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Gene Review

TH  -  tyrosine hydroxylase

Homo sapiens

Synonyms: DYT14, DYT5b, TYH, Tyrosine 3-hydroxylase, Tyrosine 3-monooxygenase
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Disease relevance of TH


Psychiatry related information on TH

  • The presence of these additional populations of TH-positive neurons in the adult primate CNS has implications for functional catecholamine neurotransmission, its derangement in disease and drug abuse, and its rescue by gene therapeutic maneuvers in neurodegenerative diseases such as Parkinson's disease [6].
  • The genetic susceptibility to Gilles de la Tourette syndrome in a large multiple affected British kindred: linkage analysis excludes a role for the genes coding for dopamine D1, D2, D3, D4, D5 receptors, dopamine beta hydroxylase, tyrosinase, and tyrosine hydroxylase [7].
  • The localization of TH to the highly polymorphic INS locus provides four new restriction fragment length polymorphisms which should help determine rapidly whether defects in TH are responsible for bipolar affective disorder in the Old Order Amish and other populations [8].
  • (v) A significant positive correlation was found between the polymorphic (TCAT)(n) repeat in the first intron of the TH gene and pretreatment levels of pHVA in delusional disorder [9].
  • Individual differences were observed among control subjects in number and distribution of TH-immunoreactive (IR) perikarya, indicating that antemortem factors may regulate TH expression [10].

High impact information on TH


Chemical compound and disease context of TH

  • The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from VHL than from MEN 2 patients [3].
  • RESULTS: When corrected for differences in tissue fibrosis, the expression of both TH (AF 0.45 +/- 0.1%, SR 0.09 +/- 0.03%, P = 0.02) and tissue NE (AF 358 +/- 49 pg/mg, SR 225 +/- 39 pg/mg, P = 0.04) was greater in atrial tissue of the AF cohort [16].
  • Human glioblastoma ADF cells express tyrosinase, L-tyrosine hydroxylase and melanosomes and are sensitive to L-tyrosine and phenylthiourea [17].
  • We previously showed that a line of C6 rat glioma cells that expresses a GFAP-TH transgene, C6-THA, displays increased transgene activity when differentiated by forskolin treatment [18].
  • Regulated, adenovirus-mediated delivery of tyrosine hydroxylase suppresses growth of estrogen-induced pituitary prolactinomas [19].

Biological context of TH

  • The data indicate that ERK activity is responsible for phosphorylating TH at Ser31 in intact cells and suggest that TH-Ser31 phosphorylation may be regulated by multiple signaling pathways that converge at or prior to the activation of the ERKs [20].
  • There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave slightly positive pairwise lod scores in Family A [21].
  • Double-label experiments in late-stage tadpoles and juvenile bullfrogs revealed that the intensely TH-positive neurons are negative for NPY [1].
  • During the last three years there has been a formidable increase in the amount of structural information about PAH and TH, which has provided new insights into the active site structure, the binding of substrates, inhibitors and pterins, as well as on the effect of disease-causing mutations in these hydroxylases [22].
  • Individuals with specific DRD2 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations [23].

Anatomical context of TH

  • In TH-null mice, adrenocortical cells were characterized by an increase in liposomes and by tubular mitochondria with reduced internal membranes, suggesting a hypofunctional state of these steroid-producing cells [24].
  • As early as one week postinjection, the histochemical examination of the rat substantia nigra showed a reduced staining of neurons expressing TH followed by a loss of TH(+) neurons at later time points [25].
  • Moreover, in a homogeneous background of methylated CpGs, a single CpG in the first exon of the gene is constantly either unmethylated or methylated in, respectively, TH-expressing or non-expressing cell lines, tissues and single cells [26].
  • Nerve fibers immunoreactive (IR) for TH or positively stained for CF were not observed in association with scleral spur cells [27].
  • A significant degree of specificity for this human TH minimal promoter was observed only for human neuronal progenitor cells (hNPCs), but not for TH-positive differentiated mouse primary striatal and substantia nigra cells, indicating a significant difference in TH gene regulation between the human and mouse systems [4].

Associations of TH with chemical compounds

  • Enzyme activity correlated positively with age in all brain areas for MAO (with both benzylamine and tryptamine substrates) but no consistent pattern of correlation was found for COMT and TH [28].
  • Moreover, cotransduction with these two AAV vectors resulted in more effective dopamine production and more remarkable behavioral recovery in 6-hydroxydopamine (6-OHDA)-lesioned rats, compared with rats receiving AAV-TH alone (p < 0.01) [29].
  • BACKGROUND: Although mutations in the gene GCH1, coding for the tetrahydrobiopterin (BH4) biosynthetic enzyme guanosine triphosphate-cyclohydrolase I, have been identified in some patients with DRD, the actual status of brain BH4 (the cofactor for tyrosine hydroxylase [TH]) is unknown [30].
  • In order to identify new regulatory elements in this region acting on gene expression, the methylation profile of the TH CpG island was investigated using the bisulfite sequencing method [26].
  • The overall methylation level of this region is correlated to TH-expressing and non-expressing status in cell lines and DNA demethylation treatment with 5-azacytidine increased TH expression [26].

