HGNC Approved Gene Symbol: HNMT
Cytogenetic location: 2q22.1 Genomic coordinates (GRCh38) : 2:137,964,473-138,016,364 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q22.1 | {Asthma, susceptibility to} | 600807 | Autosomal dominant | 3 |
| Intellectual developmental disorder, autosomal recessive 51 | 616739 | Autosomal recessive | 3 |
In mammals, histamine is metabolized primarily by histamine N-methyltransferase (HNMT; EC 2.1.1.8) and diamine oxidase (DAO; 104610). However, the relative contributions of these 2 enzymes to histamine metabolism differ among tissues. HNMT plays the dominant role in histamine biotransformation in bronchial epithelium. There are large individual variations of HNMT activity in human tissues. Biochemical genetic studies of red blood cell HNMT has demonstrated that 5-fold differences among individuals in levels of HNMT activity are due primarily to the effects of inheritance (Scott et al., 1988; Price et al., 1993).
By screening a human kidney cDNA library with rat HNMT cDNA as a probe, Yamauchi et al. (1994) cloned an HNMT cDNA encoding a deduced 292-amino acid protein that shares 82% sequence identity with rat HNMT. Northern blot analysis demonstrated a 1.6-kb mRNA in human kidney, lung, and nasal polyps. HNMT activity was high in trachea and bronchi, and the contractile response of isolated human bronchi to histamine was strongly augmented in the presence of an HNMT inhibitor. Yamauchi et al. (1994) suggested that HNMT plays an important role in degrading histamine and in regulating the airway response to histamine.
By EST database analysis and RT-PCR of brain total RNA, Barnes et al. (2004) cloned a splice variant of HNMT, designated HNMT-S, that encodes a deduced 126-amino acid protein with a calculated molecular mass of 14.2 kD. HNMT-S contains a glycosylphosphatidylinositol-anchor cleavage signal and a hydrophobic C-terminal tail, but it lacks the catalytic histamine and S-adenosine-L-methionine binding sites of full-length HNMT. Northern blot analysis using a probe specific for full-length HNMT detected transcripts of 1.6 and 3.4 kb in liver, kidney, pancreas, skeletal muscle, lung, brain, heart, and placenta. Northern blot analysis using a probe specific for HNMT-S detected a 1.0-kb transcript only in placenta. The cloning of HNMT-S by RT-PCR of brain total RNA suggested that it is also expressed in brain at levels too low to be detected by Northern blot analysis.
Barnes et al. (2004) found that HNMT-S, which lacks the catalytic domain of full-length HNMT, lacked methyltransferase activity following transfection in COS-7 cells and instead inhibited endogenous COS-7 histamine-methylating activity .
Aksoy et al. (1996) determined that the HNMT gene has 6 exons and is approximately 34 kb long.
By fluorescence in situ hybridization, Yamauchi et al. (1994) mapped the HNMT gene to chromosome 1p32. However, by PCR analysis with DNA from human-rodent cell hybrid mapping panels, Aksoy et al. (1996) mapped the HNMT gene to chromosome 2.
Gross (2016) mapped the HNMT gene to chromosome 2q22.1 based on an alignment of the HNMT sequence (GenBank BC020677) with the genomic sequence (GRCh38).
Susceptibility to Asthma
Preuss et al. (1998) demonstrated a common 314C-T polymorphism in the HNMT gene resulting in a thr105-to-ile amino acid substitution (T105I; 605238.0001). The 314T allele is associated with decreased levels of both HNMT enzymatic activity and immunoreactive protein; therefore, the presence of the 314T allele would be expected to result in reduced histamine metabolism and increased bronchoconstriction.
Yan et al. (2000) characterized the common, functionally significant 314T polymorphism in DNA samples from 237 randomly selected Caucasian control subjects and 192 samples from Caucasian asthmatic patients. The frequency of the 314T allele of the HNMT gene was 0.08 in the control samples and 0.14 in samples from Caucasian asthmatic patients (odds ratio = 1.9, P less than 0.01), indicating a significant increase in the frequency of subjects with low HNMT activity among asthmatics. In contrast, Sasaki et al. (2000), Deindl et al. (2005), and Sharma et al. (2005) found no association between the T105I polymorphism and asthma among Japanese, German pediatric, and Indian populations, respectively.
