HGNC Approved Gene Symbol: HDC
SNOMEDCT: 5158005; ICD10CM: F95.2; ICD9CM: 307.23;
Cytogenetic location: 15q21.2 Genomic coordinates (GRCh38): 15:50,241,947-50,265,726 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.2 | {Gilles de la Tourette syndrome, susceptibility to} | 137580 | Autosomal dominant | 3 |
The biogenic amine histamine is an important modulator of numerous physiologic processes, including neurotransmission, gastric acid secretion, and smooth muscle tone. The biosynthesis of histamine from histidine is catalyzed by the enzyme L-histidine decarboxylase (HDC; EC 4.1.1.22). This homodimeric enzyme is a pyridoxal phosphate (PLP)-dependent decarboxylase and is highly specific for its histidine substrate (summary by Zahnow et al., 1991).
Using a rat HDC cDNA as probe, Zahnow et al. (1991) identified and characterized a full-length cDNA encoding human HDC. The deduced 662-amino acid protein has a molecular mass of 74,148 Da. A high degree of homology was found among the HDCs and the dopa decarboxylases (DDC; 107930) of rat, mouse, and human.
By Western blot analysis of fractionated KU-812-F human basophilic leukemia cells, Yatsunami et al. (1995) identified HDC isoforms with apparent molecular masses of 74 and 54 kD in particulate and soluble fractions, respectively. Comparison with rat Hdc suggested that the 54-kD isoform is C-terminally truncated after gln477 compared with the full-length form.
Yatsunami et al. (1994) determined the structure of the HDC gene by isolating DNA from human genomic libraries. The gene contains 12 exons spanning approximately 24 kb. Genomic DNA blot analysis suggested that HDC is encoded by a single copy gene. Structural analysis showed that the observed heterogeneity of the HDC mRNA is caused by alternative splicing.
Zahnow et al. (1991) used human HDC cDNA to map the gene to chromosome 15 by analysis of human-rodent cell hybrids. Using a rat HDC probe, Bruneau et al. (1992) assigned the HDC gene to human chromosome 15 by somatic hybrid cell analysis. Richard et al. (1994) presented an integrated physical, expression, and genetic map of human chromosome 15. Mapping by PCR, they concluded that the HDC gene falls in their region IV: 15q21-q22. By isotopic in situ hybridization, Malzac et al. (1996) mapped the HDC gene to 15q15-q21.
Martin and Bulfield (1984) demonstrated that the mouse Hdc gene is located on chromosome 2. Thus, the well-known homology between human chromosome 15 and mouse chromosome 2 is extended. By isotopic in situ hybridization, Malzac et al. (1996) mapped the mouse gene to the E5-G region of chromosome 2.
Using recombinant human enzymes purified from insect cells, Yatsunami et al. (1995) determined that the 54- and 74-kD HDC isoforms showed specific histamine synthase activity comparable with that of other mammalian HDCs. Recombinant human 54-kD HDC eluted as a monomer upon gel filtration, and it required pyridoxal 5-prime-phosphate for histamine synthase activity.
Using recombinant human 54-kD HDC, Komori et al. (2012) found that serine mutation of cys180 and cys418, which are involved in homodimer formation, did not affect enzyme activity. Mutation of ser354 to gly at the active site enlarged the HDC substrate-binding pocket, reducing its affinity for histidine and permitting binding of L-DOPA. Mutant HDC with gly354 at the active site produced dopamine in reaction with L-DOPA.
By genomewide linkage analysis followed by candidate gene sequencing in a 2-generation family with Gilles de la Tourette syndrome (137580), Ercan-Sencicek et al. (2010) identified a heterozygous nonsense mutation in the HDC gene (W317X; 142704.0001) in all 9 affected individuals. In vitro studies indicated that the mutation exerted a dominant-negative effect on the protein, resulting in lack of enzyme activity. Ercan-Sencicek et al. (2010) noted that animal studies had shown that lack of Hdc in mice results in increased locomotor and stereotypic behaviors, as well as increased anxiety. Overall, the findings suggested a role for histaminergic neurotransmission in neurobehavioral actions such as tics.
