An unequal cross‐over event within the CYP2D gene cluster generates a chimeric 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 metabolizer 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 poor metabolizer phenotype associated with the XbaI‐9 kb allele, complete sequencing of the nine exons and intron‐exon boundaries of the CYP2D6 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 amplified product revealed that the XbaI‐9 kb allele corresponds to a novel rearrangement of the locus. This involved a deletion of an approximately 20 kilobase (kb) DNA segment generating a hybrid 5' CYP2D7/CYP2D6 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.

DOI: 10.1111/j.1365-2125.1995.tb04558.x

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