title: A silent mutation (2939G>A, exon 6; CYP2D6*59) leading to impaired expression and function of CYP2D6.
abstract: We analyzed CYP2D6 in two individuals characterized by impaired sparteine oxidation (intermediate metabolizer phenotype) and genotype 2D62/4 (1661G>C; 2850C>T; 4180G>C) usually associated with normal function. Full genomic sequencing and haplotype analysis confirmed the previously identified silent mutation 2939G>A in exon 6 (former allele variant 2D62J, now termed 2D659), as well as an additional novel 2291G>A change in intron 4. Transient expression in Huh7 hepatoma cells of the entire CYP2D6 gene of constructs carrying either both or only the 2939G>A change resulted in about three-fold reduced levels of mRNA, immunoreactive 2D6 protein and propafenone hydroxylase activity. These data demonstrate profound effects of a silent mutation on expression and function of CYP2D6, resulting in impaired drug oxidation phenotype. The 2939G>A single nucleotide polymorphism in exon 6 was present heterozygously in two individuals out of 308 (0.65%), corresponding to an allele frequency of 0.3%. Genotyping for this mutation thus improves phenotype-genotype correlation for CYP2D6 and may help to predict adverse drug treatment events.
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Toscano
authors.forename: Sebastian
authors.initials: S
authors.lastname: Raimundo
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klein
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D005091:Exons; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D019389:Cytochrome P-450 CYP2D6