ABSTRACT
OBJECTIVE: We analyzed in patients with essential tremor (ET) the Thr105Ile polymorphism of the Histamine N-methyltransferase (HNMT) enzyme that is associated to Parkinson's disease (PD) risk. METHODS: Leukocytary DNA from 204 ET patients and a control group of 295 unrelated healthy individuals was studied for the nonsynonymous HNMT Thr105Ile polymorphism by using amplification-restriction analyses. RESULTS: Patients with ET showed a higher frequency of homozygous HNMT 105Thr genotypes leading to high metabolic activity (p < 0.015) with a statistically significant gene-dose effect, as compared to healthy subjects. These findings were independent of gender, and of tremor localization, but the association of the HNMT polymorphism is more prominent among patients with late-onset ET (p < 0.007). CONCLUSION: These results, combined with previous findings indicating alterations in the frequency for the HNMT Thr105Ile polymorphism in patients with PD, suggest that alterations of histamine homeostasis in the SNC are associated with the risk of movement disorders.
Subject(s)
Brain Chemistry/genetics , Essential Tremor/enzymology , Essential Tremor/genetics , Genetic Predisposition to Disease/genetics , Histamine N-Methyltransferase/genetics , Polymorphism, Genetic/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Amino Acid Substitution/genetics , Child , Child, Preschool , DNA Mutational Analysis , Essential Tremor/physiopathology , Female , Genetic Testing , Histamine N-Methyltransferase/chemistry , Humans , Isoleucine/genetics , Male , Middle Aged , Threonine/genetics , Young AdultABSTRACT
BACKGROUND: Cytochrome P450 2D6 (CYP2D6) is one of the best-known polymorphic drug-metabolizing enzymes. Rapidly evolving genotyping techniques permit the identification of single-nucleotide polymorphisms (SNPs) and thereby a prediction of individual metabolic capacities for CYP2D6 substrates. A considerable part of interindividual variability in CYP2D6 enzyme activity, however, is not related to SNPs but to gene deletions and duplications. Currently used genotyping methods assume that these gene rearrangements are homogeneous. METHODS: We analyzed the interindividual variability in CYP2D6 gene arrangements in genomic DNA from 740 Caucasian individuals by allele-specific PCR to identify common SNPs of the CYP2D6 gene that correspond to the variant alleles CYP2D6*3, *4, and *9. We investigated the presence and variability of CYP2D6*5 (gene deletion), CYP2D6x2 (gene duplication), and CYP2D6xn (gene amplification) by EcoRI and XbaI restriction fragment length polymorphism analyses and by long PCR plus KpnI and BamHI digestion. The presence of new mutations at the CYP2D locus was analyzed by sequencing. RESULTS: CYP2D6 gene rearrangements were present in >12% of individuals. Variability in the rearrangements regarding both gene deletion and gene duplication existed, and one of the unusual arrangements led to incorrect phenotype prediction. The frequency for carriers of unusual gene rearrangements was <0.3% (95% confidence interval, 0%-0.6%) in the population studied. CONCLUSIONS: Heterogeneity in CYP2D6 gene rearrangement exists, but the allele frequency indicates that the risk for an erroneous phenotype prediction related to such variability is extremely low and that this risk can be neglected in routine analyses.
