title: Neutrophil-specific granule deficiency results from a novel mutation with loss of function of the transcription factor CCAAT/enhancer binding protein epsilon.
abstract: Neutrophil-specific granule deficiency (SGD) is a rare disorder characterized by recurrent pyogenic infections, defective neutrophil chemotaxis and bactericidal activity, and lack of neutrophil secondary granule proteins. CCAAT/enhancer binding protein (C/EBP)epsilon, a member of the leucine zipper family of transcription factors, is expressed primarily in myeloid cells, and its knockout mouse model possesses distinctive defects, including a lack of neutrophil secondary granule proteins. Sequence analysis of the genomic DNA of a patient with SGD revealed a five-basepair deletion in the second exon of the C/EBPepsilon locus. The predicted frame shift results in a truncation of the 32-kD major C/EBPepsilon isoform, with loss of the dimerization domain, DNA binding region, and transcriptional activity. The multiple functional defects observed in these early neutrophil progenitor cells, a consequence of C/EBPepsilon deficiency, define SGD as a defect in myelopoiesis and establish the requirement for C/EBPepsilon for the promyelocyte-myelocyte transition in myeloid differentiation.
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Lekstrom-Himes
authors.forename: S E
authors.initials: SE
authors.lastname: Dorman
authors.forename: P
authors.initials: P
authors.lastname: Kopar
authors.forename: S M
authors.initials: SM
authors.lastname: Holland
authors.forename: J I
authors.initials: JI
authors.lastname: Gallin
mesh_terms: D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D003594:Cytoplasmic Granules / Q000473:pathology / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009504:Neutrophils / Q000473:pathology / Q000502:physiology*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D016133:Polymerase Chain Reaction
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins