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Nat Med DOI:10.1038/nm.3557

Altered translation of GATA1 in Diamond-Blackfan anemia.

Publication TypeJournal Article
Year of Publication2014
AuthorsLudwig, LS, Gazda, HT, Eng, JC, Eichhorn, SW, Thiru, P, Ghazvinian, R, George, TI, Gotlib, JR, Beggs, AH, Sieff, CA, Lodish, HF, Lander, ES, Sankaran, VG
JournalNat Med
Date Published2014 Jul
KeywordsAnemia, Diamond-Blackfan, GATA1 Transcription Factor, Humans, Mutation, Protein Biosynthesis, Ribosomal Proteins, RNA, Messenger

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.


Alternate JournalNat. Med.
PubMed ID24952648
PubMed Central IDPMC4087046
Grant ListR01 HL107558 / HL / NHLBI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
K02 HL111156 / HL / NHLBI NIH HHS / United States
P01 HL032262 / HL / NHLBI NIH HHS / United States
U54 HG003067-09 / HG / NHGRI NIH HHS / United States
P01 HL32262 / HL / NHLBI NIH HHS / United States
R21 HL120791 / HL / NHLBI NIH HHS / United States
R01 HL120791-01 / HL / NHLBI NIH HHS / United States