PATTERN OF INHERITANCE IN HEREDITARY MYELOPEROXIDASE DEFICIENCY ASSOCIATED WITH THE R569W MISSENSE MUTATION

Myeloperoxidase (MPO) is an essential component of the oxygen-dependen t microbicidal system of neutrophils and monocytes. Hereditary deficie ncy of MPO occurs in 1 in 2,000 to 4,000 individuals in the general po pulation and has been generally considered an autosomal recessive trai t. Previous studies have used the peroxidase activity of blood leukocy tes to assess the phenotype of affected family members. Eosinophil per oxidase (EPO) also contributes to the peroxidase activity of blood leu kocytes. Because EPO expression is normal in MPO-deficient subjects, e osinophil contamination can significantly contribute to peroxidase act ivity iu leukocytes from family members of an MPO-deficient subject an d 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 defi ciency in sixteen individuals from five unrelated kindreds. Each kindr ed had an index case with MPO deficiency and the R569W missense mutati on, a genotype that causes MPO deficiency. Our analysis demonstrated t hat MPO deficiency was not inherited as a simple autosomal recessive t rait. Most subjects were compound heterozygotes with respect to the R5 69W mutation and demonstrated a spectrum of phenotypes. Our data demon strate the broad phenotypic impact of compound heterozygosity on the e xpression and function of a multimeric protein such as MPO.