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A Mutation in the Translation Initiation Codon of Gata-1 Disrupts Megakaryocyte Maturation and Causes Thrombocytopenia

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A Mutation in the Translation Initiation Codon of Gata-1 Disrupts Megakaryocyte Maturation and Causes Thrombocytopenia 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 Ellis§, Marina R. Carpinelli*, Sandra Mifsud*, Ladina Di Rago,* Jason Corbin*, Nicos A. Nicola*, Douglas J. Hilton*, and Warren S. Alexander*‡ *The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia; †Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia; and §Peter MacCallum Cancer Centre, Trescowthick Research Laboratories, St. Andrew’s Place, East Melbourne, Victoria 3002, Australia Contributed by Donald Metcalf, July 27, 2006 We have generated mice from a N-ethyl-N-nitrosourea mutagen- progenitors in fetal life, an abnormality that resolves spontane- esis screen that carry a mutation in the translation initiation codon ously at birth. This phenotype resembles the transient myelo- of Gata-1, termed Plt13, which is equivalent to mutations found in proliferative disorder associated with trisomy 21 that resolves patients with acute megakaryoblastic leukemia and Down syn- shortly after birth and is followed later in life by AML-M7 DS drome. The Gata-1 locus is present on the X chromosome in in a proportion of affected children (18). humans and in mice. Male mice hemizygous for the mutation We report here a N-ethyl-N-nitrosourea (ENU)-induced mu- (Gata-1Plt13͞Y) failed to produce red blood cells and died during tation in the translation initiation codon of Gata-1, designated embryogenesis at a similar stage to Gata-1-null animals. Female Plt13, which is analogous to mutations detected in patients with mice that carry the Plt13 mutation are mosaic because of random AML-M7 DS and transient myeloproliferative disorder (10–13). inactivation of the X chromosome. Adult Gata-1Plt13/؉ females Gata-1Plt13͞Y mice failed to produce red blood cells and died were not anemic, but they were thrombocytopenic and accumu- during embryogenesis at a similar stage to Gata-1-null animals. lated abnormal megakaryocytes without a concomitant increase in Female mice that carry the Plt13 mutation, mosaic because of megakaryocyte progenitor cells. Gata-1Plt13/؉ mice contained large lyonization of the X chromosome, were born at the expected numbers of blast-like colony-forming cells, particularly in the fetal frequency. Gata-1Plt13/ϩ mice displayed thrombocytopenia and liver, but also in adult spleen and bone marrow, from which accumulation of abnormal megakaryocytes. No significant in- continuous mast cells lines were readily derived. Although the crease in megakaryocyte progenitor cell numbers was observed equivalent mutation to Gata-1Plt13 in humans results in production in Gata-1Plt13/ϩ mice, but accumulation of abnormal blast-like of GATA-1s, a short protein isoform initiated from a start codon colony-forming cells was evident in the fetal liver and persisted downstream of the mutated initiation codon, Gata-1s was not throughout adult life in the bone marrow and spleen. Molecular detected in Gata-1Plt13/؉ mice. analyses showed that, unlike cells in humans bearing mutations in the initiation codon of GATA1, Gata-1Plt13/ϩ mice expressed N-ethyl-N-nitrosourea mutagenesis ͉ platelet no detectable Gata-1s protein. ata-1 is a transcription factor that is essential for appropri- Results Gate development of multiple hematopoietic lineages includ- Plt13, an ENU-Induced Mutation in Gata-1. The founder of the PLT13 ing erythroid, megakaryocytic, eosinophilic, and mast cells (1– pedigree was a thrombocytopenic female mouse (platelet count ϫ 6 4). In megakaryocyte development, Gata-1 and the of 495 10 per milliliter) identified among the G1 offspring of transcriptional cofactor Friend of Gata-1 (Fog-1) regulate ex- ENU-treated male BALB͞c mice. Several female offspring of pression of genes that are critical for megakaryocyte maturation this founder exhibited a similarly reduced platelet count, and and platelet function, including the receptor for thrombopoietin expansion of the pedigree by breeding affected G2 females with (c-mpl), platelet factor 4 (pf4), cell-surface integrin GPIb␣, and wild-type BALB͞c mice revealed that whereas Ϸ50% of female transcription factor NF-E2 (nuclear factor erythroid 2) (5–8). mice were thrombocytopenic, no affected males were produced Mice that lack Gata-1 expression only in the megakaryocyte (Fig. 1A). This result established the heritability of the throm- lineage (⌬neo⌬HS) are viable but display marked thrombocy- bocytopenia and suggested that the Plt13 mutation was X-linked, topenia and abnormal megakaryocytopoiesis (9). potentially with hemizygous lethality. In humans, GATA1 mutations