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

doi:10.1084/jem.189.11.1847

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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 $epsilon$

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, defectiveneutrophil chemotaxis and bactericidal activity, and lack of neutrophilsecondary 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 mousemodel possesses distinctive defects, including a lack of neutrophilsecondary granule proteins. Sequence analysis of the genomic DNAof a patient with SGD revealed a five-basepair deletion in thesecond exon of the C/EBP $epsilon$ locus. The predicted frame shift resultsin a truncation of the 32-kD major C/EBP $epsilon$ isoform, with loss ofthe dimerization domain, DNA binding region, and transcriptionalactivity. The multiple functional defects observed in these earlyneutrophil progenitor cells, a consequence of C/EBP $epsilon$ deficiency,define SGD as a defect in myelopoiesis and establish the requirementfor C/EBP $epsilon$ for the promyelocyte-myelocyte transition in myeloiddifferentiation.

Key words: myelopoiesis; lactoferrin; granulocyte; immunodeficiency; neutrophil

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