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Structural highlights

Disease

[GCH1_HUMAN] Defects in GCH1 are the cause of GTP cyclohydrolase 1 deficiency (GCH1D) [MIM:233910]; also known as atypical severe phenylketonuria due to GTP cyclohydrolase I deficiency;. GCH1D is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. It is also responsible for defective neurotransmission due to depletion of the neurotransmitters dopamine and serotonin. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing. Some patients may present a phenotype of intermediate severity between severe hyperphenylalaninemia and mild dystonia type 5 (dystonia-parkinsonism with diurnal fluctuation). In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia.^{[1] [2]} Defects in GCH1 are the cause of dystonia type 5 (DYT5) [MIM:128230]; also known as progressive dystonia with diurnal fluctuation, autosomal dominant Segawa syndrome or dystonia-parkinsonism with diurnal fluctuation. DYT5 is a DOPA-responsive dystonia. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT5 typically presents in childhood with walking problems due to dystonia of the lower limbs and worsening of the dystonia towards the evening. It is characterized by postural and motor disturbances showing marked diurnal fluctuation. Torsion of the trunk is unusual. Symptoms are alleviated after sleep and aggravated by fatigue and excercise. There is a favorable response to L-DOPA without side effects.^{[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]}

Function

[GCH1_HUMAN] Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown.^{[18] [19] [20] [21] [22]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Cyclohydrolase