Karagiannidis et al. (2013) genotyped samples from 520 nuclear Tourette syndrome families of various ethnic origins for SNPs in the HDC gene. There was significant overtransmission of alleles for rs854150 and rs1894236, both of which reside in intronic regions of the gene, to affected patients. SNP rs854150 resides within a 2-SNP haplotype block, which was also significantly associated with the phenotype both for the protective and the susceptibility alleles, whereas SNP rs1894236 resides in a 5-SNP haplotype block that was associated with susceptibility to the disorder.
Ohtsu et al. (2001) created Hdc-deficient mice by gene targeting. The Hdc-deficient mice were viable and fertile and were maintained on a low histamine diet. Tissues from these mice lacked histamine-synthesizing activity, and total histamine levels were close to zero in all tissues except brain. Light and electron microscopy revealed decreased numbers of mast cells, and those remaining showed altered morphology. The total number of secretory granules per mast cell was not significantly different from that in wildtype mice, but staining was heterogeneous and some mast cells possessed fairly empty granules. Western blot analysis and RT-PCR, respectively, showed that the amount of 3 mast cell proteases was greatly reduced at the protein level and that the RNA expression levels were less affected.
Kubota et al. (2002) found that Hdc-null mice had decreased nocturnal activity compared to wildtype. Hdc-null mice also showed significantly increased locomotor activity, both in the short- and long-term, in response to methamphetamine administration compared to wildtype. Neurochemical analysis showed changes in several brain regions, including increased levels of dopamine in the forebrains and no decrease of GABA in the midbrains of Hdc-null mice in response to methamphetamine treatment. Overall, the findings suggested that the histamine neuron system plays a role as an awakening amine in concert with the noradrenaline system, whereas it has an inhibitory role on the behavioral effects of methamphetamine through interaction with the GABAergic system.
Fitzpatrick et al. (2003) showed that targeted disruption of the histidine decarboxylase gene, the only histamine-synthesizing enzyme, led to histamine-deficient mice characterized by undetectable tissue histamine levels, impaired gastric acid secretion, impaired passive cutaneous anaphylaxis, and decreased mast cell degranulation. They used this model to study the role of histamine in bone physiology. Compared with wildtype mice, HDC -/- mice receiving a histamine-free diet had increased bone mineral density, increased cortical bone thickness, higher rate of bone formation, and a marked decrease in osteoblasts. After ovariectomy, cortical and trabecular bone loss was reduced by 50% in the HDC -/- mice compared with wildtype. Histamine deficiency protected the skeleton from osteoporosis directly, by inhibiting osteoclastogenesis, and indirectly, by increasing calcitriol synthesis. After ovariectomy, histamine-deficient mice were protected from bone loss by the combination of increased bone formation and reduced bone resorption.
Dere et al. (2004) found that Hdc-null mice showed decreased exploratory activity in an open-field test, but normal habituation to a novel environment. They also showed increased anxiety compared to wildtype mice, as assessed by the height-fear task and the graded anxiety test. Motor coordination on the rotarod was better than that in controls. Biochemical studies showed that Hdc-null knockout mice had higher acetylcholine concentrations and higher 5-HT turnover in the frontal cortex, but reduced acetylcholine levels in the neostriatum. These results suggested important interactions between neuronal histamine and specific neurotransmitters, which may be related to behavioral changes.
Castellan Baldan et al. (2014) found that heterozygous Hdc-null (+/-) and homozygous Hdc-null (-/-) mice showed increased motor stereotypic behavior after amphetamine administration compared to wildtype. The stereotypy was more marked in homozygous mice compared to heterozygous mice. Haloperidol pretreatment and intracerebroventricular infusion of histamine mitigated the stereotypies in both genotypes. Mutant mice had increased levels of striatal dopamine, which could be reduced by histamine infusion. Hdc+/- and Hdc-/- mice showed significant deficits in prepulse inhibition compared to wildtype, which recapitulated the human phenotype of Tourette syndrome. The results suggested that histamine regulates dopamine levels in the basal ganglia, that deficiency of histamine resulting from Hdc mutations causes dysregulation of the corticobasal ganglia circuits, and that this disruption may underlie Tourette syndrome.
