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Nat Genet. 2003 Jul;34(3):308-12.

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

Author information

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

Abstract

Mice lacking the transcriptional repressor oncoprotein Gfi1 are unexpectedly neutropenic. 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.

PMID:
12778173
PMCID:
PMC2832179
DOI:
10.1038/ng1170
[Indexed for MEDLINE]
Free PMC Article

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