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GTP cyclohydrolase I gene, tetrahydrobiopterin, and tysorine hydroxylase gene: Their relations to dystonia and parkinsonism

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Abstract

Catecholamine biosynthesis is regulated by tyrosine hydroxylase (TH) requiring tetrahydrobiopterin (BH4) as the cofactor. We found four (human TH type 1–4) and two isoforms (TH type 1 and 2) in humans and monkeys, while non-primate animals have a single TH corresponding to human TH type 1. BH4 is synthesized from GTP, and GTP cyclohydrolase I (GCH) is the first and regulatory enzyme. Mutations in GCH gene were found to cause both GCH deficiency with autosomal recessive trait and hereditary progressive dystonia with marked diurnal fluctuation (HPD) (Segawa's disease)/or DOPA-responsive dystonia (DRD) with autosomal dominant trait. When GCH activity is decreased to less than 20% of the normal value, the activity of TH in the nigrostriatal dopaminergic neurons may be first decreased resulting in decreases in TH activity and dopamine level, and in the symptoms of HPD/DRD. In contrast to HPD/DRD, juvenile parkinsonism (JP) have normal GCH activity. In Parkinson's disease (PD), GCH, TH, and dopamine in the striatum may decrease in parallel, as the secondary effects caused by cell death.

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Abbreviations

BH4:

tetrahydrobiopterin

GTP:

cyclohydrolase I

GCH:

human tyrosine hydroxylase type 1–4

hTH1-hTH4:

juvenile parkinsonism, JP

MPTP:

1-methyl-1–4-phenyl-1,2,3,6-tetrahydropyridine

PCR:

polymerase chain reaction

PD:

Parkinson's disease

RT-PCR:

reverse transcription-polymerase chain reaction

TH:

tyrosine hydroxylase

References

  1. Nagatsu, T. 1991. Genes for human catecholamine-synthesizing enzymes. Neurosci. Res. 12:315–345.

    Article  PubMed  CAS  Google Scholar 

  2. Nagatsu, T., Levitt, M., and Udenfriend, S. 1964. Tyrosine hydroxylase. The initial step in norepinephrine biosynthesis. J. Biol. Chem. 239:2910–2917.

    PubMed  CAS  Google Scholar 

  3. Levitt, M., Spector, S., Sjoerdsma, A., and Udenfriend, S. 1965. Elucidation of the rate-limiting step in norepinephrine biosynthesis in the perfused guinea-pig heart. J. Pharmacol. Exp. Therap. 148: 1–8.

    CAS  Google Scholar 

  4. Kaufman, S. 1963. The structure of the phenylalanine hydroxylation cofactor. Proc. Natl. Acad. Sci. U.S.A. 50:1085–1093.

    Article  PubMed  CAS  Google Scholar 

  5. Kaufman, S., and Fisher, D. D. 1974. Pterin-requiring aromatic amino acid hydroxylases. Pages 285–367, in Hayaishi, O. (ed.) Molecular Mechanisms of Oxygen Activation, Academic Press, New York.

    Google Scholar 

  6. Nichol, C. A., Smith, G. K., and Duch, D. S. 1985. Biosynthesis and metabolism of tetrahydrobiopterin and molybdopterin. Ann. Rev. Biochem. 54:729–764.

    Article  PubMed  CAS  Google Scholar 

  7. Grima, B., Lamouroux, A., Boni, C., Julien, J.-F., Javoy-Agid, F., and Mallet, J. 1987. A single human gene encoding multiple tyrosine hydroxylase with different predicted functional characteristics. Nature 326:707–711.

    Article  PubMed  CAS  Google Scholar 

  8. Kaneda, N., Kobayashi, K., Ichinose, H., Kishi, F., Nakazawa, A., Kurosawa, Y., Fujita, K., and Nagatsu, T. 1987. Isolation of novel cDNA for human tyrosine hydroxylase: alternative RNA splicing produces four kinds of mRNA from a single gene. Biochem. Biophys. Res. Commun. 146:971–975.

    Article  PubMed  CAS  Google Scholar 

  9. Kobayashi, K., Kaneda, N., Ichinose, H., Kishi, F., Nakazawa, A., Kurosawa, Y., Fujita, K., and Nagatsu, T. 1988. Structure of the human tyrosine hydroxylase gene: alternative splicing from a single gene accounts for generation of four mRNA types. J Biochem. 103:907–912.

