Furthermore, their azurophil granules are lighter than normal and contain little or none of the most abundant of azurophil granule proteins, human neutrophil peptides, which constitute 30–50% of the azurophil granule content in neutrophil from healthy donors. Functionally, the neutrophils are deficient in chemotaxis and have a reduced NADPH oxidase activity. The disorder is caused by mutations in the CCAAT/enhancer binding protein-e, a transcription factor essential for neutrophil development beyond the promyelocyte stage. C/EBP-e is critical for transcription of most granule proteins localized to specific and gelatinase granules as well as for azurophil granule proteins expressed in the late promyelocyte stage such as bactericidal permeability increasing protein and HNPs. HNPs and BPI localize in a subset of azurophil granules and are largely regulated similarly to specific granule proteins with peak transcription in myelocytes/metamyelocytes and are strongly MK-1775 Wee1 inhibitor induced by C/EBP-e in vitro. In accordance with this, HNPs are reduced by over 90% in SGD. The 32/30 kDa isoforms are relatively weak transactivators and require co-activators such as c-myb for optimal function. In contrast, mice only generate one C/EBP-e mRNA transcript, which can give rise to a 36 and 34 kDa isoform through use of alternative translational start sites. HNPs are small cationic peptides with broad antimicrobial properties. They are synthesized as inert and non-polar proHNPs, which are processed by unidentified protease to cationic HNPs in promyelocytes and are retained intracellularly via binding to the negatively charged proteoglycan serglycin. In myelocytes and metamyelocytes that produce large amount of proHNP, the proform is not cleaved and most is secreted into the bone marrow plasma. It has not yet been examined, whether the reduced amounts of HNPs in SGD are merely a result of reduced transcription of HNPs or whether the posttranslational processing and cellular retention of HNPs might also be impaired by lack of C/EBP-e. The Cebpe-/- mouse is an excellent model of SGD, but since mice do not express myeloid defensins, this model cannot be used directly to characterize the role of C/EBP-e in controlling HNP expression in vivo. We therefore crossed the transgenic HNP1 mouse with the Cebpe mouse to study the in vivo significance of C/EBP-e for HNP-1 transcription and processing. Neutrophils from the transgenic HNP-1 mouse contain less than 10% of the HNP-1 present in human neutrophils. This obviously limits the usefulness of the HNP-1 transgene as a mouse model for studying the role of HNP in innate immunity, but the model can be useful for studying regulatory aspects of HNP-1 expression. Myeloid a-defensin genes are subject to extensive copy number variations ranging from 2 to 22 DEFA1/DEFA3 genes per diploid genome, and neutrophil a-defensin content has been positively related to copy number.