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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    • "Lower brain HNMT activity in the brain of patients with AD could represent a compensatory mechanism leading to the increase in histamine levels . Although Ile105 allele is connected with lower HNMT activity in vivo [4] and in vitro [8] [14], we did not confirm the presumption of a higher frequency of Ile allele carriers among patients with AD. "
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    ABSTRACT: Several abnormalities, including lower histamine levels in brain, elevated serum histamine and degeneration of histaminergic neurons in tuberomammillary nucleus, were described in the histaminergic system of patients with Alzheimer's disease (AD). Histamine is a central neurotransmitter with several functions in brain including regulation of memory, cognition, locomotion, and is degraded in part by histamine N-methyltransferase (HNMT). A common Thr105Ile polymorphism within HNMT gene results in decreased enzyme activity. The Thr105Ile polymorphism was associated with Parkinson's disease, essential tremor, attention-deficit hyperactivity disorder (ADHD), asthma and alcoholism, thus we tested possible association of HNMT functional polymorphism with AD. We have tested 256 AD cases and 1190 healthy controls of Croatian origin. Thr105Ile polymorphism was determined by TaqMan RT-PCR Genotyping Assay and EcoRV digestion. Prevalence of functional HNMT polymorphism among all tested groups was similar and frequency of less active Ile105 variant was 11.5% among AD patients and 13.4% for healthy controls (p=0.26, X(2)=1.25). Our results indicate lack of the association of HNMT Thr105Ile functional polymorphism with Alzheimer's disease.
    Neuroscience Letters 02/2011; 489(2):119-21. DOI:10.1016/j.neulet.2010.11.078 · 2.06 Impact Factor
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    • "The threonine residue (polar) causes a more accessible conformation of substrate binding residues than the isoleucine variant (non-polar), resulting in higher HNMT enzymatic activity, the primary mechanism by which histamine is degraded in the central nervous system [8] [9] [10] [11]. Histamine is involved in a wide variety of functions including allergy and anaphylaxis, digestive regulation, and neurotransmission [10]. Although the histaminergic system has not been extensively studied with regard to diseases affecting dopaminergic neurons such as PD, post-mortem analysis of PD patients has shown increased density of histaminergic fibers and considerable interaction between histaminergic fibers and dopaminergic neurons in the substantia nigra [12]. "
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    ABSTRACT: A functional variant in the Histamine N-Methyltransferase gene (HNMT - rs11558538) resulting in a threonine to isoleucine substitution (Thr105Ile) has been shown to impair histamine degradation. Two recent studies reported that the threonine allele of this polymorphism might be a risk factor for Parkinson disease (PD) and essential tremor (ET) development. Although PD and ET are considered different entities, they share some clinical and pathological features, suggesting a possible joint etiology. In this study we assess the role of the Thr105Ile variant in PD and ET development, genotyping the variant in a North American Caucasian PD and ET case-control series. Statistical analysis did not identify any significant association between this variant and PD or ET; therefore, our findings do not support the HNMT Thr105Ile variant as a factor in disease development or a genetic link between the disorders.
    Parkinsonism & Related Disorders 09/2009; 16(2):112-4. DOI:10.1016/j.parkreldis.2009.08.011 · 4.13 Impact Factor
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    • "Primer pairs for these amplifications, together with their annealing temperatures and extension time, were listed in Table 1. The pair of primers for C314T was the same as previously reported [18], whereas other pairs of primers were designed on the basis of the genomic sequence information from Genbank (accession number: AC019304.3). A touchdown PCR protocol was used for all amplifications except for C314T. "
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    ABSTRACT: Introduction: Histamine plays a crucial role in the regulation of gastric acid secretion, which is involved in the pathogenesis of peptic ulcer. Histamine N-methyltransferase (HNMT) is the major metabolizing enzyme for histamine inactivation in human stomach.Objective: This study aims to determine whether there exists a relationship between HNMT gene polymorphisms and the risk for gastric ulcer (GU).Methods: 118 GU patients and 154 ethnically matched control subjects were enrolled and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays were developed to genotype all these subjects for the T-1637C, C-411T, C314T and A1097T point mutations in HNMT gene. Haplotypes were reconstructed from the genotype data.Results: Frequencies of the variant alleles in cases and controls were 0.398 vs 0.396 for T-1637C, 0.144 vs 0.110 for C-411T, 0.034 vs 0.042 for C314T, and 0.242 vs 0.273 for A1097T, respectively, with no significant difference for any locus between the two groups (all P > 0.05). Also the frequencies of genotypes, haplotypes and haplotype pairs based on these polymorphisms did not differ significantly between cases and controls.Conclusion: This study provided no evidence for the involvement of HNMT polymorphisms in the susceptibility to GU.
    Inflammation Research 08/2004; 53(9):484-488. DOI:10.1007/s00011-004-1290-0 · 2.14 Impact Factor
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