Human histamine N-methyltransferase pharmacogenetics: common genetic polymorphisms that alter activity.

Department of Pharmacology, Mayo Medical School, Mayo Foundation, Rochester, Minnesota 55905, USA.
Molecular Pharmacology (Impact Factor: 4.12). 05/1998; 53(4):708-17.
Source: PubMed

ABSTRACT Histamine N-methyltransferase (HNMT) catalyzes a major pathway in histamine metabolism. Levels of HNMT activity in humans are regulated by inheritance. We set out to study the molecular basis for this genetic regulation. Northern blot analysis showed that HNMT is highly expressed in the kidney, so we determined levels of enzyme activity and thermal stability in 127 human renal biopsy samples. DNA was isolated from 12 kidney samples with widely different HNMT phenotypes, and exons of the HNMT gene were amplified with the polymerase chain reaction. In these 12 samples, we observed a C314T transition that resulted in a Thr105Ile change in encoded amino acid, as well as an A939G transition within the 3'-untranslated region. All remaining renal biopsy samples then were genotyped for these two variant sequences. Frequencies of the alleles encoding Thr105 and Ile105 in the 114 samples studied were 0.90 and 0.10, respectively, whereas frequencies for the nucleotide A939 and G alleles were 0.79 and 0.21, respectively. Kidney samples with the allele encoding Ile105 had significantly lower levels of HNMT activity and thermal stability than did those with the allele that encoded Thr105. These observations were confirmed by transient expression in COS-1 cells of constructs that contained all four alleles for these two polymorphisms. COS-1 cells transfected with the Ile105 allele had significantly lower HNMT activity and immunoreactive HNMT protein than did those transfected with the Thr105 allele. These observations will make it possible to test the hypothesis that genetic polymorphisms for HNMT may play a role in the pathophysiology of human disease.

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    ABSTRACT: Two potential single-nucleotide polymorphisms (SNP) (C314T and A595G) exist in the gene for human histamine N-methyltransferase (HNMT). A radiochemical microassay was used to measure the erythrocyte HNMT activities, whereas the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed to perform the genetic analysis in 247 unrelated Chinese Han subjects. All subjects had detectable HNMT activity. The activity of HNMT was gender related (males>females, p<0.0001), with a 5.5-fold individual variation. The distribution of HNMT activity was compatible with a normal distribution. There were 28 heterozygotes for the variant T314 allele among the 247 subjects, whereas no A595G transition was observed. All heterozygotes for the T314 allele displayed an intermediate or low HNMT activity, with an average HNMT activity being 34.0% lower than those with wild-type genotype (623.1+/-136.0 vs. 944.8+/-249.3 U/ml red blood cells [RBC], p<0.0001). The C314T polymorphism was functionally important and contributes in part to phenotypic variance of HNMT activity in Chinese Han population. Additional unknown genetic or epigenetic factors should also play important roles in the regulation of HNMT activity.
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    ABSTRACT: Histamine N-methyltransferase (HNMT) plays an important role in the metabolism of histamine, a biogenic amine that has many physiologic and pathological roles in human tissues. A missense mutation C314T (Thr105Ile) in the HNMT gene has been identified to represent a common functional polymorphism in Caucasians, whereas an A595G (Ile199Val) variant has been reported in one HNMT cDNA from a Japanese subject. By using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, the point mutations C314T and A595G within HNMT were both detected in 352 unrelated Chinese Han subjects. None of the 352 subjects contained the A595G mutation, whereas 40 (11.6%) heterozygotes and 1 (0.3%) homozygote for the variant T314 allele were detected. The frequency of the variant T314 allele in this Chinese population was 0.060 (95% CI: 0.042-0.078), not different from Japanese but significantly lower than American Caucasians. The C314T mutation represents a common functional genetic polymorphism in the Chinese Han population with a variant T314 allele frequency similar to Japanese but lower than American Caucasians, whereas the A595G mutation does not appear to exist in this population.
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