AN UNEQUAL CROSS-OVER EVENT WITHIN THE CYP2D GENE-CLUSTER GENERATES ACHIMERIC CYP2D7 CYP2D6 GENE WHICH IS ASSOCIATED WITH THE POOR METABOLIZER PHENOTYPE/

1 The study of the CYP2D genotype and phenotype of a Caucasian family revealed that a XbaI-9 kb allele was associated with the poor metaboli zer phenotype. 2 A Polymerase Chain Reaction (PCR)-based assay showed that the previously described mutations D6A and D6B are not associated with the XbaI-9 kb allele. 3 To explore the molecular basis of the po or metabolizer phenotype associated with the XbaI-9 kb allele, complet e sequencing of the nine exons and intron-exon boundaries of the CYP2D 6 gene was undertaken after amplification by PCR. 4 All the exons were successfully amplified using CYP2D6 gene-specific primers except exon 1 which required a combination of CYP2D7 gene-specific 5' primer and a CYP2D6 gene-specific 3' primer. 5 Sequence data derived from this am plified product revealed that the XbaI-9 kb allele corresponds to a no vel rearrangement of the locus. This involved a deletion of an approxi mately 20 kilobase (kb) DNA segment generating a hybrid 5' CYP2D7/CYP2 Dd 3' gene. 6 The chimeric gene is non-functional presumably due to an insertion in exon 1 (characteristic of the exon 1 of the CYP2D7 gene) which causes a shift in the reading frame with premature termination of translation.