Intellectual Developmental Disorder, Autosomal Recessive 51
In affected members of 2 unrelated consanguineous families with autosomal recessive intellectual developmental disorder-51 (MRT51; 616739), Heidari et al. (2015) identified 2 different homozygous missense mutations in the HNMT gene (G60D, 605238.0002 and L208P, 605238.0003). The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the families. Patient lymphoblasts showed increased vulnerability to the toxic effects of high histamine levels compared to controls. In vitro studies showed that the G60D mutation disrupted enzymatic activity, and that the L208P mutation resulted in reduced protein stability. Thus, both mutations impaired the function of HNMT and decreased the inactivation of histamine, a neurotransmitter important for the developing brain.
Preuss et al. (1998) demonstrated a common 314C-T polymorphism of the HNMT gene resulting in a thr105-to-ile (T105I) amino acid difference. The enzyme containing isoleucine as residue 105 was associated with decreased levels of HNMT activity and immunoreactivity.
Yan et al. (2000) demonstrated an increased frequency of the T105I polymorphism in Caucasian patients with asthma (600807). In contrast, Sasaki et al. (2000), Deindl et al. (2005), and Sharma et al. (2005) found no association between the T105I polymorphism and asthma among Japanese, German pediatric, and Indian populations, respectively.
In 4 sibs, born of consanguineous parents of Turkish descent, with autosomal recessive intellectual developmental disorder-51 (MRT51; 616739), Heidari et al. (2015) identified a homozygous c.179G-A transition (c.179G-A, NM_006895.2) in the HNMT gene, resulting in a gly60-to-asp (G60D) substitution in the conserved MTase region I, which is part of the SAM cofactor-binding pocket. The mutation was predicted to affect both the short and long isoforms of the protein. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Sequencing Project databases. It was present in 2 of 125,604 alleles in the ExAC database. The mutation was also not found in 200 ethnically matched control chromosomes or in an in-house database of 521 exomes. Patient lymphoblasts were more susceptible to the toxic effects of high histamine levels compared to controls, suggesting a defect in HNMT function. Although expression and cellular localization of the mutant protein was similar to wildtype, the mutant G60D protein showed decreased thermal stability and decreased affinity for SAM compared to wildtype, thus significantly disrupting HNMT catalytic activity.
In 3 sibs, born of consanguineous parents of Kurdish descent, with autosomal recessive intellectual developmental disorder-51 (MRT51; 616739), Heidari et al. (2015) identified a homozygous c.623T-C transition (c.623T-C, NM_006895.2) in the HNMT gene, resulting in a leu208-to-pro (L208P) substitution at a highly conserved residue. The mutation was predicted to affect only the long isoform of the protein. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Sequencing Project databases, or an in-house database of 521 exomes. It was present in 1 of 126,358 alleles in the ExAC database. The Pro substitution was predicted to alter the helical conformation of the protein and to affect protein function by destabilization. Patient lymphoblasts were more susceptible to the toxic effects of high histamine levels compared to controls, suggesting a defect in HNMT function. Cellular expression studies suggested that the L208P protein formed abnormal punctate aggregates, and soluble protein could not be detected, suggesting misfolding and rapid degradation. Additional functional studies could not be performed on the mutant protein. (In the article by Heidari et al. (2015), the nucleotide change is given as c.632T-C in Table 1 and Figure 2, but as c.623T-C in the text; Vincent (2016) confirmed that c.623T-C is correct.)
