Neutrophil-specific granule deficiency:: homozygous recessive inheritance of a frameshift mutation in the gene encoding transcription factor CCAAT/enhancer binding protein-ε

Neutrophil-specific granule deficiency (SGD) is a rare congenital disorder. The neutrophils of individuals with SGD display atypical bi-lobed nuclei, lack expression of all secondary and tertiary granule proteins, and possess defects in chemotaxis, disaggregation, receptor up-regulation, and bactericidal activity, resulting in frequent and severe bacterial infections. Previously, a homozygous mutation in the CCAAT/enhancer binding protein-epsilon (C/EBP epsilon) gene was reported for one case of SGD. To substantiate the role of C/EBP epsilon in the development of SGD and elucidate its mechanism of inheritance, the mutational status of the gene was determined in a second individual. An A-nucleotide insertion in the coding region of the C/EBP epsilon gene was detected. This mutation completely abolished the predicted translation of all C/EBP epsilon isoforms. Microsatellite and nucleotide sequence analyses of the C/EBP epsilon locus in the parents of the proband indicated that the disorder may have resulted from homozygous recessive inheritance of the mutant allele from an ancestor shared by both parents. The mutant C/EBP epsilon (32) protein localized in the cytoplasm rather than the nucleus and was unable to activate transcription. Consistent with this, a significant decrease in the levels of the messenger RNAs (mRNAs) encoding the secondary granule protein human 18-kd cationic antimicrobial protein (hCAP-18)/LL-37 and the primary granule protein bactericidal/permeability-increasing protein were observed in the patient. The hCAP-18 mRNA was induced by overexpression of C/EBP epsilon (32) in the human myeloid leukemia cell line, U937, supporting the hypothesis that C/EBP epsilon is a key regulator of granule gene synthesis. This study strongly implicates mutation of the C/EBP epsilon gene as the primary genetic defect involved in the development of neutrophil SGD and defines its mechanism of inheritance. (Blood, 2001;97:2561-2567) (C) 2001 by The American Society of Hematology.