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An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis

Nature Genetics volume 38, pages 807812 (2006) | Download Citation



Acquired somatic mutations1,2,3,4,5,6 in exon 2 of the hematopoietic transcription factor GATA-1 have been found in individuals with Down syndrome with both transient myeloproliferative disorder2,3,4,5,6,7,8,9,10 and acute megakaryoblastic leukemia1,2,3,4,6,8,9,10. These mutations prevent the synthesis of the full-length protein but allow the synthesis of its short isoform, GATA-1s. Experiments in mice11 suggest that GATA-1s supports normal adult megakaryopoiesis, platelet formation and erythropoiesis. Here we report a mutation, 332G → C, in exon 2 of GATA1, leading to the synthesis of only the short isoform in seven affected males from two generations of a family. Hematological profiles of affected males demonstrate macrocytic anemia, normal platelet counts and neutropenia in most cases. Altogether, data suggest that GATA-1s alone, produced in low or normal levels, is not sufficient to support normal erythropoiesis. Moreover, this is the first study to indicate that a germline splicing mutation does not lead to leukemia in the absence of other cooperating events, such as Down syndrome.

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We thank N. Conran for her English revision of the manuscript and suggestions; S. Gambero and C. Lanaro for technical assistance with Genorm analysis and Real Time PCR; C.A. Chagas, J.C. Moraes, T.E. Prates for technical assistance with the immunohistochemical study in bone marrow biopsies; R. Secolin for technical assistance with Lod Score analyses; T. Machado for technical assistance with the analysis of plasma coagulation factors and the plasma coagulation assay; F.G. Pereira for technical assistance with flow cytometric analysis of platelet membrane glycoproteins in platelet-rich plasma and J.L. Saturno for technical assistance with ultrastructural analysis of platelets. This work was supported by Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP; grant no. 02/13801-7); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; grant no. 301310/2004-1) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; grant no. DS-108/00).

Author information


  1. Department of Internal Medicine, Hemocentro, School of Medical Science, Universidade Estadual de Campinas, Campinas, São Paulo 13083-970, Brazil.

    • Luciana M Hollanda
    • , Carmen S P Lima
    • , Anderson F Cunha
    • , Dulcinéia M Albuquerque
    • , Margareth C Ozelo
    • , Sara T O Saad
    •  & Fernando F Costa
  2. Department of Pathological Anatomy, School of Medical Sciences, Campinas, São Paulo 13083-970, Brazil.

    • José Vassallo
  3. Department of Histology, Institute of Biology, Universidade Estadual de Campinas, Campinas, São Paulo 13083-970, Brazil.

    • Paulo P Joazeiro


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L.M.H. performed and processed most of experiments and wrote the first draft of the manuscript. C.S.P.L. contributed for the clinical and bone marrow morphology data of individuals. A.F.C. and D.M.A. performed some experiments and assisted L.M.H. in a number of procedures. J.V. contributed to the morphological and immunohistochemical study in bone marrow biopsies. M.C.O. contributed to the study of plasma coagulation factors, platelet aggregation assays and flow cytometric analysis of platelet membrane glycoproteins in platelet-rich plasma. P.P.J. contributed for the ultrastructural analysis of platelets. S.T.O.S. contributed to analysis of the clinical and laboratory data. F.F.C. conceived and designed the study and was responsible for the final draft of the manuscript. All authors were involved in the final revision of the article, contributed to the interpretation of the data and gave final approval to the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Fernando F Costa.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Relative expression of mRNA obtained by real-time PCR of GATA1 and GATA1s from K562 cells, individual III-16, and pooled normal bone marrow cells.

  2. 2.

    Supplementary Table 1

    Clinical laboratory findings and morphological characteristics of peripheral blood and bone marrow in affected males.

  3. 3.

    Supplementary Table 2

    Hematological data from heterozygous families.

  4. 4.

    Supplementary Table 3

    Platelet functional studies of the unaffected, heterozygous and hemizygous family members.

  5. 5.

    Supplementary Table 4

    Primer sequences for PCR and RT-PCR.

  6. 6.

    Supplementary Table 5

    Primer sequences for real-time quantitative PCR.

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