title: A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPε Leads to Neutrophil-Specific Granule Deficiency.
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.
authors.affiliation: Department of Pediatrics, Institute of Medical, Pharmaceutical and Health Sciences, School of Medicine, Kanazawa University, Kanazawa 920-8641, Japan; taizo@staff.kanazawa-u.ac.jp.
authors.forename: Taizo
authors.initials: T
authors.lastname: Wada
authors.affiliation: Department of Stem Cell Biology, Institute of Medical, Pharmaceutical and Health Sciences, School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan;
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Akagi
authors.affiliation: Department of Pediatrics, Institute of Medical, Pharmaceutical and Health Sciences, School of Medicine, Kanazawa University, Kanazawa 920-8641, Japan;
authors.forename: Masahiro
authors.initials: M
authors.lastname: Muraoka
authors.affiliation: Department of Pediatrics, Institute of Medical, Pharmaceutical and Health Sciences, School of Medicine, Kanazawa University, Kanazawa 920-8641, Japan;
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toma
authors.affiliation: Department of Dermatology, Komatsu Municipal Hospital, Komatsu 923-0961, Japan;
authors.forename: Kenzo
authors.initials: K
authors.lastname: Kaji
authors.affiliation: Department of Infection and Host Defense, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan;
authors.forename: Kazunaga
authors.initials: K
authors.lastname: Agematsu
authors.affiliation: Division of Hematology and Oncology, Cedars-Sinai Medical Center, University of California Los Angeles School of Medicine, Los Angeles, CA 90048; and Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.affiliation: Department of Stem Cell Biology, Institute of Medical, Pharmaceutical and Health Sciences, School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokota
authors.affiliation: Department of Pediatrics, Institute of Medical, Pharmaceutical and Health Sciences, School of Medicine, Kanazawa University, Kanazawa 920-8641, Japan;
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
mesh_terms: D000328:Adult; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000276:immunology*; D003594:Cytoplasmic Granules / Q000276:immunology / Q000473:pathology; D047093:Eosinophil Major Basic Protein / Q000235:genetics / Q000276:immunology; D005260:Female; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D007781:Lactoferrin / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D007960:Leukocyte Disorders / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology; D017384:Sequence Deletion; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D047093:Eosinophil Major Basic Protein; D050982:GATA1 Transcription Factor; D007781:Lactoferrin; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C494688:GATA1 protein, human; C070790:CEBPE protein, human; C074129:PRG2 protein, human