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Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2

Nature Genetics volume 34, pages 308–312 (2003)Cite this article

Abstract

Mice lacking the transcriptional repressor oncoprotein Gfi1 are unexpectedly neutropenic1,2. We therefore screened GFI1 as a candidate for association with neutropenia in affected individuals without mutations in ELA2 (encoding neutrophil elastase), the most common cause of severe congenital neutropenia (SCN; ref. 3). We found dominant negative zinc finger mutations that disable transcriptional repressor activity. The phenotype also includes immunodeficient lymphocytes and production of a circulating population of myeloid cells that appear immature. We show by chromatin immunoprecipitation, gel shift, reporter assays and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA2, linking these two genes in a common pathway involved in myeloid differentiation.

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Figure 1: GFI1 mutations and hematopoietic phenotype.
Figure 2: Transcriptional and DNA-binding consequences of mutations in GFI1.
Figure 3: ChIP assay showing Gfi1 targeting of ELA2.

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Acknowledgements

We thank P. Tsichlis for reagents and advice, J. Miller for advice, K. Williams for technical assistance and the subjects for their cooperation. M.H. thanks the late D.M. Horwitz for his encouragement and support. This work was supported by the U.S. National Institutes of Health, Doris Duke Foundation, Leukemia & Lymphoma Society and Burroughs-Wellcome grants (M.H.) and Hope Street Kids grant (H.L.G.).

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Author notes

  1. Richard E Person, Feng-Qian Li and Zhijun Duan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, University of Washington School of Medicine, Box 357720, Seattle, 98195, Washington, USA

    Richard E Person

  2. Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Box 357720, Seattle, 98195, Washington, USA

    Feng-Qian Li, Zhijun Duan, Kathleen F Benson, Jeremy Wechsler & Marshall Horwitz

  3. Department of Hematology, University of Crete School of Medicine, University Hospital of Heraklion, P.O. Box 1352, Crete, Greece

    Helen A Papadaki & George Eliopoulos

  4. Institute for Cellular Therapeutics and Department of Surgery, University of Louisville School of Medicine, Louisville, 40202, Kentucky, USA

    Christina Kaufman & H Leighton Grimes

  5. Division of Hematology/Oncology, Department of Pediatrics, University of Louisville School of Medicine, Louisville, 40202, Kentucky, USA

    Salvatore J Bertolone

  6. Division of Hematology, Department of Medicine, University of Washington School of Medicine, Box 357720, Seattle, 98195, Washington, USA

    Betty Nakamoto & Thalia Papayannopoulou

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  1. Richard E Person
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  13. Marshall Horwitz
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Corresponding author

Correspondence to Marshall Horwitz.

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Person, R., Li, FQ., Duan, Z. et al. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat Genet 34, 308–312 (2003). https://doi.org/10.1038/ng1170

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