References

1. ↑ Ichinose H, Ohye T, Segawa M, Nomura Y, Endo K, Tanaka H, Tsuji S, Fujita K, Nagatsu T. GTP cyclohydrolase I gene in hereditary progressive dystonia with marked diurnal fluctuation. Neurosci Lett. 1995 Aug 18;196(1-2):5-8. PMID:7501255
2. ↑ Furukawa Y, Kish SJ, Bebin EM, Jacobson RD, Fryburg JS, Wilson WG, Shimadzu M, Hyland K, Trugman JM. Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations. Ann Neurol. 1998 Jul;44(1):10-6. PMID:9667588 doi:10.1002/ana.410440107
3. ↑ Ichinose H, Ohye T, Segawa M, Nomura Y, Endo K, Tanaka H, Tsuji S, Fujita K, Nagatsu T. GTP cyclohydrolase I gene in hereditary progressive dystonia with marked diurnal fluctuation. Neurosci Lett. 1995 Aug 18;196(1-2):5-8. PMID:7501255
4. ↑ Ichinose H, Ohye T, Takahashi E, Seki N, Hori T, Segawa M, Nomura Y, Endo K, Tanaka H, Tsuji S, et al.. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet. 1994 Nov;8(3):236-42. PMID:7874165 doi:http://dx.doi.org/10.1038/ng1194-236
5. ↑ Hirano M, Tamaru Y, Ito H, Matsumoto S, Imai T, Ueno S. Mutant GTP cyclohydrolase I mRNA levels contribute to dopa-responsive dystonia onset. Ann Neurol. 1996 Nov;40(5):796-8. PMID:8957022 doi:10.1002/ana.410400517
6. ↑ Bandmann O, Nygaard TG, Surtees R, Marsden CD, Wood NW, Harding AE. Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity. Hum Mol Genet. 1996 Mar;5(3):403-6. PMID:8852666
7. ↑ Beyer K, Lao-Villadoniga JI, Vecino-Bilbao B, Cacabelos R, De la Fuente-Fernandez R. A novel point mutation in the GTP cyclohydrolase I gene in a Spanish family with hereditary progressive and dopa responsive dystonia. J Neurol Neurosurg Psychiatry. 1997 Apr;62(4):420-1. PMID:9120469
8. ↑ Jarman PR, Bandmann O, Marsden CD, Wood NW. GTP cyclohydrolase I mutations in patients with dystonia responsive to anticholinergic drugs. J Neurol Neurosurg Psychiatry. 1997 Sep;63(3):304-8. PMID:9328244
9. ↑ Bandmann O, Valente EM, Holmans P, Surtees RA, Walters JH, Wevers RA, Marsden CD, Wood NW. Dopa-responsive dystonia: a clinical and molecular genetic study. Ann Neurol. 1998 Oct;44(4):649-56. PMID:9778264 doi:10.1002/ana.410440411
10. ↑ Hwu WL, Wang PJ, Hsiao KJ, Wang TR, Chiou YW, Lee YM. Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation. Hum Genet. 1999 Sep;105(3):226-30. PMID:10987649
11. ↑ Suzuki T, Ohye T, Inagaki H, Nagatsu T, Ichinose H. Characterization of wild-type and mutants of recombinant human GTP cyclohydrolase I: relationship to etiology of dopa-responsive dystonia. J Neurochem. 1999 Dec;73(6):2510-6. PMID:10582612
12. ↑ Brique S, Destee A, Lambert JC, Mouroux V, Delacourte A, Amouyel P, Chartier-Harlin MC. A new GTP-cyclohydrolase I mutation in an unusual dopa-responsive dystonia, familial form. Neuroreport. 1999 Feb 25;10(3):487-91. PMID:10208576
13. ↑ Hirano M, Komure O, Ueno S. A novel missense mutant inactivates GTP cyclohydrolase I in dopa-responsive dystonia. Neurosci Lett. 1999 Feb 5;260(3):181-4. PMID:10076897
14. ↑ Tassin J, Durr A, Bonnet AM, Gil R, Vidailhet M, Lucking CB, Goas JY, Durif F, Abada M, Echenne B, Motte J, Lagueny A, Lacomblez L, Jedynak P, Bartholome B, Agid Y, Brice A. Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations? Brain. 2000 Jun;123 ( Pt 6):1112-21. PMID:10825351
15. ↑ Steinberger D, Korinthenberg R, Topka H, Berghauser M, Wedde R, Muller U. Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa. German Dystonia Study Group. Neurology. 2000 Dec 12;55(11):1735-7. PMID:11113234
16. ↑ Leuzzi V, Carducci C, Carducci C, Cardona F, Artiola C, Antonozzi I. Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive myoclonus-dystonia syndrome. Neurology. 2002 Oct 22;59(8):1241-3. PMID:12391354
17. ↑ Ohta E, Funayama M, Ichinose H, Toyoshima I, Urano F, Matsuo M, Tomoko N, Yukihiko K, Yoshino S, Yokoyama H, Shimazu H, Maeda K, Hasegawa K, Obata F. Novel mutations in the guanosine triphosphate cyclohydrolase 1 gene associated with DYT5 dystonia. Arch Neurol. 2006 Nov;63(11):1605-10. PMID:17101830 doi:10.1001/archneur.63.11.1605
18. ↑ Gutlich M, Jaeger E, Rucknagel KP, Werner T, Rodl W, Ziegler I, Bacher A. Human GTP cyclohydrolase I: only one out of three cDNA isoforms gives rise to the active enzyme. Biochem J. 1994 Aug 15;302 ( Pt 1):215-21. PMID:8068008
19. ↑ Katusic ZS, Stelter A, Milstien S. Cytokines stimulate GTP cyclohydrolase I gene expression in cultured human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol. 1998 Jan;18(1):27-32. PMID:9445252
20. ↑ Cai S, Alp NJ, McDonald D, Smith I, Kay J, Canevari L, Heales S, Channon KM. GTP cyclohydrolase I gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells: effects on nitric oxide synthase activity, protein levels and dimerisation. Cardiovasc Res. 2002 Sep;55(4):838-49. PMID:12176133
21. ↑ Duan CL, Su Y, Zhao CL, Lu LL, Xu QY, Yang H. The assays of activities and function of TH, AADC, and GCH1 and their potential use in ex vivo gene therapy of PD. Brain Res Brain Res Protoc. 2005 Dec;16(1-3):37-43. PMID:16338639 doi:S1385-299X(05)00087-5
22. ↑ Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, Ehnert C, Nejim J, Marian C, Scholz J, Wu T, Allchorne A, Diatchenko L, Binshtok AM, Goldman D, Adolph J, Sama S, Atlas SJ, Carlezon WA, Parsegian A, Lotsch J, Fillingim RB, Maixner W, Geisslinger G, Max MB, Woolf CJ. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006 Nov;12(11):1269-77. Epub 2006 Oct 22. PMID:17057711 doi:10.1038/nm1490
23. ↑ Auerbach G, Herrmann A, Bracher A, Bader G, Gutlich M, Fischer M, Neukamm M, Garrido-Franco M, Richardson J, Nar H, Huber R, Bacher A. Zinc plays a key role in human and bacterial GTP cyclohydrolase I. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13567-72. PMID:11087827 doi:10.1073/pnas.240463497