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Gene Review

GCH1  -  GTP cyclohydrolase 1

Homo sapiens

Synonyms: DYT14, DYT5, DYT5a, GCH, GTP cyclohydrolase I, ...
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Disease relevance of GCH1

  • We describe two previously unrecognized splice site mutations of GCH1 in Dopa responsive dystonia (DRD) [1].
  • CONCLUSIONS: These findings show that a proportion of patients with apparent primary torsion dystonia and a good response to anticholinergic drugs have GCH1 mutations and therefore have a variant of dopa responsive dystonia [2].
  • These findings on DRD indicate that the nigrostriatal DA neurons may be most susceptible to the decreases in GCH1 activity, BH4 level, TH activity, and DA level, and that DRD is the DA deficiency without neuronal death in contrast to juvenile parkinsonism or Parkinson's disease with DA cell death [3].
  • We have studied the GTP-cyclohydrolase 1 (GCH-1) gene in 30 patients with the diagnosis of clinically definite (n = 20) or possible (n = 10) dopa-responsive dystonia (DRD) as well as in a child with atypical phenylketonuria due to complete GCH-1 deficiency [4].
  • The phenotypes of recessive GCH deficiency are severe and complex, such as hyperphenylalaninemia, muscle hypotonia, epilepsy, and fever episode, and may be caused by deficiencies of various neurotransmitters, including dopamine, norepinephrine, serotonin, and NO [5].

Psychiatry related information on GCH1

  • A novel mutation, X251R, was identified in the GCH1 gene of 2 distantly related Danish patients with DRD, one of whom also had Tourette syndrome (TS) [6].

High impact information on GCH1

  • Although GTPCH is believed to be the rate-limiting step, control of endothelial PTPS expression by cytokines may play an important role in regulating BH4-dependent nitric oxide production in the vascular system [7].
  • Recently the GTP cyclohydrolase I (GTPCH) gene was isolated as the first causative gene for dopa-responsive dystonia (DRD) [8].
  • Amplifying all six exons, we analyzed the GTPCH gene in nine British families with 33 affected family members and in three sporadic cases and found six new mutations [8].
  • No mutations were found in exons of GCH1 and SPG3A, two genes from the candidate region involved in movement disorders [9].
  • Moreover, Hsp90 inhibitor geldanamycin destroyed the wild-type GCH level, and heat shock increased the synthesis of GCH protein [10].

Chemical compound and disease context of GCH1


Biological context of GCH1

  • There was no mutation in the promoter region of GCH1 in any patient [15].
  • To discover novel GCH1 protein binding partners, we used the yeast 2-hybrid system to screen a human brain library with GCH1 N-terminal amino acids 1-96 as prey [16].
  • The yeast 2-hybrid system was used to identify protein domains involved in the oligomerization of human guanosine 5'-triphosphate (GTP) Cyclohydrolase I (GCH1) and the interaction of GCH1 with its regulatory partner, GCH1 feedback regulatory protein (GFRP) [16].
  • The clinical phenotype of patients with and without GCH1 mutations was similar [2].
  • The GCH1 activities of the HAC-carrying human fibroblast cell lines were elevated but still highly sensitive to IFN-gamma induction, mimicking the response of the gene expression from the authentic chromosomal genes [17].

Anatomical context of GCH1

  • In the autopsied putamen of an asymptomatic GCH1 mutation carrier, we found that brain biopterin loss (-82%) paralleled that reported in dopa-responsive dystonia patients (-84%) [18].
  • Two cell lines carrying a HAC with GCH1 genes were obtained [17].
  • We proved that the GCH1 gene is the causative gene for HPD/DRD based on the identification of mutations of the gene in the patients and decreases in the enzyme activity expressed in mononuclear blood cells to 2-20% of the normal value [3].
  • We sought to investigate the signaling pathways whereby cytokines induce GTPCH I expression in human umbilical vein endothelial cells (HUVECs) [19].
  • However, the molecular mechanisms of cytokine-mediated GTPCH I induction in the endothelium are not entirely clear [19].

