DNA polymorphism and mutations in CPN1, including the genomic basis of carboxypeptidase N deficiency.

Carboxypeptidase N (EC 3.4.17.3) regulates the activity of peptides such as kinins and anaphylatoxins. Although deficiency of carboxypeptidase N (MIM 212070) produces a severe allergic syndrome, no human mutations have ever been described. Therefore, using archival genomic DNA from a subject with documented carboxypeptidase N deficiency, we sequenced CPN1 (MIM 603103), which encodes the catalytic subunit of carboxypeptidase N. In the genomic DNA of the proband, we discovered three CPN1 variants: (1) 385fsInsG, a frameshift mutation in exon 1 due to a single G insertion at nucleotide 385; (2) 746G>A single-nucleotide polymorphism (SNP), a missense mutation in exon 3 that predicted substitution of aspartic acid for the wild-type conserved glycine at amino acid 178 (G178D); and (3) IVS1 +6C>T, an SNP in intron 1. Among 128 normal Caucasians, the 385fsInsG mutation was absent and the G178D mutation had a frequency of 0.0078, suggesting that these were rare molecular events that likely contributed to the carboxypeptidase N deficiency phenotype. The frequency of the IVS1 +6C>T polymorphism was 0.051. The reagents described here provide tools for further study of association with clinical and biochemical phenotypes related to allergy and immunity.