title: Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2.
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.
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Box 357720, Seattle, Washington 98195, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Person
authors.forename: Feng-Qian
authors.initials: FQ
authors.lastname: Li
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Duan
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Benson
authors.forename: Jeremy
authors.initials: J
authors.lastname: Wechsler
authors.forename: Helen A
authors.initials: HA
authors.lastname: Papadaki
authors.forename: George
authors.initials: G
authors.lastname: Eliopoulos
authors.forename: Christina
authors.initials: C
authors.lastname: Kaufman
authors.forename: Salvatore J
authors.initials: SJ
authors.lastname: Bertolone
authors.forename: Betty
authors.initials: B
authors.lastname: Nakamoto
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
authors.forename: H Leighton
authors.initials: HL
authors.lastname: Grimes
authors.forename: Marshall
authors.initials: M
authors.lastname: Horwitz
mesh_terms: D000328:Adult; D000368:Aged; D002675:Child, Preschool; D002875:Chromosomes / Q000276:immunology; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D019272:Leukocyte Elastase / Q000235:genetics*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D009503:Neutropenia / Q000097:blood / Q000209:etiology / Q000235:genetics*; D009504:Neutrophils / Q000201:enzymology; D010375:Pedigree; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors; D008156:Luciferases; D019272:Leukocyte Elastase