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

Charles V. Preuss, Thomas C. Wood, Carol L. Szumlanski, Rebecca B. Raftogianis, Diane M. Otterness, Blanka Girard, Mary C. Scott, Richard M Weinshilboum

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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 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 Thr105lle 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 lle105 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 lle105 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 lle105 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.

Original languageEnglish (US)
Pages (from-to)708-717
Number of pages10
JournalMolecular Pharmacology
Volume53
Issue number4
StatePublished - Apr 1998

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Histamine N-Methyltransferase
Pharmacogenetics
Genetic Polymorphisms
Alleles
Kidney
COS Cells
Hot Temperature
Biopsy
3' Untranslated Regions
Gene Frequency
Human Activities
Northern Blotting
Histamine
Molecular Biology
Exons
Nucleotides

ASJC Scopus subject areas

  • Pharmacology

Cite this

Preuss, C. V., Wood, T. C., Szumlanski, C. L., Raftogianis, R. B., Otterness, D. M., Girard, B., ... Weinshilboum, R. M. (1998). Human histamine N-methyltransferase pharmacogenetics: Common genetic polymorphisms that alter activity. Molecular Pharmacology, 53(4), 708-717.

Human histamine N-methyltransferase pharmacogenetics : Common genetic polymorphisms that alter activity. / Preuss, Charles V.; Wood, Thomas C.; Szumlanski, Carol L.; Raftogianis, Rebecca B.; Otterness, Diane M.; Girard, Blanka; Scott, Mary C.; Weinshilboum, Richard M.

In: Molecular Pharmacology, Vol. 53, No. 4, 04.1998, p. 708-717.

Research output: Contribution to journalArticle

Preuss, CV, Wood, TC, Szumlanski, CL, Raftogianis, RB, Otterness, DM, Girard, B, Scott, MC & Weinshilboum, RM 1998, 'Human histamine N-methyltransferase pharmacogenetics: Common genetic polymorphisms that alter activity', Molecular Pharmacology, vol. 53, no. 4, pp. 708-717.
Preuss CV, Wood TC, Szumlanski CL, Raftogianis RB, Otterness DM, Girard B et al. Human histamine N-methyltransferase pharmacogenetics: Common genetic polymorphisms that alter activity. Molecular Pharmacology. 1998 Apr;53(4):708-717.
Preuss, Charles V. ; Wood, Thomas C. ; Szumlanski, Carol L. ; Raftogianis, Rebecca B. ; Otterness, Diane M. ; Girard, Blanka ; Scott, Mary C. ; Weinshilboum, Richard M. / Human histamine N-methyltransferase pharmacogenetics : Common genetic polymorphisms that alter activity. In: Molecular Pharmacology. 1998 ; Vol. 53, No. 4. pp. 708-717.
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