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A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPε Leads to Neutrophil-Specific Granule Deficiency.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2015 Jul 01; Vol. 195 (1), pp. 80-6. Date of Electronic Publication: 2015 May 27. - Publication Year :
- 2015
-
Abstract
- 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.<br /> (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Subjects :
- Adult
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 genetics
Lactoferrin immunology
Leukocyte Disorders immunology
Leukocyte Disorders pathology
Male
Middle Aged
Molecular Sequence Data
Neutrophils pathology
Protein Binding
Protein Structure, Tertiary
Proteoglycans genetics
Proteoglycans immunology
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins immunology
Signal Transduction
Trans-Activators genetics
Trans-Activators immunology
Transcription, Genetic
Base Sequence
CCAAT-Enhancer-Binding Proteins genetics
CCAAT-Enhancer-Binding Proteins immunology
Lactoferrin deficiency
Leukocyte Disorders genetics
Neutrophils immunology
Sequence Deletion
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 195
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 26019275
- Full Text :
- https://doi.org/10.4049/jimmunol.1402222