Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan.

Hereditary deficiency of myeloperoxidase (MPO) is a common disorder but its genetic basis is unknown. We have reported that neutrophils from individuals with MPO deficiency lack enzymatic and immunochemical evidence for mature MPO but have a 90-kDa precursor protein. We have thus hypothesized that hereditary MPO deficiency reflects a defect in processing of a mutated primary translation product. Genomic DNA's from normal subjects digested with BglII and probed with radiolabeled cDNA for MPO have a 2.6-kilobase (kb) band. Previously we described the presence of an aberrant 2.1-kb fragment in BglII digests from most individuals with either partial or complete MPO deficiency. We describe here the responsible mutation. The substitution of thymidine for cytosine in exon 10 at nucleotide 8,089 of the genomic sequence results in generation of a recognition site for BglII not present normally and converts the normal 2.6-kb BglII fragment to the 2.1-kb fragment associated with MPO deficiency. At the amino acid level this mutation would replace arginine at codon 569 with tryptophan. Six of seven patients with complete MPO deficiency had this mutation. One subject was homozygous for this mutation whereas five others were heterozygous at this locus. The seventh patient was the only completely deficient subject without this mutation. Thus, at least two mutations and three genotypes can produce the phenotype of MPO deficiency.