The most recent information on GCH1 is here. Click here for the function of GCH1. Edit this page in Wiki Genes - GCH1 or see Wiki Gene. Clinical and genetic features of DYT1 and DYT5. Paper-11319739. Mutations of GCH1 in Dopa-responsive dystonia. Paper-9433198. Importantly, IL-1beta induced PTPS rather than GTPCH. Paper-10116955. Endothelial GTPCH in eNOS uncoupling and atherosclerosis. Paper-13297094. We mainly discussed two subtypes, DYT1 and DYT5, in this review. Paper-11319739. No other putative disease causing TH or GCH1 mutations were found. Paper-11826871. A novel mutation in GCH-1 gene in a case of dopa-responsive dystonia. Paper-13413859. GCH1 mutation in a patient with adult-onset oromandibular dystonia. Paper-1810146. Novel GCH1 mutation in a Brazilian family with dopa-responsive dystonia. Paper-12722446. Utility of MLPA in deletion analysis of GCH1 in dopa-responsive dystonia. Paper-13095102. We found a recessive GTPCH mutation (R249S, 747C-->G in a dystonia patient. Paper-8312585. Fluvastatin was also observed to enhance GTPCH and eNOS mRNA levels. Paper-9773781. Gene symbol: GTP cyclohydrolase I (GCH-I). Disease: dopa-responsive dystonia. Paper-11232765. In contrast to HPD/DRD, juvenile parkinsonism (JP) have normal GCH activity. Paper-1021297. No difference in expression was detected for CBR1, CBR3, and GCH1. Paper-13136535. These data indicate that RNF4 imposes functional importance on GCH promoter. Paper-10848859. A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia. Paper-13457760. DHFR but not GTPCH1 knockdown increased reactive oxygen species (ROS) production. Paper-13748668. Thus, GCH activity indirectly regulates TH activity and catecholamine levels. Paper-1849900. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. Paper-12782518. Familial young-onset primary dystonia is commonly due to the DYT1 gene mutation. Paper-13906568. The mRNA of GTPCH, as well as of eNOS, was upregulated in HUVECs treated with cerivastatin. Paper-9773781. Hsp27 decreases inclusion body formation from mutated GTP-cyclohydrolase I protein. Paper-12747043. A virus expressing only TH was less effective, and one expressing GTPCH1 alone was ineffective. Paper-1754889. Serum prolactin in symptomatic and asymptomatic dopa-responsive dystonia due to a GCH1 mutation. Paper-9916616. These changes in GTPCH and BH4 had no effect on GFRP expression or protein levels. Paper-13760894. Namely, GCH in some cases was found to develop into ECA apparently through the change from ADH to ATH. Paper-4315854. However, some neurons in the dorsal and dorsomedial hypothalamic nuclei are stained only for GCH or TH. Paper-11589777. Mutations in the GTP cyclohydrolase I ( GTP-CH-I) gene were recently identified as the cause of HPD/ DRD. Paper-1405575. Phenocopies in a large GCH1 mutation positive family with dopa responsive dystonia: confusing the picture? Paper-9209691. Confocal and electron microscopy analyses confirmed GTPCH I colocalization with caveolin-1. Paper-13586072. Autosomal Dominant GTP Cyclohydrolase I (AD GCH 1) Deficiency (Segawa Disease, Dystonia 5; DYT 5). Paper-13670014. Genetic testing for GTP cyclohydrolase I, tyrosine hydroxylase, and sepiapterin reductase was negative. Paper-10844878. Molecular analyses of GCH-1, TH and parkin genes in Chinese dopa-responsive dystonia families. Paper-13078526. Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT5. Paper-12782518. Immunostimulation alters protein expression of GTPCH I and GFRP in a way that favors BH(4) synthesis. Paper-9896940. Silencing primary dystonia: lentiviral-mediated RNA interference therapy for DYT1 dystonia. Paper-11469656. The clinical manifestations common to the patients with HPD/ DRD with a mutated GTP-CH-I gene were also identified. Paper-1405575. Her PHA- stimulated mononuclear blood cells had a normal amount of GTPCH mRNA, but low GTPCH activity. Paper-8312585. We report a new nonsense mutation in the GTP cyclohydrolase I ( GCH1) gene in a family with dopa-responsive dystonia. Paper-8840273. The de novo synthesis of 6-BH4 depends on the induction of GTP-CH-1, e.g., by tumor necrosis factor-alpha ( TNF alpha). Paper-1060807. AR GTPCH I deficiency can present without hyperphenylalaninemia and with normal or subtle CSF neurotransmitter profiles. Paper-12762279. Recently the GTP cyclohydrolase I ( GTPCH) gene was isolated as the first causative gene for dopa-responsive dystonia (DRD). Paper-804519. The assays of activities and function of TH, AADC, and GCH1 and their potential use in ex vivo gene therapy of PD. Paper-11155660. Moreover, a previously unknown role of the extended N-terminal alpha-helix in the interaction of GCH1 and GFRP was revealed. Paper-12004980. Pure GCH was observed in 112 cases (60.9%), GCH with ADH in 56 cases (30.4%), and GCH with ATH in 11 cases (6.0%). Paper-4315854. Dopa-responsive dystonia and early-onset Parkinson's disease in a patient with GTP cyclohydrolase I deficiency? Paper-12105158. Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. Paper-13855836. Incubating HUVECs with tumor necrosis factor ( TNF-alpha) was observed to increase GTPCH mRNA while decreasing eNOS mRNA. Paper-9773781. A new mutation (Thr106Ile) of the GTP cyclohydrolase 1 gene associated with DYT5 dystonia (Segawa disease). Paper-11029678. Two previously unrecognized splicing mutations of GCH1 in Dopa-responsive dystonia: exon skipping and one base insertion. Paper-2161814. High penetrance and pronounced variation in expressivity of GCH1 mutations in five families with dopa-responsive dystonia. Paper-1413836. Dopa responsive dystonia (DRD) is an autosomal dominant dystonia caused by mutations in the gene GCH1 in about 50% of cases. Paper-9433198. In most families the disease displays autosomal dominant inheritance due to mutations in the GTP cyclohydrolase 1 gene ( GCH1). Paper-13786263. CONCLUSION: GTPCH gene transfer reconstitutes iNOS activity in BH4-deficient cells despite poor transfer efficiency. Paper-643862. There is a significant negative correlation between severity of dystonia and basal ganglia size in DYT1 mutation carriers. Paper-13906568. Mutations in the GCH1 gene cause both dopa-responsive dystonia (McKusick 128230) and recessive GTP-CH1 deficiency (McKusick 600225). Paper-10536496. In addition, our findings provide new insights into the regulation of GTPCH I activity by the caveolar coat protein, caveolin-1. Paper-13586072. The novel mutations are Leu91Val, Pro95Leu, Val204Gly and 628delC in GCH-1 gene; Gly216Ser in TH gene; and Cys253Phe in parkin gene. Paper-13078526. Clinical genetics of functionally mild non-coding GTP cyclohydrolase 1 ( GCH1) polymorphisms modulating pain and cardiovascular risk. Paper-12922203. A case of late-onset Segawa syndrome (autosomal dominant dopa-responsive dystonia) with a novel mutation of the GTP-cyclohydrase I ( GCH1) gene. Paper-12315999. Moreover, Hsp90 inhibitor geldanamycin destroyed the wild-type GCH level, and heat shock increased the synthesis of GCH protein. Paper-10209035. Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa. German Dystonia Study Group. Paper-8579475. Therefore, type II mRNA may regulate GCH and then contribute to the regulation of NO production by BH4-dependent iNOS in mononuclear cells. Paper-9769043. However, normal fibroblasts do not express GTPCH, and fibroblasts from PTPS patients lack two biosynthetic enzymes for BH4 production. Paper-11546010. BACKGROUND: A haplotype in the GTP cyclohydrolase 1 (dopa-responsive dystonia) gene ( GCH1) is associated with decreased persistent pain. Paper-13249844. These findings demonstrate that GCH1 mutations must be considered even in patients with dystonic symptoms not typical of dopa-responsive dystonia. Paper-1810146. Recombinant adeno-associated viruses expressing human TH or GTP cyclohydrolase 1 ( GTPCH1) were injected into the striatum of DA-/- mice. Paper-1754889. GTPCH and iNOS enzymes did not have to coexist in the same cell for the synthesized BH4 to support iNOS activity. Paper-643862. 