have been associated with In human populations, mutations in GATA1 have been asso- X-linked anemia and thrombocytopenia. Recently, GATA1 mu- ciated with X-linked thrombocytopenia (19–22). Accordingly, ϩ tations have been identified in patients with acute megakaryo- genomic DNA was isolated from affected Gata-1Plt13/ mice for blastic leukemia accompanying Down syndrome (AML-M7 DS) analysis of Gata-1 by DNA sequencing. A single base pair change (10, 11). The mutations occur in the second exon of GATA1 and (T3A transversion) was identified in the second exon of Gata-1 are either small insertions or deletions that introduce premature in affected mice, which disrupts the translation initiation codon stop codons or mutations that disrupt splicing or the start codon of GATA1 (10–13). These mutations all prevent translation of full-length GATA1 and result in the synthesis of a shorter Author contributions: I.J.M., D.M., L.A.M., D.L.K., S.E., M.R.C., N.A.N., D.J.H., and W.S.A. designed research; I.J.M., D.M., L.A.M., D.L.K., S.E., M.R.C., S.M., L.D.R., and J.C. performed GATA1 isoform (GATA1s) that is initiated at Met-84. research; I.J.M., D.M., L.A.M., D.L.K., S.E., M.R.C., D.J.H., and W.S.A. analyzed data; and The N terminus of Gata-1 contains a highly acidic region, I.J.M. and W.S.A. wrote the paper. deletion of which reduces transactivation activity (14). Never- The authors declare no conflict of interest. theless, expression of Gata-1s at high levels is able to drive Abbreviations: ENU, N-ethyl-N-nitrosourea; AML-M7 DS, acute megakaryoblastic leukemia megakaryocytic maturation (7, 15, 16), and mice engineered to and Down syndrome. express Gata-1s using the endogenous Gata-1 promoter (Gata- ‡To whom correspondence may be addressed. E-mail: [email protected] or alexandw@ ⌬ 1 e2) show no signs of anemia or thrombocytopenia in adult life wehi.edu.au. (17). These mice accumulate hyperproliferative megakaryocytic © 2006 by The National Academy of Sciences of the USA 14146–14151 ͉ PNAS ͉ September 19, 2006 ͉ vol. 103 ͉ no. 38 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0606439103 Downloaded by guest on September 26, 2021 Table 1. Peripheral blood profile of Gata-1Plt13/؉ mice Genotype Blood cell parameter Gata-1ϩ/ϩ Gata-1Plt13/ϩ Platelet count (ϫ10Ϫ6 per ml) 1,009 Ϯ 139 473 Ϯ 143* Mean platelet volume, fl 7.1 Ϯ 1.0 8.3 Ϯ 0.8 Red cell count (ϫ10Ϫ9 per ml) 11.1 Ϯ 0.3 10.4 Ϯ 0.8 Hematocrit, % 53.3 Ϯ 1.7 52.4 Ϯ 3.9 White cell count (ϫ10Ϫ6 per ml) 9.2 Ϯ 1.6 9.1 Ϯ 1.9 No. of neutrophils 1.3 Ϯ 0.3 1.3 Ϯ 0.4 No. of lymphocytes 7.6 Ϯ 1.4 7.5 Ϯ 1.6 No. of monocytes 0.06 Ϯ 0.02 0.06 Ϯ 0.02 No. of eosinophils 0.16 Ϯ 0.02 0.10 Ϯ 0.04 Means Ϯ SD are shown (n ϭ 54–58 mice per group). Statistical analysis was by ANOVA with correction for multiple testing (*, P Ͻ 0.001). quency at embryonic day 10.5 [Gata-1ϩ͞Y (10), Gata-1Plt13͞Y (7), Gata-1ϩ/ϩ (8), and Gata-1Plt13/ϩ (8)]; however, by embryonic day 13.5 Gata-1Plt13͞Y embryos were present at a reduced frequency [Gata-1ϩ͞Y (15), Gata-1Plt13͞Y (6), Gata-1ϩ/ϩ (17), and Gata-1Plt13/ϩ (12)], were smaller than wild-type embryos, were pallid consistent with severe anemia, and upon histological examination exhibited regions of necrosis and little or no fetal liver (data not shown). Whereas no Gata-1Plt13͞Y mice survived to birth, female heterozygote (Gata-1Plt13/ϩ) embryos exhibited no evidence of anemia or other abnormalities and were born at the expected frequency. MEDICAL SCIENCES Abnormal Megakaryocytopoiesis in Gata-1Plt13/؉ Mice. Analysis of peripheral blood from a cohort of female Gata-1Plt13/ϩ mice confirmed a 60% reduction in the number of circulating platelets when compared with wild-type littermates, but there was no significant increase in mean platelet volume (Table 1). Although Gata-1 is an essential regulator of red blood cell maturation, affected mice displayed normal numbers of red blood cells and Fig. 1. The Plt13 mutation affects the translation initiation codon of Gata-1. a normal hematocrit. White blood cell counts were within the (A) The PLT13 founder (G1, arrow) was identified because of a low platelet normal range (Table 1). count (495 ϫ 106 per milliliter) and bred to test the heritability of the The spleen and bone marrow of Gata-1Plt13/ϩ mice demon- phenotype. G2 mice that displayed a reduced platelet count (filled circles) strated a significant accumulation of megakaryocytes (Figs. 2A were selected for breeding, and data from their offspring (G3) were separated and 3A), and a uniform finding in all Gata-1Plt13/ϩ mice was the by sex to demonstrate that the phenotype was X-linked. Platelet counts from presence of small numbers of single megakaryocytes in the liver G3 mice were tabulated (mean Ϯ SD), and mice that had a platelet count Ͻ800 ϫ 106 per milliliter were considered affected.
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