Abstract
The identification of a novelCYP2D6 allele from a healthy Caucasian poor metabolizer was achieved by using a previously described polymerase chain reaction/single-strand conformation polymorphism strategy. Among the four point mutations that this allele carries, a missense mutation in exon 1 (212 G → A or D6-H) seems to be responsible for the loss of CYP2D6 function. Although the mutation D6-H has a low prevalence in a randomly selected population of healthy Caucasians, its identification should further increase the phenotype prediction rate by genotyping.
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Broly F, Gaedigk A, Heim M, Eichelbaum M, Morike K, Meyer UA (1991) Debrisoquine/sparteine hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population. DNA Cell Biol 8:545–558
Broly F, Marez D, Lo-Guidice JM, Sabbagh N, Legrand M, Boone P, Meyer UA (1996) A nonsense mutation in the cytochrome P450 CYP2D6 gene identified in a Caucasian with an enzyme deficiency. Hum Genet 96:601–603
Broly F, Marez D, Sabbagh N, Legrand M, Lo-Guidice JM, Boone P, Meyer UA (1995) An efficient strategy for detection of known and new mutations of the CYP2D6 gene using single strand conformation polymorphism analysis. Pharmacogenetics 5:373–384
Brén K, Nielsen PN, Brusgaard K, Gram LF, Skjodt K (1994) CYP2D6 genotype determination in the Danish population. Eur J Clin Pharmacol 47:221–225
Dahl ML, Johansson I, Porsmyr Palmertz M, Ingelman-Sundberg M, Sjöqvist F (1992) Analysis of the CYP2D6 gene in relation to the debrisoquine and desipramine hydroxylation in a Swedish population. Clin Pharmacol Ther 51:12–17
Daly AK, Cholerton S, Armstrong M, Idle JR (1994) Genotyping for polymorphisms in xenobiotic metabolism as a predictor of disease susceptibility. Environ Health Perspect 102:55–61
Daly AK, Leathart JBS, London SJ, Idle JR (1995) An inactive cytochrome P450 CYP2D6 allele containing a deletion and a base substitution. Hum Genet 95:337–341
Evert B, Griese EU, Eichelbaum M (1994a) A missense mutation in exon 6 of the CYP2D6 gene leading to a histidine 324 to proline exchange is associated with the poor metabolizer phenotype of sparteine. Naunyn Schiedebergs Arch Pharmacol 350: 434–439
Evert B, Griese EU, Eichelbaum M (1994b) Cloning and sequencing of a new non-functional CYP2D6 allele: deletion of T1795 in exon 3 generates a premature stop codon Pharmacogenetics 4:271–274
Gonzalez FJ, Idle JR (1994) Pharmacogenetic phenotyping and genotyping: present status and future potential. Clin Pharmacokinet 26:59–70
Heim M, Meyer UA (1990) Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 336: 529–532
Johansson I, Lundqvist E, Bertilsson L, Dahl ML, Sjöist F, Ingelman-Sundberg M (1993) Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 90:11825–11829
Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA (1990) Multiple mutations of the human cytochrome P450II6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. J Biol Chem 265:17209–17214
Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez F (1989) The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene and a pseudogene. Am J Hum Genet 45: 889–904
Koymans LMH, Vermeulen NPE, Baarslag A, Donné-Op den Kelder GM (1993) A preliminary 3D model for cytochrome P450 2D6 constructed model building. J Computer Aided Mol Design 7:281–289
Marez D, Sabbagh N, Legrand M, Lo-Guidice JM, Boone P, Broly F (1995) A novel CYP2D6 allele with an abolished splice recognition site associated with the poor metabolizer phenotype. Pharmacogenetics 5:305–311
Saxena R, Shaw GL, Relling MV, Frame JN, Moir DT, Evans WE, Caporaso N, Weiffenbach B (1994) Identification of a new variant CYP2D6 allele with a single base deletion in exon 3 and its association with the poor metabolizer phenotype. Hum Mol Genet 3:923–926
Sheffield VC, Beck JS, Kwitek AE, Sandstrom DW, Stone EM (1993) The sensitivity of single-strand conformation polymorphism analysis for the detection of single base substitutions. Genomics 16:325–332
Tucker GT (1994) Clinical implications of genetic polymorphism in drug metabolism. J Pharm Pharmacol 46:417–424
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Marez, D., Legrand, M., Sabbagh, N. et al. An additional allelic variant of the CYP2D6 gene causing impaired metabolism of sparteine. Hum Genet 97, 668–670 (1996). https://doi.org/10.1007/BF02281880
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DOI: https://doi.org/10.1007/BF02281880