AN INACTIVE CYTOCHROME-P450 CYP2D6 ALLELE CONTAINING A DELETION AND ABASE SUBSTITUTION

The cytochrome P450 CYP2D6 is a polymorphic enzyme, for which 5%-10% o f Caucasians (poor metabolizers) lack activity. The majority of mutati ons giving rise to the deficiency have now been identified but some in dividuals show anomalous phenotype-genotype relationships when screene d for the common mutant alleles. We have sequenced all nine exons and intron-exon boundaries in a subject who was phenotypically a poor meta bolizer but genotypically heterozygous when screened for the common al leles. A single base-pair deletion (T-1795) was detected in exon 3 and a base substitution (G(2064)A) resulting in an amino acid substitutio n (G(212)E) in exon 4. The deletion results in premature termination o f translation and a truncated protein. Tn a group of 50 white American s, the allele frequency for the new mutant allele was 0.01. The new al lele explains some cases of anomalous genotype/phenotype relationships for CYP2D6.