Aksoy, S., Raftogianis, R., Weinshilboum, R. Human histamine N-methyltransferase gene: structural characterization and chromosomal localization. Biochem. Biophys. Res. Commun. 219: 548-554, 1996. [PubMed: 8605025] [Full Text: https://doi.org/10.1006/bbrc.1996.0271]
Barnes, W. G., Grinde, E., Crawford, D. R., Herrick-Davis, K., Hough, L. B. Characterization of a new mRNA species from the human histamine N-methyltransferase gene. Genomics 83: 168-171, 2004. [PubMed: 14667820] [Full Text: https://doi.org/10.1016/s0888-7543(03)00236-2]
Deindl, P., Peri-Jerkan, S., Deichmann, K., Niggemann, B., Lau, S., Sommerfeld, C., Sengler, C., Muller, S., Wahn, U., Nickel, R., Heinzmann, A., German Multicenter Atopy Study Group. No association of histamine-N-methyltransferase polymorphism with asthma or bronchial hyperresponsiveness in two German pediatric populations. Pediat. Allergy Immun. 16: 40-42, 2005. [PubMed: 15693910] [Full Text: https://doi.org/10.1111/j.1399-3038.2005.00218.x]
Gross, M. B. Personal Communication. Baltimore, Md. 1/29/2016.
Heidari, A., Tongsook, C., Najafipour, R., Musante, L., Vasli, N., Garshasbi, M., Hu, H., Mittal, K., McNaughton, A. J. M., Sritharan, K., Hudson, M., Stehr, H., and 22 others. Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability. Hum. Molec. Genet. 24: 5697-5710, 2015. [PubMed: 26206890] [Full Text: https://doi.org/10.1093/hmg/ddv286]
Preuss, C. V., Wood, T. C., Szumlanski, C. L., Raftogianis, R. B., Otterness, D. M., Girard, B., Scott, M. C., Weinshilboum, R. M. Human histamine N-methyltransferase pharmacogenetics: common genetic polymorphisms that alter activity. Molec. Pharm. 53: 708-717, 1998. [PubMed: 9547362] [Full Text: https://doi.org/10.1124/mol.53.4.708]
Price, R. A., Scott, M. C., Weinshilboum, R. M. Genetic segregation analysis of red blood cell (RBC) histamine N-methyltransferase (HNMT) activity. Genet. Epidemiol. 10: 123-131, 1993. [PubMed: 8339926] [Full Text: https://doi.org/10.1002/gepi.1370100205]
Sasaki, Y., Ihara, K., Ahmed, S., Yamawaki, K., Kusuhara, K., Nakayama, H., Nishima, S., Hara, T. Lack of association between atopic asthma and polymorphisms of the histamine H1 receptor, histamine H2 receptor, and histamine N-methyltransferase genes. Immunogenetics 51: 238-240, 2000. [PubMed: 10752634] [Full Text: https://doi.org/10.1007/s002510050037]
Scott, M. C., Van Loon, J. A., Weinshilboum, R. M. Pharmacogenetics of N-methylation: heritability of human erythrocyte histamine N-methyltransferase activity. Clin. Pharm. Ther. 43: 256-262, 1988. [PubMed: 3345617] [Full Text: https://doi.org/10.1038/clpt.1988.30]
Sharma, S., Mann, D., Singh, T. P., Ghosh, B. Lack of association of histamine-N-methyltransferase (HNMT) polymorphisms with asthma in the Indian population. J. Hum. Genet. 50: 611-617, 2005. [PubMed: 16205835] [Full Text: https://doi.org/10.1007/s10038-005-0302-4]
Vincent, J. Personal Communication. Toronto, Ontario, Canada 1/27/2016.
Yamauchi, K., Sekizawa, K., Suzuki, H., Nakazawa, H., Ohkawara, Y., Katayose, D., Ohtsu, H., Tamura, G., Shibahara, S., Takemura, M., Maeyama, K., Watanabe, T., Sasaki, H., Shirato, K., Takishima, T. Structure and function of human histamine N-methyltransferase: critical enzyme in histamine metabolism in airway. Am. J. Physiol. 267: L342-L349, 1994. [PubMed: 7943261] [Full Text: https://doi.org/10.1152/ajplung.1994.267.3.L342]
Yan, L., Galinsky, R. E., Bernstein, J. A., Liggett, S. B., Weinshilboum, R. M. Histamine N-methyltransferase pharmacogenetics: association of a common functional polymorphism with asthma. Pharmacogenetics 10: 261-266, 2000. [PubMed: 10803682] [Full Text: https://doi.org/10.1097/00008571-200004000-00007]