Human Gene GCH1 (uc001xbh.1)
  Description: Homo sapiens GTP cyclohydrolase 1 (GCH1), transcript variant 2, mRNA.
RefSeq Summary (NM_001024024): This gene encodes a member of the GTP cyclohydrolase family. The encoded protein is the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, catalyzing the conversion of GTP into 7,8-dihydroneopterin triphosphate. BH4 is an essential cofactor required by aromatic amino acid hydroxylases as well as nitric oxide synthases. Mutations in this gene are associated with malignant hyperphenylalaninemia and dopa-responsive dystonia. Several alternatively spliced transcript variants encoding different isoforms have been described; however, not all variants give rise to a functional enzyme. [provided by RefSeq, Jul 2008].
Transcript (Including UTRs)
   Position: hg19 chr14:55,308,724-55,369,542 Size: 60,819 Total Exon Count: 7 Strand: -
Coding Region
   Position: hg19 chr14:55,310,735-55,369,381 Size: 58,647 Coding Exon Count: 6 

Page IndexSequence and LinksUniProtKB CommentsPrimersGenetic AssociationsMalaCards
CTDGene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein Structure
Other SpeciesGO AnnotationsmRNA DescriptionsPathwaysOther NamesGeneReviews
Model InformationMethods
Data last updated at UCSC: 2013-06-14

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr14:55,308,724-55,369,542)mRNA (may differ from genome)Protein (250 aa)
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BioGrid CRISPR DB

-  Comments and Description Text from UniProtKB
  ID: GCH1_HUMAN
DESCRIPTION: RecName: Full=GTP cyclohydrolase 1; EC=3.5.4.16; AltName: Full=GTP cyclohydrolase I; Short=GTP-CH-I;
FUNCTION: 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.
CATALYTIC ACTIVITY: GTP + H(2)O = formate + 2-amino-4-hydroxy-6- (erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate.
ENZYME REGULATION: GTP shows a positive allosteric effect, and tetrahydrobiopterin inhibits the enzyme activity. Zinc is required for catalytic activity. Inhibited by Mg(2+).
BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=116 uM for GTP; pH dependence: Optimum pH is 7.7 in phosphate buffer; Temperature dependence: Relatively stable at high temperatures. Retains 50% of its activity after incubation at 70 degrees Celsius for 15 minutes;
PATHWAY: Cofactor biosynthesis; 7,8-dihydroneopterin triphosphate biosynthesis; 7,8-dihydroneopterin triphosphate from GTP: step 1/1.
SUBUNIT: Toroid-shaped homodecamer, composed of a dimer of pentamers. The inactive isoforms also form decamers and may possibly be incorporated into GCH1 heterodecamers, decreasing enzyme stability and activity. Interacts with AHSA1 and GCHFR/GFRP.
INTERACTION: O95433:AHSA1; NbExp=3; IntAct=EBI-958183, EBI-448610; P63104:YWHAZ; NbExp=4; IntAct=EBI-958183, EBI-347088;
SUBCELLULAR LOCATION: Cytoplasm. Nucleus.
TISSUE SPECIFICITY: In epidermis, expressed predominantly in basal undifferentiated keratinocytes and in some but not all melanocytes (at protein level).
INDUCTION: Up-regulated by IFNG/IFN-gamma, TNF, IL1B/interleukin-1 beta, bacterial lipopolysaccharides (LPS) and phenylalanine, and down-regulated by dibutyryl-cAMP, iloprost and 8-bromo-cGMP in HUVEC cells. Up-regulation of GCH1 expression, in turn, stimulates production of tetrahydrobiopterin, with subsequent elevation of endothelial nitric oxide synthase activity. Cytokine-induced GCH1 up-regulation in HUVECs in response to TNF and IFNG/IFN-gamma involves cooperative activation of both the NF-kappa-B and JAK2/STAT pathways. Also up-regulated by hydrogen peroxide in human aorta endothelial cells (HAECs).
PTM: Phosphorylated by casein kinase II at Ser-81 in HAECs during oscillatory shear stress; phosphorylation at Ser-81 results in increased enzyme activity.
DISEASE: 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.
DISEASE: 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.
SIMILARITY: Belongs to the GTP cyclohydrolase I family.
WEB RESOURCE: Name=BIOMDB; Note=Db of mutations causing tetrahydrobiopterin deficiencies; URL="http://www.bh4.org/biodef1.html";
WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GCH1";

-  Primer design for this transcript
 

Primer3Plus can design qPCR Primers that straddle exon-exon-junctions, which amplify only cDNA, not genomic DNA.
Click here to load the transcript sequence and exon structure into Primer3Plus

Exonprimer can design one pair of Sanger sequencing primers around every exon, located in non-genic sequence.
Click here to open Exonprimer with this transcript

To design primers for a non-coding sequence, zoom to a region of interest and select from the drop-down menu: View > In External Tools > Primer3