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. Paper-8579475. The authors report a mutation in exon 5 of GCH1 in a patient with adult-onset oromandibular dystonia and no obvious family history of dystonia. Paper-1810146. To date, 4 enzyme deficiencies ( GTPCH, PTPS, DHPR, PCD) have been reported and they all follow an autosomal recessive mode of inheritance. Paper-9456554. CONCLUSIONS: This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. Paper-12782518. While DRD is mostly caused by autosomal dominant mutations in the GTP cyclohydrolase I gene ( GCH1), SR deficiency is an autosomal recessive disease. Paper-9002929. During the study of human disease dopa-responsive dystonia, we found that coactivator RNF4 is involved in the GCH gene expression. Paper-10848859. GTPCH reconstituted near-maximal iNOS activity in 3T3- iNOS cells despite a gene transfer efficiency of less than 1%. Paper-643862. To further classify the mechanism involved in the regulation of BH(4) synthesis, we measured expression of GTPCH I and GFRP in different human tissues. Paper-9896940. De novo synthesis of 6BH(4) is dependent on the rate-limiting enzyme GTP cyclohydrolase I (GTPCHI) together with its feedback regulatory protein ( GFRP). Paper-13602083. A clarification of the mechanism of striatal TH protein loss in GTPCH-deficient DRD may provide a new clue to the pathogenesis of this major form of DRD. Paper-9738521. A significant induction of guanosine triphosphate cyclohydrolase I ( GTPCH) mRNA was observed in response to TNF, IL-1beta, and IFNgamma in ECV and HUVEC. Paper-1155657. The present study aims at elucidating whether GCH and TH coexist in the same neurons of the human brain with the aid of immunohistochemical dual labeling. Paper-11589777. In Parkinson's disease (PD), GCH, TH, and dopamine in the striatum may decrease in parallel, as the secondary effects caused by cell death. Paper-1021297. In this study, we demonstrated that GTPCH I is localized to caveolar membrane microdomains along with caveolin-1 and endothelial NO synthase. Paper-13586072. Estradiol can regulate TH, DBH and GTPCH gene expression, as well as to modulate its response to other second messenger such as cAMP. Paper-13451316. The symptomatic treatment of dopa-responsive dystonia (DRD) emphasizes the importance of molecular analyses of the GCH-1, TH and parkin genes. Paper-13078526. GTP cyclohydrolase 1 ( GCH1) is rate limiting in the provision of the cofactor tetrahydrobiopterin for biosynthesis of catecholamines and NO. Paper-13420893. To evaluate the iNOS cofactor tetrahydrobiopterin (BH(4)), the expression of the key enzyme GTP cyclohydrolase ( GTPCH) was determined by real-time PCR. Paper-12689489. Cytokine-stimulated GTP cyclohydrolase I expression in endothelial cells requires coordinated activation of nuclear factor-kappaB and Stat1/ Stat3. Paper-10788016. When we stimulate peripheral blood mononuclear cells by PHA, the transcription of full-length GCH mRNA increased, but that of type II mRNA decreased transiently. Paper-9769043. Dopamine production can be restored to specific brain regions by using adeno-associated viruses expressing TH and GTP cyclohydrolase 1 ( GTPCH1). Paper-9818769. This is the first demonstration that cytokine-stimulated iNOS and GTPCH expression, and therefore NO and BH(4) biosynthesis, may be regulated by discrete pathways. Paper-8492900. The results demonstrate gender-related incomplete