Associations of GCH1 with chemical compounds

  • 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 [20].
  • Analysis of the gene GCH1 in 58 patients with dystonia and a positive response to L-dopa revealed mutations in 30 individuals from 22 families [15].
  • Until recently, few studies have investigated the relation between DA production and PD improvement and respective expressed human tyrosine hydroxylase (hTH), human GTP-cyclohydrolase 1 (hGCH1), and human aromatic acid decarboxylase (hAADC) in ex vivo gene therapy for PD [21].
  • The F3.TH.GTPCH human NSC line expresses TH and GTPCH phenotypes as determined by RT-PCR, western blotting and immunocytochemistry, and shows a 800 to 2000-fold increase in production of L-dihydroxyphenyl alanine in HPLC analysis [22].
  • Our data demonstrate a new phenotype of GCH deficiency associated with compound heterozygosity for GCH gene mutations and suggest the usefulness of combined BH4 and levodopa therapy for this disorder [23].

Regulatory relationships of GCH1

  • Thus, GCH activity indirectly regulates TH activity and catecholamine levels [24].
  • GTP cyclohydrolase I (GCH1) activity in phytohemaglutinin (PHA)-stimulated mononuclear blood cells (MBCs) is a useful clinical marker for diagnosis of tetrahydrobiopterin (BH4)-related genetic disorders such as recessively inherited GCH1 deficiency and dominantly inherited dopa-responsive dystonia (Segawa's disease) [25].

Other interactions of GCH1

  • Moreover, a previously unknown role of the extended N-terminal alpha-helix in the interaction of GCH1 and GFRP was revealed [16].
  • CONCLUSION: The triple transduction of TH, AADC and GCH genes with separate AAV vectors is effective, which might be important to gene therapy for Parkinson's disease [26].
  • The results indicate that there might be a BH4 biosynthetic pathway where GCH is not involved and that SPR might have some yet unidentified function(s) in addition to BH4 biosynthesis [27].
  • Coinduction of NO and BH4 synthesis in thyrocytes was preceded by coexpression of messenger RNAs for NOS and GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme for de novo synthesis of BH4 [28].
  • Moreover, expression of the GTPCH feedback regulatory protein, which if decreased might increase GTPCH activity, was not affected by TNF-alpha or ceramide [29].

Analytical, diagnostic and therapeutic context of GCH1

  • When interpreted within the structural framework derived from crystallography, our results indicate that the GCH1 N-terminal alpha-helices are not the only domains involved in the formation of dimers from monomers and also suggest an important role for the C-terminal alpha-helix in the assembly of dimers to form decamers [16].
  • CONCLUSION: These HACs will provide a useful system for analysis of the complex regulatory circuit of the GCH1 gene in vivo and also function as a tool for gene delivery in animal models or in therapeutic trials [17].
  • GTPCH I enzymatic activity, BH4, and oxidized biopterin levels were detected with the use of HPLC, and cGMP was measured with the use of radioimmunoassay [30].
  • METHODS: Using HPLC, we measured endogenous neopterin, the main byproduct of the GCH1 reaction, in lymphoblasts under basal conditions and following GCH1 stimulation conditions [12].
  • Virulence in cell culture was mildly or markedly lower in the 5 isolates tested (4 H and 1 C) compared with the GCH1 reference isolate [31].