    PubMed  CAS  Google Scholar 

  10. Kobayashi, K., Kiuchi, K., Ishii, A., Kaneda, N., Kurosawa, Y., Fujita, K., and Nagatsu, T. 1988. Expression of four types of human tyrosine hydroxylase in COS cells. FEBS Lett. 238:431–434.

    Article  PubMed  CAS  Google Scholar 

  11. Nasrin, S., Ichinose, H., Hidaka, H., and Nagatsu, T. 1994. Recombinant human tyrosine hydroxylase types 1–4 show regulatory properties for the natural (6R)-tetrahydrobiopterin cofactor. J. Biochem. 116:393–398.

    PubMed  CAS  Google Scholar 

  12. Ichinose, H., Ohye, T., Fujita, K., Pantucek, F., Lange, K., Riederer, P., and Nagatsu, T. 1994. Quantification of mRNA of tyrosine hydroxylase and aromatic L-amino acid decarboxylase in the substantia nigra in Parkinson's disease and schizophrenia. J. Neural Transm. [P-D Sect] 8:149–158.

    Article  CAS  Google Scholar 

  13. Ichinose, H., Ohye, T., Fujita, K., Yoshida, M., Ueda, S., and Nagatsu, T. 1993. Increased heterogeneity of tyrosine hydroxylase in humans. Biochem. Biophys. Res. Commun. 195:158–165.

    Article  PubMed  CAS  Google Scholar 

  14. Davis, G. C., Williams, A. C., Markey, S. P., Ebert, M. H., Vaine, E. D., Reichert, C. M., and Kopin, I. J. 1979. Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res. 1:249–254.

    Article  PubMed  CAS  Google Scholar 

  15. Langston, J. W., Ballard, P., Tetrud, J. W., and Irwin, I. 1983. Chronic parkinsonism in humans due to a product of meperidineanalog synthesis. Science 219:979–980.

    Article  PubMed  CAS  Google Scholar 

  16. Burns, S. B., Lewitt, P. A., Ebert, M. H., Pakkenberg, H., and Kopin, I. J. 1985. The chronic syndrome of striatal dopamine deficiency. Parkinsonism induced by 1-methyl-1,2,3,6-tetrahydropyridine (MPTP). New Engl. J. Med. 312:1418–1421.

    Article  PubMed  CAS  Google Scholar 

  17. Ohye, T., Ichinose, H., Ogawa, M., Yoshida, M., and Nagatsu, T. 1995. Alterations in multiple tyrosine hydroxylase mRNAs in the substantia nigra, locus coeruleus and adrenal gland of MPTP-treated parkinsonian monkeys. 4:81–85.

    CAS  Google Scholar 

  18. Nagatsu, T., Naoi, M., Niwa, T., and Yoshida, M. 1994. Pages 149–159,in Mizuno, Y., Calne, D. B., and Horowski, R. (eds.), Advances in Research on Neurodegeneration Volume 2, Birkhäuser, Boston.

    Google Scholar 

  19. Ichinose, H., Ohye, T., Matsuda, Y., Hori, T., Blau, N., Burlina, A., Rouse, B., Matalon, R., Fujita, K., and Nagatsu, T. 1995. Characterization of mouse and human GTP cyclohydrolase I genes. Mutations in patients with GTP cyclohydrolase I deficiency. J. Biol. Chem. 270:10062–10071.

    Article  PubMed  CAS  Google Scholar 

  20. Niederwieser, A., Blau, N., Wang, M., Joller, P., Atarés, M., and Cardesa Garcia, J., 1984. GTP cyclohydrolase I deficiency, a new enzyme defect causing hyperphenylalaninemia with neopterin, biopterin, dopamine, and serotonin deficiencies and muscular hypotonia. Eur. J. Pediatr. 141:208–214.

    Article  PubMed  CAS  Google Scholar 

  21. Blau, N., Ichinose, H., Nagatsu, T., Heizmann, C. W., Zacchello, F., and Burlina, A. B. 1995. A missense mutation in a patient with guanosine triphosphate cyclohydrolase I deficiency missed in the newborn screening program. J. Pediatrics 126:401–405.

    Article  CAS  Google Scholar 

  22. Segawa, M., Ohmi, K., Itoh, S., Aoyama, Y., and Hayakawa, H. 1971. Childhood basal ganglia disease with remarkable response to L-DOPA, hereditary basal ganglia disease with marked diurnal fluctuation. Shinryo (Tokyo) 24:667–672.