-  Genetic Association Studies of Complex Diseases and Disorders
  Genetic Association Database (archive): GCH1
CDC HuGE Published Literature: GCH1
Positive Disease Associations: Arthritis, Rheumatoid , broad range of clinical presentations
Related Studies:
  1. Arthritis, Rheumatoid
    Yukinori Okada et al. Nature genetics 2012, Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population., Nature genetics. [PubMed 22446963]
  2. broad range of clinical presentations
    Markova ED et al. 1999, A novel mutation in the GTP cyclohydrolase I gene associated with a broad range of clinical presentations in a family with autosomal dominant dopa-responsive dystonia., European journal of neurology. 1999 Sep;6(5):605-8. [PubMed 10457396]

-  MalaCards Disease Associations
  MalaCards Gene Search: GCH1
Diseases sorted by gene-association score: hyperphenylalaninemia, bh4-deficient, b* (1692), dystonia, dopa-responsive, with or without hyperphenylalaninemia* (1227), segawa syndrome, recessive* (283), gtp cyclohydrolase 1-deficient dopa-responsive dystonia* (100), gtp cyclohydrolase 1-related disorders* (100), dystonia (36), hyperphenylalaninemia (34), tetrahydrobiopterin deficiency (28), hereditary dystonia (27), oromandibular dystonia (23), movement disease (13), tyrosine hydroxylase deficiency (12), cervical dystonia (12), dystonia-1, torsion (11), dystonia-12 (9), non-gestational choriocarcinoma (9), phenylketonuria (8), segmental dystonia (8), dystonia-11, myoclonic (8), early-onset generalized dystonia (7), dystonia-parkinsonism, x-linked (7), blepharospasm (5), thiamine metabolism dysfunction syndrome 2 (5), degenerative disc disease (5), somatoform disorder (5), leukodystrophy, hypomyelinating, 2 (5), cranio-facial dystonia (5), meige syndrome (5), vitiligo-associated multiple autoimmune disease susceptibility 1 (5), hemidystonia (5), oculogyric crisis (4), gliosarcoma (3), parkinson disease, late-onset (2)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

+  Common Gene Haplotype Alleles
  Press "+" in the title bar above to open this section.

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 29.79 RPKM in Liver
Total median expression: 202.87 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -72.90161-0.453 Picture PostScript Text
3' UTR -247.471065-0.232 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR001474 - GTP_CycHdrlase_I
IPR020602 - GTP_CycHdrlase_I/CN_OxRdtase
IPR018234 - GTP_CycHdrlase_I_CS

Pfam Domains:
PF01227 - GTP cyclohydrolase I

SCOP Domains:
55620 - Tetrahydrobiopterin biosynthesis enzymes-like

Protein Data Bank (PDB) 3-D Structure
MuPIT help
1FB1 - X-ray MuPIT


ModBase Predicted Comparative 3D Structure on P30793
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-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologGenome BrowserNo orthologNo orthologNo orthologNo ortholog
Gene DetailsGene Details    
Gene SorterGene Sorter    
 RGD    
 Protein Sequence    
 Alignment    

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0000166 nucleotide binding
GO:0003824 catalytic activity
GO:0003924 GTPase activity
GO:0003934 GTP cyclohydrolase I activity
GO:0005509 calcium ion binding
GO:0005515 protein binding
GO:0005525 GTP binding
GO:0008270 zinc ion binding
GO:0016787 hydrolase activity
GO:0030742 GTP-dependent protein binding
GO:0031369 translation initiation factor binding
GO:0042803 protein homodimerization activity
GO:0046872 metal ion binding
GO:0050662 coenzyme binding
GO:0051019 mitogen-activated protein kinase binding

Biological Process:
GO:0006729 tetrahydrobiopterin biosynthetic process
GO:0006809 nitric oxide biosynthetic process
GO:0008152 metabolic process
GO:0008217 regulation of blood pressure
GO:0010460 positive regulation of heart rate
GO:0014916 regulation of lung blood pressure
GO:0032496 response to lipopolysaccharide
GO:0034341 response to interferon-gamma
GO:0034612 response to tumor necrosis factor
GO:0035998 7,8-dihydroneopterin 3'-triphosphate biosynthetic process
GO:0042311 vasodilation
GO:0042416 dopamine biosynthetic process
GO:0042559 pteridine-containing compound biosynthetic process
GO:0045776 negative regulation of blood pressure
GO:0046654 tetrahydrofolate biosynthetic process
GO:0048265 response to pain
GO:0050884 neuromuscular process controlling posture
GO:0051000 positive regulation of nitric-oxide synthase activity
GO:0051066 dihydrobiopterin metabolic process
GO:0051186 cofactor metabolic process
GO:0051260 protein homooligomerization
GO:0051291 protein heterooligomerization
GO:0065003 macromolecular complex assembly
GO:2000121 regulation of removal of superoxide radicals

