HEREDITARY MYELOPEROXIDASE DEFICIENCY DUE TO A MISSENSE MUTATION OF ARGININE-569 TO TRYPTOPHAN

Hereditary deficiency of myeloperoxidase (MPO) is a common disorder bu t its genetic basis is unknown. We have reported that neutrophils from individuals with MPO deficiency lack enzymatic and immunochemical evi dence for mature MPO but have a 90-kDa precursor protein. We have thus hypothesized that hereditary MPO deficiency reflects a defect in proc essing of a mutated primary translation product. Genomic DNA's from no rmal subjects digested with BglII and probed with radiolabeled cDNA fo r MPO have a 2.6-kilobase (kb) band. Previously we described the prese nce of an aberrant 2.1-kb fragment in BglII digests from most individu als with either partial or complete MPO deficiency. We describe here t he responsible mutation. The substitution of thymidine for cytosine in exon 10 at nucleotide 8,089 of the genomic sequence results in genera tion 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 wi th MPO deficiency. At the amino acid level this mutation would replace arginine at codon 569 with tryptophan. Six of seven patients with com plete MPO deficiency had this mutation. One subject was homozygous for this mutation whereas five others were heterozygous at this locus. Th e seventh patient was the only completely deficient subject without th is mutation. Thus, at least two mutations and three genotypes can prod uce the phenotype of MPO deficiency.