Pattern of inheritance in hereditary myeloperoxidase deficiency associated with the R569W missense mutation

Abstract

Myeloperoxidase (MPO) is an essential component of the oxygen-dependent microbicidal system of neutrophils and monocytes. Hereditary deficiency of MPO occurs in 1 in 2,000 to 4,000 individuals in the general population and has been generally considered an autosomal recessive trait. Previous studies have used the peroxidase activity of blood leukocytes to assess the phenotype of affected family members. Eosinophil peroxidase (EPO) also contributes to the peroxidase activity of blood leukocytes. Because EPO expression is normal in MPO-deficient subjects, eosinophil contamination can significantly contribute to peroxidase activity in leukocytes from family members of an MPO-deficient subject and thereby undermine correct interpretation of the inheritance pattern. To avoid this potential problem, we used cytochemical, immunochemical, and genetic techniques to assess the inheritance pattern of MPO deficiency in sixteen individuals from five unrelated kindreds. Each kindred had an index case with MPO deficiency and the R569W missense mutation, a genotype that causes MPO deficiency. Our analysis demonstrated that MPO deficiency was not inherited as a simple autosomal recessive trait. Most subjects were compound heterozygotes with respect to the R569W mutation and demonstrated a spectrum of phenotypes. Our data demonstrate the broad phenotypic impact of compound heterozygosity on the expression and function of a multimeric protein such as MPO.

Regulation of innate immunity by NADPH oxidase

“…The myeloperoxidase-hydrogen peroxide-halide system in neutrophils has potent antimicrobial activity and cytotoxicity (9). Myeloperoxidase deficiency is common, affecting 1 in 2,000 to 4,000 individuals in the general population (10). In contrast to the severe infectious complications in CGD, myeloperoxidase deficiency is usually asymptomatic in the absence of co-existing conditions such as diabetes mellitus (11).…”

Association of Primary Myeloperoxidase Deficiency and Myeloproliferative Neoplasm

“…Primary myeloperoxidase (MPO) deficiency is caused by a mutation within the MPO gene, while the expression of eosinophil peroxidase, the gene of which is independent of MPO, is normal (1,2). It remains to be determined whether the association of MPO-deficiency with MPN in the current patient is coincidental or whether there is a causal relationship between the two conditions.…”

NQO1, MPO, and the risk of lung cancer: A HuGE review

“…Three missense mutations associated with MPO deficiency have been described, namely Tyr173Cys (exon 4), 102 Met251Thr (exon 6, T4311C), 103 and Arg569Trp (exon 10). 104 Recently, another G-to-A transition at position -129 in the promoter region of the MPO gene was described. 105 There are no reports of these polymorphisms in relation to lung cancer risk.…”