Homologous unequal cross-over within the human CYP2A gene cluster as a mechanism for the deletion of the entire CYP2A6 gene associated with the poor metabolizer phenotype.
To clarify the molecular mechanisms involved in the generation of the CYP2A6 gene deletion (E-type variant), we analyzed the CYP2A7 gene, which is located in the 5'-flanking region of the CYP2A6 gene, from individuals with the E-type variant and compared it with the sequences of wild type CYP2A7 and CYP2A6 genes. The 3'-downstream sequence (up to 324 bp from the SacI site in exon 9) of the CYP2A7 gene of the E-type variant is identical to that of the wild CYP2A7 gene. However, the 3'-downstream sequence (starting from 325 bp from the SacI site in exon 9) of the CYP2A7 gene of the E-type variant is identical to that of the wild CYP2A6 gene, indicating that the 3'-downstream region of CYP2A7 and the 3'-downstream region of CYP2A6 linked directly eliminating the whole CYP2A6 gene. PCR analysis using primers specific to the CYP2A7 gene and the CYP2A6 and CYP2A7 genes confirmed that all DNA samples obtained from 7 individuals carrying the E-type variant possessed the same break points. These results indicate that the breakpoint of the CYP2A6 gene deletion lies in the 3'-downstream region of the CYP2A7 and CYP2A6 genes.
Nunoya
K
K
Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan.
Yokoi
T
T
Takahashi
Y
Y
Kimura
K
K
Kinoshita
M
M
Kamataki
T
T
D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D015139:Blotting, Southern; D003434:Crossing Over, Genetic; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D005091:Exons; D017353:Gene Deletion; D015723:Gene Library; D006801:Humans; D008214:Lymphocytes; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D005810:Multigene Family; D010641:Phenotype; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D016415:Sequence Alignment; D013250:Steroid Hydroxylases / Q000235:genetics*
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C423964:CYP2A7 protein, human; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; C022657:steroid hormone 6-beta-hydroxylase