A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPε Leads to Neutrophil-Specific Granule Deficiency

J Immunol. 2015 Jul 1;195(1):80-6. doi: 10.4049/jimmunol.1402222. Epub 2015 May 27.


Neutrophil-specific granule deficiency (SGD) is a rare autosomal recessive primary immunodeficiency characterized by neutrophil dysfunction, bilobed neutrophil nuclei and lack of neutrophil-specific granules. Defects in a myeloid-specific transcription factor, CCAAT/enhancer binding protein-ε (C/EBPε), have been identified in two cases in which homozygous frameshift mutations led to loss of the leucine zipper domain. In this study, we report a 55-y-old woman affected with SGD caused by a novel homozygous 2-aa deletion (ΔRS) in the leucine zipper domain of the C/EBPε gene. The patient showed characteristic neutrophil abnormalities and recurrent skin infections; however, there was no history of deep organ infections. Biochemical analysis revealed that, in contrast to the two frameshift mutations, the ΔRS mutant maintained normal cellular localization, DNA-binding activity, and dimerization, and all three mutants exhibited marked reduction in transcriptional activity. The ΔRS mutant was defective in its association with Gata1 and PU.1, as well as aberrant cooperative transcriptional activation of eosinophil major basic protein. Thus, the ΔRS likely impairs protein-protein interaction with other transcription factors, resulting in a loss of transcriptional activation. These results further support the importance of the leucine zipper domain of C/EBPε for its essential function, and indicate that multiple molecular mechanisms lead to SGD.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence*
  • CCAAT-Enhancer-Binding Proteins / genetics*
  • CCAAT-Enhancer-Binding Proteins / immunology*
  • Cytoplasmic Granules / immunology
  • Cytoplasmic Granules / pathology
  • Eosinophil Major Basic Protein / genetics
  • Eosinophil Major Basic Protein / immunology
  • Female
  • GATA1 Transcription Factor / genetics
  • GATA1 Transcription Factor / immunology
  • Gene Expression Regulation
  • Homozygote
  • Humans
  • Lactoferrin / deficiency*
  • Lactoferrin / genetics
  • Lactoferrin / immunology
  • Leukocyte Disorders / genetics*
  • Leukocyte Disorders / immunology
  • Leukocyte Disorders / pathology
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Neutrophils / immunology*
  • Neutrophils / pathology
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteoglycans / genetics
  • Proteoglycans / immunology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology
  • Sequence Deletion*
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / immunology
  • Transcription, Genetic


  • CCAAT-Enhancer-Binding Proteins
  • GATA1 Transcription Factor
  • GATA1 protein, human
  • Proteoglycans
  • Proto-Oncogene Proteins
  • Trans-Activators
  • proto-oncogene protein Spi-1
  • CEBPE protein, human
  • PRG2 protein, human
  • Eosinophil Major Basic Protein
  • Lactoferrin

Supplementary concepts

  • Specific Granule Deficiency