    Google Scholar 

  23. Segawa, M., Hosaka, A., Miyagawa, F., Nomura, Y., and Imai, H. 1976. Hereditary progressive dystonia with marked diurnal fluctuation. Pages 215–233,in Eldridge, R., and Fahn, S. (eds.), Advances in Neurology Volume 14, Raven Press, New York.

    Google Scholar 

  24. Nygaard, T. G., Marsden, C. D., and Duvoisin, R. C. 1988. Dopa-responsive dystonia. Pages 377–384,in Fahn, S., Marsden, C. D., and Calne, D. B. (eds.), Advances in Neurology Volume 50, Raven Press, New York.

    Google Scholar 

  25. Nygaard, T. G., Snow, B. J., Fahn, S., and Calne, D. B. 1993. Dopa-responsive dystonia: clinical characteristics and definition. Pages 21–35,in Segawa, M. (ed.) Hereditary Progressive Dystonia with Marked Diurnal Fluctuation, Parthenon, Carnforth, UK.

    Google Scholar 

  26. Togari, A., Ichinose, H., Matsumoto, S., Fujita, K., and Nagatsu, T. 1992. Muttiple mRNA forms of human GTP cyclohydrolase I. Biochem. Biophys. Res. Commun. 187:359–365.

    Article  PubMed  CAS  Google Scholar 

  27. Ichinose, H., Ohye, T., Takahashi, E., Seki, N., Hori, T., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji S., Fujita, K., and Nagatsu, T. 1994. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nature Genetics 8:236–242.

    Article  PubMed  CAS  Google Scholar 

  28. Nygaard, T. G., Wilhelmsen, K. C., Risch, N. J., Brown, D. L., Trugman, J. M., Gilliam, T. C., Fahn, S., and Weeks, D. E., 1993. Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q. Nature Genetics 5:386–391.

    Article  PubMed  CAS  Google Scholar 

  29. Tanaka, H., Endo, K., Tsuji, S., Nygaard, T. G., Weeks, D. E., Nomura, Y., and Segawa, M. 1995. The gene for hereditary progressive dystonia with marked diurnal fluctuation maps to chromosome 14q. Ann. Neurol. 37:405–408.

    Article  PubMed  CAS  Google Scholar 

  30. Levine, R. A., Miller, L. P., and Lovenberg, W. 1981. Tetrahydrobiopterin in striatum: localization in dopamine nerve terminals and role in catecholamine synthesis. Science, 214:919–921.

    Article  PubMed  CAS  Google Scholar 

  31. Kettler, R., Bartholini, G., and Pletscher, A. 1974. In vivo enhancement of tyrosine hydroxylation in rat striatum by tetrahydrobiopterin. Nature 249:476–478.

    Article  PubMed  CAS  Google Scholar 

  32. Nagatsu, T. 1985. Biopterin cofactor and monoamine-synthesizing monooxygenases. Pages 325–340, in Osborne, N. N. (ed.), Selected Topics in Neurochemistry, Pergamon Press, Oxford.

    Google Scholar 

  33. Niwa, S., Watanabe, Y., and Hayaishi, O. 1985. 6R-L-erythro-5, 6, 7, 8-tetrahydrobiopterin as a regulator of dopamine and serotonin biosynthesis in the rat brain. Arch. Biochem. Biophys. 239: 234–241.

    Article  Google Scholar 

  34. Ichinose, H., Ohye, T., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji, S., Fujita, K., and Nagatsu, T. 1995. GTP cyclohydrolase I gene in hereditary progressive dystonia with marked diurnal fluctuation. Neurosci. Lett. 196:5–8.

    Article  PubMed  CAS  Google Scholar 

  35. Fink, J. K., Barton, N., Cohen, W., Lovenberg, W., Burns, R. S., and Hallett, M. 1988. Dystonia marked diurnal variation associated with biopterin deficiency. Neurology 38:707–711.

    PubMed  CAS  Google Scholar 

  36. Furukawa, Y., Nishi, K., Kondo, T., Mizuno, Y., and Narabayashi, H. 1993. CSF biopterin levels and clinical features of patients with juvenile parkinsonism. Pages 562–567,in Narabayashi, H., Nagatsu, T., Yanagisawa, N., and Mizuno Y. (eds.) Advances in Neurology Volume 60, Raven Press, New York.