In 9 affected members of a 2-generation family with Gilles de la Tourette syndrome (137580), Ercan-Sencicek et al. (2010) identified a heterozygous 951G-A transition in exon 9 of the HDC gene, resulting in a trp317-to-ter (W317X) substitution predicted to result in a truncated protein lacking key segments of the active domain. Studies of mRNA from patient cells suggested that the mutation escaped nonsense-mediated decay. The mutation was not found in 3,000 control chromosomes from northern and western Europe. In vitro studies in E. coli indicated that the mutant protein acted in a dominant-negative manner, resulting in lack of enzyme activity. All 9 affected individuals had Tourette syndrome, 4 also had obsessive-compulsive disorder (OCD; 164230), and 1 also had Asperger syndrome (see 608638).
Castellan Baldan et al. (2014) found that 9 patients with Tourette syndrome carrying the W317X mutation had impaired prepulse inhibition of the startle response to an auditory stimulus. PET scanning of 4 patients showed dysregulated binding of dopamine receptors in the substantia nigra. Studies in Hdc knockout mice recapitulated the abnormalities, suggesting that dysregulation of histamine-dopamine interactions in the basal ganglia may underlie Tourette syndrome.
Bruneau, G., Nguyen, V. C., Gros, F., Bernheim, A., Thibault, J. Preparation of a rat brain histidine decarboxylase (HDC) cDNA probe by PCR and assignment of the human HDC gene to chromosome 15. Hum. Genet. 90: 235-238, 1992. [PubMed: 1487235] [Full Text: https://doi.org/10.1007/BF00220068]
Castellan Baldan, L., Williams, K. A., Gallezot, J.-D., Pogorelov, V., Rapanelli, M., Crowley, M., Anderson, G. M., Loring, E., Gorczyca, R., Billingslea, E., Wasylink, S., Panza, K. E., and 12 others. Histidine decarboxylase deficiency causes Tourette syndrome: parallel findings in humans and mice. Neuron 81: 77-90, 2014. Note: Erratum: Neuron 82: 1186-1187, 2014. [PubMed: 24411733] [Full Text: https://doi.org/10.1016/j.neuron.2013.10.052]
Dere, E., De Souza-Silva, M. A., Spieler, R. E., Lin, J. S., Ohtsu, H., Haas, H. L., Huston, J. P. Changes in motoric, exploratory and emotional behaviours and neuronal acetylcholine content and 5-HT turnover in histidine decarboxylase-KO mice. Europ. J. Neurosci. 20: 1051-1058, 2004. [PubMed: 15305873] [Full Text: https://doi.org/10.1111/j.1460-9568.2004.03546.x]
Ercan-Sencicek, A. G., Stillman, A. A., Ghosh, A. K., Bilguvar, K., O'Roak, B. J., Mason, C. E., Abbott, T., Gupta, A., King, R. A., Pauls, D. L., Tischfield, J. A., Heiman, G. A., and 16 others. L-histidine decarboxylase and Tourette's syndrome. New Eng. J. Med. 362: 1901-1908, 2010. [PubMed: 20445167] [Full Text: https://doi.org/10.1056/NEJMoa0907006]
Fitzpatrick, L. A., Buzas, E., Gagne, T. J., Nagy, A., Horvath, C., Ferencz, V., Mester, A., Kari, B., Ruan, M., Falus, A., Barsony, J. Targeted deletion of histidine decarboxylase gene in mice increases bone formation and protects against ovariectomy-induced bone loss. Proc. Nat. Acad. Sci. 100: 6027-6032, 2003. [PubMed: 12716972] [Full Text: https://doi.org/10.1073/pnas.0934373100]