Physical interactions of TH


Regulatory relationships of TH


Other interactions of TH


Analytical, diagnostic and therapeutic context of TH

  • There was a 5-fold increase in the expression of proenkephalin mRNA (502.8 +/- 142% vs. 100 +/- 17.5%, P = 0.016) and a 2-fold increase in the expression of neuropeptide Y (213.4 +/- 41.2% vs. 100 +/- 59.9%, P = 0.014) in the TH-null animals as determined by quantitative TaqMan (Perkin-Elmer) PCR [24].
  • These results suggest that GCH, in addition to TH and AADC, is important for effective gene therapy of PD [44].
  • The quantity of GH released (as assessed by both RIA and reverse hemolytic plaque assay) under basal and stimulated conditions did not differ among TH-hGH and WT pituitary cell cultures [45].
  • In vitro complementary information was obtained: TH-positive cells represented about 3% of the total cell population after a week in culture, based upon accurate anatomical dissection [46].
  • Double-staining immunohistochemistry showed that TH and SPR were colocalized in the SN dopamine neurons [47].


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  3. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. Eisenhofer, G., Walther, M.M., Huynh, T.T., Li, S.T., Bornstein, S.R., Vortmeyer, A., Mannelli, M., Goldstein, D.S., Linehan, W.M., Lenders, J.W., Pacak, K. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  4. Tyrosine hydroxylase gene regulation in human neuronal progenitor cells does not depend on Nurr1 as in the murine and rat systems. Jin, H., Romano, G., Marshall, C., Donaldson, A.E., Suon, S., Iacovitti, L. J. Cell. Physiol. (2006) [Pubmed]
  5. Catecholamine-synthesizing enzymes in carcinoid tumors and pheochromocytomas. Meijer, W.G., Copray, S.C., Hollema, H., Kema, I.P., Zwart, N., Mantingh-Otter, I., Links, T.P., Willemse, P.H., de Vries, E.G. Clin. Chem. (2003) [Pubmed]
  6. Three Types of Tyrosine Hydroxylase-Positive CNS Neurons Distinguished by Dopa Decarboxylase and VMAT2 Co-Expression. Weihe, E., Depboylu, C., Sch??tz, B., Sch??fer, M.K., Eiden, L.E. Cell. Mol. Neurobiol. (2006) [Pubmed]
  7. The genetic susceptibility to Gilles de la Tourette syndrome in a large multiple affected British kindred: linkage analysis excludes a role for the genes coding for dopamine D1, D2, D3, D4, D5 receptors, dopamine beta hydroxylase, tyrosinase, and tyrosine hydroxylase. Brett, P.M., Curtis, D., Robertson, M.M., Gurling, H.M. Biol. Psychiatry (1995) [Pubmed]
  8. Human tyrosine hydroxylase and insulin genes are contiguous on chromosome 11. O'Malley, K.L., Rotwein, P. Nucleic Acids Res. (1988) [Pubmed]
  9. Delusional disorder: molecular genetic evidence for dopamine psychosis. Morimoto, K., Miyatake, R., Nakamura, M., Watanabe, T., Hirao, T., Suwaki, H. Neuropsychopharmacology (2002) [Pubmed]
  10. Individual differences in the expression of tyrosine hydroxylase mRNA in neurosecretory neurons of the human paraventricular and supraoptic nuclei: positive correlation with vasopressin mRNA. Panayotacopoulou, M.T., Malidelis, Y., van Heerikhuize, J., Unmehopa, U., Swaab, D. Neuroendocrinology (2005) [Pubmed]
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  12. Mutations in NR4A2 associated with familial Parkinson disease. Le, W.D., Xu, P., Jankovic, J., Jiang, H., Appel, S.H., Smith, R.G., Vassilatis, D.K. Nat. Genet. (2003) [Pubmed]
  13. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Kaplitt, M.G., Leone, P., Samulski, R.J., Xiao, X., Pfaff, D.W., O'Malley, K.L., During, M.J. Nat. Genet. (1994) [Pubmed]
  14. Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Roy, N.S., Cleren, C., Singh, S.K., Yang, L., Beal, M.F., Goldman, S.A. Nat. Med. (2006) [Pubmed]
