Nature Genetics
34, 308 - 312 (2003)
Published online: 1 June 2003; | doi:10.1038/ng1170
Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2Richard E Person1, 7, Feng-Qian Li2, 7, Zhijun Duan2, 7, Kathleen F Benson2, Jeremy Wechsler2, Helen A Papadaki3, George Eliopoulos3, Christina Kaufman4, Salvatore J Bertolone5, Betty Nakamoto6, Thalia Papayannopoulou6, H Leighton Grimes4
& Marshall Horwitz21
Department of Pathology, University of Washington School of Medicine, Box 357720, Seattle, Washington 98195, USA. 2
Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Box 357720, Seattle, Washington 98195, USA. 3
Department of Hematology, University of Crete School of Medicine, University Hospital of Heraklion, P.O. Box 1352, Crete, Greece. 4
Institute for Cellular Therapeutics and Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. 5
Division of Hematology/Oncology, Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. 6
Division of Hematology, Department of Medicine, University of Washington School of Medicine, Box 357720, Seattle, Washington 98195, USA. 7
These authors contributed equally to this work.
Correspondence should be addressed to Marshall Horwitz horwitz@u.washington.eduMice 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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