A mutation in the translation initiation codon of Gata-1 disrupts megakaryocyte maturation and causes thrombocytopenia

Ian J Majewski, Donald Metcalf, Lisa A Mielke, Danielle L Krebs, Sarah L Ellis, Marina Carpinelli, Sandra Mifsud, Ladina Di Rago, Jason E Corbin, Nicos A Nicola, Douglas Hilton, Warren Alexander

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19 Citations (Scopus)


We have generated mice from a N-ethyl-N-nitrosourea mutagenesis screen that carry a mutation in the translation initiation codon of Gata-1, termed Plt13, which is equivalent to mutations found in patients with acute megakaryoblastic leukemia and Down syndrome. The Gata-1 locus is present on the X chromosome in humans and in mice. Male mice hemizygous for the mutation (Gata-1 Plt13/Y) failed to produce red blood cells and died during embryogenesis at a similar stage to Gata-1-null animals. Female mice that carry the Plt13 mutation are mosaic because of random inactivation of the X chromosome. Adult Gata-1plt13/+ females were not anemic, but they were thrombocytopenic and accumulated abnormal megakaryocytes without a concomitant increase in megakaryocyte progenitor cells. Gata-1Plt13/+ mice contained large numbers of blast-like colony-forming cells, particularly in the fetal liver, but also in adult spleen and bone marrow, from which continuous mast cells lines were readily derived. Although the equivalent mutation to Gata-1plt13 in humans results in production of GATA-1s, a short protein isoform initiated from a start codon downstream of the mutated initiation codon, Gata-1s was not detected in Gata-1Plt13/+ mice. ? 2006 by The National Academy of Sciences of the USA.
Original languageEnglish
Pages (from-to)14146-14151
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number38
Publication statusPublished - Sep 2006
Externally publishedYes

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