 mutations that reduce full-length protein levels of this critical hematopoietic transcription factor can cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can similarly reduce translation of GATA1 mRNA - a phenomenon that appears to result from this mRNA having a higher threshold for initiation of translation. In primary hematopoietic cells from patients with RPS19 mutations, a transcriptional signature of GATA1 target genes is globally and specifically reduced, confirming that the activity, but not the mRNA level, of GATA1 is reduced in DBA patients with ribosomal protein mutations. The defective hematopoiesis observed in DBA patients with ribosomal protein haploinsufficiency can be at least partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations in ubiquitous ribosomal proteins can result in human disease.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:13890685
- HMS Scholarly Articles