Myeloperoxidase is an enzyme found in neutrophils that is thought to play a significant role in host defense against microbial infection. Myeloperoxidase deficiency affects one in two thousand people making this the most common of the identified defects of polymorphonuclear leukocytes. Neutrophils isolated from totally deficient individuals have a severely diminished capacity to kill micro-organisms. If also suffering from diabetes, myeloperoxidase deficient people can have major systemic infections. The enzyme is synthesized only during the promyelocytic stage of myeloid differentiation and as a larger precursor. It is extensively processed as it matures and is transported to its correct subcellular compartment. With the goal of understanding myeloperoxidase expression in both normal and deficient people, we have isolated and sequenced cDNA and genomic clones. We have found that normal humans produce two messages for the enzyme and that the gene covers some 15 kilobases. To extend our knowledge of the myeloperoxidase gene and its expression in normal and deficient states, the following studies are proposed: 1. Characterize in detail the two mRNAs for myeloperoxidase and identification of regions of the molecule important for transport to its correct subcellular compartment. 2. Complete the characterization of the genomic clones and identify sequences 5' of the coding region that regulate expression of the gene. 3. Identify proteins that interact with the regulatory sequences with the goal of understanding the tissue and temporal specificity of myeloperoxidase gene expression. 4. Utilize the information about the mRNAs and gene expression in normal people to begin the characterization of the lesions involved in myeloperoxidase deficiency.