  1. Two previously unrecognized splicing mutations of GCH1 in Dopa-responsive dystonia: exon skipping and one base insertion. Weber, Y., Steinberger, D., Deuschl, G., Benecke, R., Müller, U. Neurogenetics (1997) [Pubmed]
  2. GTP cyclohydrolase I mutations in patients with dystonia responsive to anticholinergic drugs. Jarman, P.R., Bandmann, O., Marsden, C.D., Wood, N.W. J. Neurol. Neurosurg. Psychiatr. (1997) [Pubmed]
  3. Molecular genetics of dopa-responsive dystonia. Ichinose, H., Suzuki, T., Inagaki, H., Ohye, T., Nagatsu, T. Biol. Chem. (1999) [Pubmed]
  4. Dopa-responsive dystonia: a clinical and molecular genetic study. Bandmann, O., Valente, E.M., Holmans, P., Surtees, R.A., Walters, J.H., Wevers, R.A., Marsden, C.D., Wood, N.W. Ann. Neurol. (1998) [Pubmed]
  5. Regulation of pteridine-requiring enzymes by the cofactor tetrahydrobiopterin. Nagatsu, T., Ichinose, H. Mol. Neurobiol. (1999) [Pubmed]
  6. Dopa-responsive dystonia and Tourette syndrome in a large Danish family. Romstad, A., Dupont, E., Krag-Olsen, B., Østergaard, K., Guldberg, P., Güttler, F. Arch. Neurol. (2003) [Pubmed]
  7. Regulation of 6-pyruvoyltetrahydropterin synthase activity and messenger RNA abundance in human vascular endothelial cells. Linscheid, P., Schaffner, A., Blau, N., Schoedon, G. Circulation (1998) [Pubmed]
  8. Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity. Bandmann, O., Nygaard, T.G., Surtees, R., Marsden, C.D., Wood, N.W., Harding, A.E. Hum. Mol. Genet. (1996) [Pubmed]
  9. Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Bouslam, N., Benomar, A., Azzedine, H., Bouhouche, A., Namekawa, M., Klebe, S., Charon, C., Durr, A., Ruberg, M., Brice, A., Yahyaoui, M., Stevanin, G. Ann. Neurol. (2005) [Pubmed]
  10. Molecular chaperones affect GTP cyclohydrolase I mutations in dopa-responsive dystonia. Hwu, W.L., Lu, M.Y., Hwa, K.Y., Fan, S.W., Lee, Y.M. Ann. Neurol. (2004) [Pubmed]
  11. Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations? Tassin, J., Dürr, A., Bonnet, A.M., Gil, R., Vidailhet, M., Lücking, C.B., Goas, J.Y., Durif, F., Abada, M., Echenne, B., Motte, J., Lagueny, A., Lacomblez, L., Jedynak, P., Bartholomé, B., Agid, Y., Brice, A. Brain (2000) [Pubmed]
  12. Reduced lymphoblast neopterin detects GTP cyclohydrolase dysfunction in dopa-responsive dystonia. Bezin, L., Nygaard, T.G., Neville, J.D., Shen, H., Levine, R.A. Neurology (1998) [Pubmed]
  13. Viral restoration of dopamine to the nucleus accumbens is sufficient to induce a locomotor response to amphetamine. Heusner, C.L., Hnasko, T.S., Szczypka, M.S., Liu, Y., During, M.J., Palmiter, R.D. Brain Res. (2003) [Pubmed]
  14. Decrease in tetrahydrobiopterin as a possible cause of nephropathy in type II diabetic rats. Okumura, M., Masada, M., Yoshida, Y., Shintaku, H., Hosoi, M., Okada, N., Konishi, Y., Morikawa, T., Miura, K., Imanishi, M. Kidney Int. (2006) [Pubmed]
  15. Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa. German Dystonia Study Group. Steinberger, D., Korinthenberg, R., Topka, H., Berghäuser, M., Wedde, R., Müller, U. Neurology (2000) [Pubmed]
  16. A yeast 2-hybrid analysis of human GTP cyclohydrolase I protein interactions. Swick, L., Kapatos, G. J. Neurochem. (2006) [Pubmed]