    Google Scholar 

  37. Takahashi, H., Levine, R. A., Glloway, M. P., Snow, B. J., Calne, D. B., and Nygaard, T. G. 1994. Biochemical and fluorodopa positron emission tomographic findings in an asymptomatic carrier of the gene for dopa-responsive dystonia. Ann. Neurol. 35:354–356.

    Article  PubMed  CAS  Google Scholar 

  38. Williams, A., Eldridge, R., Levine, R., Lovenberg, W., and Paulson, G. 1979. Low CSF hydroxylase cofactor (tetrahydrobiopterin) levels in inherited dystonia. Lancet 2:410–411.

    Article  PubMed  CAS  Google Scholar 

  39. Bernheimer, H., Birkmayer, W., Hornykiewicz, O., Jellinger, K., and Seitelberger, F. 1973. Brain dopamine and the symptoms of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J. Neurol. Sci. 20:415–455.

    Article  PubMed  CAS  Google Scholar 

  40. Rajput, A. H., Gibb, W. R. G., Zhong, X. H., Shannak, K. S. Kish, S., Chang, L. G., and Hornykiewicz, O. 1994. Dopa-responsive dystonia: pathological and biochemical observations in a case. Ann. Neurol. 35:396–402.

    Article  PubMed  CAS  Google Scholar 

  41. Lüdecke, B., Dworniczak, B., and Bartholomé K. 1995. A point mutation in the tyrosine hyfroxylase gene asspciated with Segawa's syndrome. Human Genet. 95:123–125.

    Google Scholar 

  42. Knappskog, P. M., Flatmark, T., Mallet, J, Lüdecke, B., and Bartholomé, K. 1995. Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q 381 K) in the tyrosine hydroxylase gene. Human Mol. Genetics 4:1209–1212.

    CAS  Google Scholar 

  43. Hirano, M., Tamaru, Y., Nagai, Y., Ito, H., Imai, T., and Ueno, S. 1995. Exon skipping caused by a base substitution at a splice site in the GTP cyclohydrolase I gene in a Japanese family with hereditary progressive dystonia/dopa responsive dystonia. Biochem. Biophys. Res. Commun. 213:645–651.

    Article  PubMed  CAS  Google Scholar 

  44. Narabayashi, H., Yokochi, M., Iizuka, R., and Nagatsu, T. 1986. Juvenile parkinsonism. Pags 153–165, in Vinken, P. J., Bruyn, G. W., and Klawans, H. L. (eds.), Handbook of Clinical Neurology Volume 49 Extrapyramidal Disorders, Elsevier, Amsterdam.

    Google Scholar 

  45. Yokochi, M., 1993. Nosological concept of juvenile parkinsonism with reference to the dopa-responsive dystonia Pages 548–552,in Narabayashi, H., Nagatsu, T., Yanagisawa, N., and Mizuno, Y. (eds.), Advances in Neurology Volume 60, Raven Press, New York.

    Google Scholar 

  46. Ichinose, H., Ohye T., Yokochi, M., Fujita, K., and Nagatsu, T. 1995. GTP cyclohydrolase I activity in mononuclear blood cells in juvenile parkinsonism. Neurosci. Lett. 190:140–142.

    Article  PubMed  CAS  Google Scholar 

  47. Nagatsu, T., Horikoshi, T., Sawada, M., Nagatsu, I., Kondo, T., Iizuka, R., and Narabayashi, H. 1986. Biosynthesis of tetrahydrobiopterin in parkinsonian human brain. Pages 223–226,in Yah, M. D. and Bergman, K. I. (eds.), Advances in Neurology Volume 45, Raven Press, New York.

    Google Scholar 

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  1. Institute for Comprehensive Medical Science, School of Medicine, Fujita Health University, 470-11, Toyake, Aichi, Japan

    T. Nagatsu & H. Ichinose

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  1. T. Nagatsu
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  2. H. Ichinose
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Special issue dedicated to Dr. Kinya Kuriyama.

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Nagatsu, T., Ichinose, H. GTP cyclohydrolase I gene, tetrahydrobiopterin, and tysorine hydroxylase gene: Their relations to dystonia and parkinsonism. Neurochem Res 21, 245–250 (1996). https://doi.org/10.1007/BF02529141

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