Karagiannidis, I., Dehning, S., Sandor, P., Tarnok, Z., Rizzo, R., Wolanczyk, T., Madruga-Garrido, M., Hebebrand, J., Nothen, M. M., Lehmkuhl, G., Farkas, L., Nagy, P., and 12 others. Support of the histaminergic hypothesis in Tourette syndrome: association of the histamine decarboxylase gene in a large sample of families. J. Med. Genet. 50: 760-764, 2013. [PubMed: 23825391] [Full Text: https://doi.org/10.1136/jmedgenet-2013-101637]
Komori, H., Nitta, Y., Ueno, H., Higuchi, Y. Structural study reveals that Ser-354 determines substrate specificity on human histidine decarboxylase. J. Biol. Chem. 287: 29175-29183, 2012. [PubMed: 22767596] [Full Text: https://doi.org/10.1074/jbc.M112.381897]
Kubota, Y., Ito, C., Sakurai, E., Sakurai, E., Watanabe, T., Ohtsu, H. Increased methamphetamine-induced locomotor activity and behavioral sensitization in histamine-deficient mice. J. Neurochem. 83: 837-845, 2002. [PubMed: 12421355] [Full Text: https://doi.org/10.1046/j.1471-4159.2002.01189.x]
Malzac, P., Mattei, M.-G., Thibault, J., Bruneau, G. Chromosomal localization of the human and mouse histidine decarboxylase genes by in situ hybridization: exclusion of the HDC gene from the Prader-Willi syndrome region. Hum. Genet. 97: 359-361, 1996. [PubMed: 8786082] [Full Text: https://doi.org/10.1007/BF02185772]
Martin, S. A. M., Bulfield, G. The structural gene (Hdc-s) for mouse kidney histidine decarboxylase. Biochem. Genet. 22: 645-656, 1984. [PubMed: 6497830] [Full Text: https://doi.org/10.1007/BF00485850]
Ohtsu, H., Tanaka, S., Terui, T., Hori, Y., Makabe-Kobayashi, Y., Pejler, G., Tchougounova, E., Hellman, L., Gertsenstein, M., Hirasawa, N., Sakurai, E., Buzas, E., and 13 others. Mice lacking histidine decarboxylase exhibit abnormal mast cells. FEBS Lett. 502: 53-56, 2001. [PubMed: 11478947] [Full Text: https://doi.org/10.1016/s0014-5793(01)02663-1]
Richard, I., Broux, O., Chiannilkulchai, N., Fougerousse, F., Allamand, V., Bourg, N., Brenguier, L., Devaud, C., Pasturaud, P., Roudaut, C., Lorenzo, F., Sebastiani-Kabatchis, C., Schultz, R. A., Polymeropoulos, M. H., Gyapay, G., Auffray, C., Beckmann, J. S. Regional localization of human chromosome 15 loci. Genomics 23: 619-627, 1994. [PubMed: 7851890] [Full Text: https://doi.org/10.1006/geno.1994.1550]
Yatsunami, K., Ohtsu, H., Tsuchikawa, M., Higuchi, T., Ishibashi, K., Shida, A., Shima, Y., Nakagawa, S., Yamauchi, K., Yamamoto, M., Hayashi, N., Watanabe, T., Ichikawa, A. Structure of the L-histidine decarboxylase gene. J. Biol. Chem. 269: 1554-1559, 1994. [PubMed: 8288622]
Yatsunami, K., Tsuchikawa, M., Kamada, M., Hori, K., Higuchi, T. Comparative studies of human recombinant 74- and 54-kDa L-histidine decarboxylases. J. Biol. Chem. 270: 30813-30817, 1995. [PubMed: 8530524] [Full Text: https://doi.org/10.1074/jbc.270.51.30813]
Zahnow, C. A., Yi, H.-F., McBride, O. W., Joseph, D. R. Cloning of the cDNA encoding human histidine decarboxylase from an erythroleukemia cell line and mapping of the gene locus to chromosome 15. DNA Seq. 1: 395-400, 1991. [PubMed: 1768863] [Full Text: https://doi.org/10.3109/10425179109020795]