Cellular Component:
GO:0005634 nucleus
GO:0005654 nucleoplasm
GO:0005737 cytoplasm
GO:0005829 cytosol
GO:0031410 cytoplasmic vesicle
GO:0031965 nuclear membrane
GO:0032991 macromolecular complex
GO:0044306 neuron projection terminus


-  Descriptions from all associated GenBank mRNAs
  U66095 - Homo sapiens cell-line THP-1 GTP cyclohydrolase I mRNA, complete cds.
U66097 - Homo sapiens cell-line THP-1 GTP cyclohydrolase I mRNA, complete cds.
BC025415 - Homo sapiens GTP cyclohydrolase 1, mRNA (cDNA clone MGC:12737 IMAGE:4129035), complete cds.
U19523 - Human GTP cyclohydrolase I mRNA, complete cds.
Z29433 - Homo sapiens mRNA for GTP cyclohydrase I, clone 1.
S44053 - GTP cyclohydrolase I {alternatively spliced, clone hGCH-2} [human, liver, mRNA, 994 nt].
AF321276 - Homo sapiens GTP cyclohydrolase I mRNA, partial cds.
AY137463 - Homo sapiens GTP cyclohydrolase I type IV mRNA, partial cds; alternatively spliced.
AY137464 - Homo sapiens GTP cyclohydrolase I type V mRNA, partial cds; alternatively spliced.
AY137465 - Homo sapiens GTP cyclohydrolase I type VI mRNA, partial cds; alternatively spliced.
S44049 - GTP cyclohydrolase I {clone hGCH-1} [human, liver, mRNA, 1180 nt].
Z29434 - Homo sapiens mRNA for GTP cyclohydrase I, clone 2.
CR536551 - Homo sapiens full open reading frame cDNA clone RZPDo834G0222D for gene GCH1, GTP cyclohydrolase 1 (dopa-responsive dystonia); complete cds, incl. stopcodon.
DQ892998 - Synthetic construct clone IMAGE:100005628; FLH191518.01X; RZPDo839E0277D GTP cyclohydrolase 1 (dopa-responsive dystonia) (GCH1) gene, encodes complete protein.
DQ896245 - Synthetic construct Homo sapiens clone IMAGE:100010705; FLH191514.01L; RZPDo839E0267D GTP cyclohydrolase 1 (dopa-responsive dystonia) (GCH1) gene, encodes complete protein.
Z16418 - Homo sapiens mRNA for GTP cyclohydrolase I.
S43856 - GTP cyclohydrolase I {clone hGCH-3} [human, liver, mRNA, 819 nt].
JD563028 - Sequence 544052 from Patent EP1572962.
JD110657 - Sequence 91681 from Patent EP1572962.
JD047001 - Sequence 28025 from Patent EP1572962.
JD262826 - Sequence 243850 from Patent EP1572962.
JD088759 - Sequence 69783 from Patent EP1572962.
JD499469 - Sequence 480493 from Patent EP1572962.
JD119947 - Sequence 100971 from Patent EP1572962.
JD173666 - Sequence 154690 from Patent EP1572962.
JD374094 - Sequence 355118 from Patent EP1572962.
JD250704 - Sequence 231728 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa00790 - Folate biosynthesis
hsa01100 - Metabolic pathways

Reactome (by CSHL, EBI, and GO)

Protein P30793 (Reactome details) participates in the following event(s):

R-HSA-1474158 GCHFR binds to GCH1 and negatively regulates its activity
R-HSA-1474146 GCH1 reduces GTP to dihydroneopterin triphosphate
R-HSA-1474151 Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
R-HSA-8978934 Metabolism of cofactors
R-HSA-196854 Metabolism of vitamins and cofactors
R-HSA-1430728 Metabolism

-  Other Names for This Gene
  Alternate Gene Symbols: DYT5, GCH, GCH1_HUMAN, NM_001024024, NP_001019195, P30793, Q6FHY7, Q9Y4I8
UCSC ID: uc001xbh.1
RefSeq Accession: NM_001024024
Protein: P30793 (aka GCH1_HUMAN)
CCDS: CCDS9720.1

-  GeneReviews for This Gene
  GeneReviews article(s) related to gene GCH1:
drd (GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia)
dystonia-ov (Hereditary Dystonia Overview)

-  Gene Model Information
 
category: coding nonsense-mediated-decay: no RNA accession: NM_001024024.1
exon count: 7CDS single in 3' UTR: no RNA size: 1995
ORF size: 753CDS single in intron: no Alignment % ID: 99.95
txCdsPredict score: 1706.00frame shift in genome: no % Coverage: 99.20
has start codon: yes stop codon in genome: no # of Alignments: 1
has end codon: yes retained intron: no # AT/AC introns 0
selenocysteine: no end bleed into intron: 0# strange splices: 0
Click here for a detailed description of the fields of the table above.

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.