  15. Local gene knockdown in the brain using viral-mediated RNA interference. Hommel, J.D., Sears, R.M., Georgescu, D., Simmons, D.L., DiLeone, R.J. Nat. Med. (2003) [Pubmed]
  16. Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation. Gould, P.A., Yii, M., McLean, C., Finch, S., Marshall, T., Lambert, G.W., Kaye, D.M. Pacing and clinical electrophysiology : PACE. (2006) [Pubmed]
  17. Human glioblastoma ADF cells express tyrosinase, L-tyrosine hydroxylase and melanosomes and are sensitive to L-tyrosine and phenylthiourea. Bonfigli, A., Zarivi, O., Colafarina, S., Cimini, A.M., Ragnelli, A.M., Aimola, P., Natali, P.G., Cerù, M.P., Amicarelli, F., Miranda, M. J. Cell. Physiol. (2006) [Pubmed]
  18. Gene therapy in a rodent model of Parkinson's disease using differentiated C6 cells expressing a GFAP-tyrosine hydroxylase transgene. Trejo, F., Vergara, P., Brenner, M., Segovia, J. Life Sci. (1999) [Pubmed]
  19. Regulated, adenovirus-mediated delivery of tyrosine hydroxylase suppresses growth of estrogen-induced pituitary prolactinomas. Williams, J.C., Stone, D., Smith-Arica, J.R., Morris, I.D., Lowenstein, P.R., Castro, M.G. Mol. Ther. (2001) [Pubmed]
  20. ERK1 and ERK2, two microtubule-associated protein 2 kinases, mediate the phosphorylation of tyrosine hydroxylase at serine-31 in situ. Haycock, J.W., Ahn, N.G., Cobb, M.H., Krebs, E.G. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  21. Genetic linkage studies in autosomal dominant parkinsonism: evaluation of seven candidate genes. Gasser, T., Wszolek, Z.K., Trofatter, J., Ozelius, L., Uitti, R.J., Lee, C.S., Gusella, J., Pfeiffer, R.F., Calne, D.B., Breakefield, X.O. Ann. Neurol. (1994) [Pubmed]
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  23. Dopamine-related genes and their relationships to monoamine metabolites in CSF. Jönsson, E., Sedvall, G., Brené, S., Gustavsson, J.P., Geijer, T., Terenius, L., Crocq, M.A., Lannfelt, L., Tylec, A., Sokoloff, P., Schwartz, J.C., Wiesel, F.A. Biol. Psychiatry (1996) [Pubmed]
  24. Deletion of tyrosine hydroxylase gene reveals functional interdependence of adrenocortical and chromaffin cell system in vivo. Bornstein, S.R., Tian, H., Haidan, A., Böttner, A., Hiroi, N., Eisenhofer, G., McCann, S.M., Chrousos, G.P., Roffler-Tarlov, S. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  25. HIV-1 Tat-mediated inhibition of the tyrosine hydroxylase gene expression in dopaminergic neuronal cells. Zauli, G., Secchiero, P., Rodella, L., Gibellini, D., Mirandola, P., Mazzoni, M., Milani, D., Dowd, D.R., Capitani, S., Vitale, M. J. Biol. Chem. (2000) [Pubmed]
  26. The tissue-specific methylation of the human tyrosine hydroxylase gene reveals new regulatory elements in the first exon. Arányi, T., Faucheux, B.A., Khalfallah, O., Vodjdani, G., Biguet, N.F., Mallet, J., Meloni, R. J. Neurochem. (2005) [Pubmed]
  27. Innervation of myofibroblast-like scleral spur cells in human monkey eyes. Tamm, E.R., Koch, T.A., Mayer, B., Stefani, F.H., Lütjen-Drecoll, E. Invest. Ophthalmol. Vis. Sci. (1995) [Pubmed]
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  29. Behavioral recovery in 6-hydroxydopamine-lesioned rats by cotransduction of striatum with tyrosine hydroxylase and aromatic L-amino acid decarboxylase genes using two separate adeno-associated virus vectors. Fan, D.S., Ogawa, M., Fujimoto, K.I., Ikeguchi, K., Ogasawara, Y., Urabe, M., Nishizawa, M., Nakano, I., Yoshida, M., Nagatsu, I., Ichinose, H., Nagatsu, T., Kurtzman, G.J., Ozawa, K. Hum. Gene Ther. (1998) [Pubmed]
  30. Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia. Furukawa, Y., Nygaard, T.G., Gütlich, M., Rajput, A.H., Pifl, C., DiStefano, L., Chang, L.J., Price, K., Shimadzu, M., Hornykiewicz, O., Haycock, J.W., Kish, S.J. Neurology (1999) [Pubmed]
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