title: A mutation in the translation initiation codon of Gata-1 disrupts megakaryocyte maturation and causes thrombocytopenia.
abstract: 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-1Plt13/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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Majewski
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mielke
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Krebs
authors.forename: Sarah
authors.initials: S
authors.lastname: Ellis
authors.forename: Marina R
authors.initials: MR
authors.lastname: Carpinelli
authors.forename: Sandra
authors.initials: S
authors.lastname: Mifsud
authors.forename: Ladina
authors.initials: L
authors.lastname: Di Rago
authors.forename: Jason
authors.initials: J
authors.lastname: Corbin
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Nicola
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
mesh_terms: D000477:Alkylating Agents / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D003062:Codon; D005038:Ethylnitrosourea / Q000378:metabolism; D005260:Female; D050982:GATA1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013921:Thrombocytopenia / Q000235:genetics* / Q000378:metabolism; D024363:Transcription Initiation Site
chemical_list: D000477:Alkylating Agents; D003062:Codon; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D020033:Protein Isoforms; D005038:Ethylnitrosourea