A mutation in the translation initiation codon of Gata-1 disrupts megakaryocyte maturation and causes thrombocytopenia.
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.
Majewski
Ian J
IJ
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Metcalf
Donald
D
Mielke
Lisa A
LA
Krebs
Danielle L
DL
Ellis
Sarah
S
Carpinelli
Marina R
MR
Mifsud
Sandra
S
Di Rago
Ladina
L
Corbin
Jason
J
Nicola
Nicos A
NA
Hilton
Douglas J
DJ
Alexander
Warren S
WS
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
D000477:Alkylating Agents; D003062:Codon; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D020033:Protein Isoforms; D005038:Ethylnitrosourea