  17. Generation of human artificial chromosomes expressing naturally controlled guanosine triphosphate cyclohydrolase I gene. Ikeno, M., Inagaki, H., Nagata, K., Morita, M., Ichinose, H., Okazaki, T. Genes Cells (2002) [Pubmed]
  18. Brain biopterin and tyrosine hydroxylase in asymptomatic dopa-responsive dystonia. Furukawa, Y., Kapatos, G., Haycock, J.W., Worsley, J., Wong, H., Kish, S.J., Nygaard, T.G. Ann. Neurol. (2002) [Pubmed]
  19. Cytokine-stimulated GTP cyclohydrolase I expression in endothelial cells requires coordinated activation of nuclear factor-kappaB and Stat1/Stat3. Huang, A., Zhang, Y.Y., Chen, K., Hatakeyama, K., Keaney, J.F. Circ. Res. (2005) [Pubmed]
  20. 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]
  21. The assays of activities and function of TH, AADC, and GCH1 and their potential use in ex vivo gene therapy of PD. Duan, C.L., Su, Y., Zhao, C.L., Lu, L.L., Xu, Q.Y., Yang, H. Brain Res. Brain Res. Protoc. (2005) [Pubmed]
  22. Brain transplantation of human neural stem cells transduced with tyrosine hydroxylase and GTP cyclohydrolase 1 provides functional improvement in animal models of Parkinson disease. Kim, S.U., Park, I.H., Kim, T.H., Kim, K.S., Choi, H.B., Hong, S.H., Bang, J.H., Lee, M.A., Joo, I.S., Lee, C.S., Kim, Y.S. Neuropathology : official journal of the Japanese Society of Neuropathology. (2006) [Pubmed]
  23. Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations. Furukawa, Y., Kish, S.J., Bebin, E.M., Jacobson, R.D., Fryburg, J.S., Wilson, W.G., Shimadzu, M., Hyland, K., Trugman, J.M. Ann. Neurol. (1998) [Pubmed]
  24. Molecular biology of catecholamine-related enzymes in relation to Parkinson's disease. Nagatsu, T., Ichinose, H. Cell. Mol. Neurobiol. (1999) [Pubmed]
  25. Normal values and age-dependent changes in GTP cyclohydrolase I activity in stimulated mononuclear blood cells measured by high-performance liquid chromatography. Hibiya, M., Ichinose, H., Ozaki, N., Fujita, K., Nishimoto, T., Yoshikawa, T., Asano, Y., Nagatsu, T. J. Chromatogr. B Biomed. Sci. Appl. (2000) [Pubmed]
  26. Adeno-associated virus vector-mediated triple gene transfer of dopamine synthetic enzymes. Fan, D., Shen, Y., Kang, D., Nakano, I., Ozawa, K. Chin. Med. J. (2001) [Pubmed]
  27. Localization of sepiapterin reductase in the human brain. Ikemoto, K., Suzuki, T., Ichinose, H., Ohye, T., Nishimura, A., Nishi, K., Nagatsu, I., Nagatsu, T. Brain Res. (2002) [Pubmed]
  28. Regulation of inducible nitric oxide production by cytokines in human thyrocytes in culture. Kasai, K., Hattori, Y., Nakanishi, N., Manaka, K., Banba, N., Motohashi, S., Shimoda, S. Endocrinology (1995) [Pubmed]
  29. Divergence in regulation of nitric-oxide synthase and its cofactor tetrahydrobiopterin by tumor necrosis factor-alpha. Ceramide potentiates nitric oxide synthesis without affecting GTP cyclohydrolase I activity. Vann, L.R., Twitty, S., Spiegel, S., Milstien, S. J. Biol. Chem. (2000) [Pubmed]
  30. In vivo expression and function of recombinant GTPCH I in the rabbit carotid artery. Hynes, S.O., Smith, L.A., Richardson, D.M., Kovesdi, I., O'Brien, T., Katusic, Z.S. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  31. Genotypic and phenotypic characterization of Cryptosporidium parvum isolates from people with AIDS. Widmer, G., Tzipori, S., Fichtenbaum, C.J., Griffiths, J.K. J. Infect. Dis. (1998) [Pubmed]
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