Molecular analysis of myeloperoxidase deficiency shows heterogeneous patterns of the complete deficiency state manifested at the genomic, mRNA, and protein levels

Abstract

Myeloperoxidase (MPO) is a glycosylated hemoprotein contained in the azurophil granules of human polymorphonuclear leukocytes (PMNs). MPO is thought to play a role in the oxidative antimicrobial activity of neutrophils by catalyzing the formation of hypochlorous acid, a potent microbicide, from hydrogen peroxide and chloride anions. Seven unrelated individuals with complete MPO deficiency, a relatively common heritable defect of neutrophils, were identified during routine blood tests. Molecular analyses were conducted to determine the level of the abnormality in these individuals. Western blot analysis showed that 6 of the 7 donors were devoid of immunoreactive MPO protein, while neutrophils from one individual contained only the 55-Kd subunit. Northern analysis of bone marrow RNA from one MPO-deficient donor showed the presence of the normal-sized 3.3-kb transcript indicating that the defect in MPO biosynthesis in this case was posttranscriptional. Southern analysis of four MPO-deficient donors showed a normal Bgl II digestion pattern, whereas an abnormal restriction pattern was observed in a fifth individual. Although the Bgl II pattern was similar to that observed in an unrelated subject described by Nauseef (Blood 73:290, 1989), our study strongly suggests that the point mutation does not reflect a polymorphism. Taken together, these analyses show the existence of diverse abnormalities associated with MPO-deficiency that may be detected at the level of the MPO polypeptide, mRNA, and gene.

Myeloperoxidase in kidney disease

“…Primary MPO deficiency is a relatively frequent event with a prevalence of 2.5 to 7.5 per 10000 people [37]. It can be attributed to DNA missense mutations/deletions, as well as to impairment of transcriptional activity or attributed to mutations leading to defective proteolytic processing [38][39][40][41][42]. Generally, hereditary MPO deficiency has been considered an autosomal-recessive trait; however, some pedigrees did not show a simple Mendelian mode of inheritance [38,43].…”

Effect of the R569W Missense Mutation on the Biosynthesis of Myeloperoxidase

“…Taken together, data from the studies presented provide an experimental framework for characterization of additional features of normal synthesis, processing, and lysosomal targeting of MPO. It is clear that there is molecular heterogeneity underlying MPO deficiency (44), and this system may be useful for identifying specific events in MPO expression which are abnormal in other genotypes of the disorder, including pretranslational (45) as well as posttranslational defects (21,46). On a larger scale, this expression system may be applicable for the study of biosynthesis of other heme-containing proteins.…”

Lethal candida sepsis associated with myeloperoxidase deficiency and pre‐eclampsia

“…In this regard, MPO‐deficiency is a remarkable finding, as MPO has been identified as a factor important for candidacidal activity of human polymorphonuclear neutrophil leukocytes (4), and severe impairment in the early host defense against C. albicans has been demonstrated in MPO‐deficient mice (5). In pregnancy, MPO‐deficiency may occur as a secondary disorder (6).…”