J. Exp. Med., Volume 189, Number 11, June 7, 1999 1847-1852

Neutrophil-specific Granule Deficiency Results from a Novel Mutation with Loss of Function of the Transcription Factor CCAAT/Enhancer Binding Protein  

By Julie A. Lekstrom-Himes, Susan E. Dorman, Piroska Kopar, Steven M. Holland, and John I. Gallin

From the Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

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), 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/EBP locus. The predicted frame shift results in a truncation of the 32-kD major C/EBP 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/EBP deficiency, define SGD as a defect in myelopoiesis and establish the requirement for C/EBP for the promyelocyte-myelocyte transition in myeloid differentiation.

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