Characterization and PCR-based detection of two different hybrid CYP2D7P/CYP2D6 alleles associated with the poor metabolizer phenotypes

被引:44
作者
Daly, AK
Fairbrother, KS
Andreassen, OA
London, SJ
Idle, JR
Steen, VM
机构
[1] HAUKELAND HOSP,CTR MOL MED,DR EINAR MARTENS RES GRP BIOL PSYCHIAT,N-5021 BERGEN,NORWAY
[2] UNIV SO CALIF,SCH MED,DEPT PREVENT MED,LOS ANGELES,CA 90033
来源
PHARMACOGENETICS | 1996年 / 6卷 / 04期
关键词
cytochrome P450; CYP2D6; polymorphism; debrisoquine;
D O I
10.1097/00008571-199608000-00005
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
The majority of humans deficient in the cytochrome P450 CYP2D6 enzyme, so-called poor metabolizers (PMs), can now be identified by genotyping for several different PM-associated mutations, However, additional null alleles remain to be identified as demonstrated by subjects with the PM phenotype in the absence of a corresponding genotype, The rare 11 kb band on Xba I RFLP analysis, which is distinct from the 13 kb CYP2D6D (CYP2D6*5) allele, has been proposed to constitute such a unique non-functional allele, Here we demonstrate that the 11 kb band represents at least two different nine exon CYP2D7P/CYP2D6 hybrids generated by large deletions in the CYP2D gene cluster due to unequal cross-oner or looping-out mechanisms, The total allele frequency was approximately 0.001-0.01 in European and North American Caucasians, The most common variant (CYP2D6*16) had breakpoints lying between the end of exon 7 and the start of exon 9 of the respective genes, The 'CPP2D7-like' part of the gene was most homologous to the previously described CYP2D7AP and CYP2D7(44/11.5) sequences, The other chimeric allele consisted of exon 1 of CYP2D7 and exons 2-9 from CYP2D6, and may be similar to a hybrid gene termed CYP2D6*13 recently described in a French individual, Two different routine PCR assays were developed for rapid and sensitive detection of these alleles, namely amplification of a 8 kb fragment from both CYP2D6*13 and CYP2D6*16, together with a CYP2D6*16-specific method which gave a 1.4 kb PCR product, The 8 kb assay for the CYP2D6*13 and CYP2D6*16 alleles also produced a 9.5 kb fragment in samples positive for the 13 kb CYP2D6*5 allele, Therefore, it is now possible to screen for the large CYP2D gene deletions by a single long PCR method.
引用
收藏
页码:319 / 328
页数:10
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