penetrance of GCH gene mutations in HPD/DRD and suggest that this may not be due to genomic imprinting. Paper-1396860. Incubation of HUVEC with interferon-gamma (100 U/ml) showed an increase of GTPCH I mRNA and a significant downregulation of GFRP mRNA after 24 hours (p = 0.03). Paper-9896940. Moreover, expression of the GTPCH feedback regulatory protein, which if decreased might increase GTPCH activity, was not affected by TNF-alpha or ceramide. Paper-8492900. H(2)O(2) increases de novo synthesis of (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin via GTP cyclohydrolase I and its feedback regulatory protein in vitiligo. Paper-13602083. GTPCH expression is regulated by inflammatory stimuli, in association with reduced expression of GTP cyclohydrolase feedback regulatory protein ( GFRP). Paper-13760894. TH activity is regulated by the concentration of the cofactor tetrahydrobiopterin ( BH4), whose level is regulated by GTP cyclohydrolase I ( GCH) activity. Paper-1849900. The interaction of one of these clones, Activator of Heat Shock 90 kDa Protein ( Aha1), with GCH1 was validated by glutathione-s-transferase (GST) pull-down assay. Paper-12004980. In this study, using MALDI-TOF/ MS, PMF, Western immunoblotting (WB), and antibody microarrays we identified several proteins coimmunoprecipitating with GCH1. Paper-13704414. In addition, neither estradiol, nor the selective agonists activated GTPCH promoter without transfection of appropriate estrogen receptor expression vectors. Paper-12136528. The role of IFN-gamma was also Stat1-dependent as Stat1-null cells exhibited no GTPCH I induction in response to cytokines. Paper-10788016. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. Paper-10848859. Dopa-responsive-dystonia is a heterogeneous group with several causes ( GCH1 mutations, compound mutations in GCH1, mutations in TH gene, or in 6-PTS gene). Paper-10169746. Primary early-onset generalized dystonia is an autosomal dominant disorder caused by a deletion (DeltaGAG) in the DYT1 gene encoding torsinA. Paper-11086185. The monomer fold of epimerase is also topologically similar to that of GTP cyclohydrolase I ( GTP CH-1), 6-pyrovoyl tetrahydropterin synthase ( PTPS) and uroate oxidase (UO). Paper-8316164. The data obtained in this study suggest that DAHP reduced VCAM-1 and GTPCH protein synthesis at least partially via suppressing the NF-kappaB level in the nucleus of HUVEC. Paper-12821351. Detailed clinical descriptions and genetic analysis of patients with phenotypes intermediate between HPD/DRD (mild) and GCH-deficient HPA (severe) have not been reported. Paper-1483111. 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. Paper-12004980. Alternatively, a DYT1 gene dependent primary defect of motor circuit development may lead to stress- induced remodelling of the basal ganglia and hence dystonia. Paper-13906568. Our findings suggest that printor is a new component of the DYT1 pathogenic pathway and provide a potential molecular target for therapeutic intervention in dystonia. Paper-13909487. Analysis of the GTP cyclohydrolase I gene ( GCH1) and the tyrosine hydroxylase gene ( TH), mutated in dopa-responsive dystonia and juvenile PD, have also been included. Paper-11826871. None of our DRD patients without a mutation in GCH-1 had the 3-bp deletion recently detected in DYT1, the causative gene for idiopathic torsion dystonia with linkage to 9q34. Paper-1605671. We cloned the human GTP cyclohydrolase I ( GCH1) gene, and mapped the gene to chromosome 14q22.1-q22.2 within the HPD/DRD locus, which had been identified by linkage analysis. Paper-2118431. GTPCH can deliver a cofactor to targeted cells even if it is synthesized in neighboring cells, and may be a means to concurrently deliver BH4 with iNOS in vivo. Paper-643862. BACKGROUND: Segawa disease (autosomal dominant guanosine triphosphate cyclohydrolase I [GTP-I] deficiency, DYT5) is a hereditary dopa-responsive generalized dystonia. Paper-12476000. The female-to-male ratio of the HPD/DRD patients was 4.3 with the penetrance of GCH gene mutations in women being 2.3 times higher than that in men (87% versus 38%, p = 0.026). Paper-1396860. In the presence of cerivastatin, the TNF-alpha- mediated increase in GTPCH mRNA was enhanced, and the TNF-alpha- mediated decrease in eNOS mRNA was attenuated. Paper-9773781. We conducted genomic DNA sequencing of the GCH gene in two patients (Cases 1 and 2) manifesting generalized dystonia responsive to levodopa and severe developmental motor delay. Paper-1483111. 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. Paper-8896469. However, the relative importance of GTPCH expression versus GTPCH activity and the role of GFRP in relation to BH4 bioavailability remain uncertain. Paper-13760894. Conversely, overexpression of Jak2 effectively substituted for IFN-gamma in supporting TNF-alpha- mediated GTPCH I induction. Paper-10788016. However, Stat1 activation with oncostatin M failed to support TNF-alpha- mediated GTPCH I induction because of concomitant Stat3 activation. Paper-10788016. Autosomal dominantly inherited defects in the GTPCH gene ( GCH1) cause a form of dystonia that is responsive to treatment with levodopa (dopa-responsive dystonia [DRD]). Paper-9875209. 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. Paper-9281295. Consistent with this finding we found a decrease in CCR2-mediated, but not CCR5-mediated, chemotaxis in vascular tissue and plasma samples from GCH/ApoE-KO animals. Paper-12954365. Additionally, these observations suggest that GTPCH may be a rational target to augment endothelial BH4 and normalise eNOS activity in endothelial dysfunction states. Paper-9533631. 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%). Paper-9507521. Next, we co-transduced the F3 NSC line with genes encoding tyrosine hydroxylase ( TH) and GTP cyclohydrolase 1 ( GTPCH1) in order to generate dopamine-producing NSC. Paper-12010487. BACKGROUND: GTP-cyclohydrolase I, encoded by the GCH1 gene, is the rate-limiting enzyme in the biosynthesis of BH4, an eNOS cofactor important for maintaining enzymatic coupling. Paper-12868661. BH4 biosynthesis is carried out in a three-enzyme pathway involving GTP cyclohydrolase I ( GTPCH), 6-pyruvoyl-tetrahydropterin synthase ( PTPS) and sepiapterin reductase ( SR). Paper-11546010. In the nine HPD/DRD pedigrees, we found independent mutations of the GCH gene (five deletions, one insertion, one nonsense mutation, and two point mutations at splice acceptor sites). Paper-1396860. These results suggest that some novel mutations should exist on one of the alleles in some unknown region of the GCH1 gene, and may decrease the GCH1 mRNA causing the HPD/DRD symptoms. Paper-1936177. The spectrum of mutations causing a reduction in one of the three biosynthetic ( GTPCH, PTPS, and SR) or the two regenerating enzymes ( PCD and DHPR) is tabulated and reviewed. Paper-12200833. Expression of both iNOS and GTP cyclohydrolase I ( GTPCH), the rate-limiting enzyme in the BH(4) biosynthetic pathway, was also markedly increased, as were their activities and protein levels. Paper-8492900. Indeed, overexpression of caveolin-1 inhibits GTPCH I activity, and tetrahydrobiopterin biosynthesis is activated by the disruption of caveolae structure. Paper-13586072. Dopamine biosynthesis in different groups of dopamine neurons may be differentially regulated by TH activity, depending on intracellular BH4 concentrations and GCH activity. Paper-1860718. We conducted genomic DNA sequencing of the GCH gene in five HPD/DRD families having at least two generations of affected members and in four apparently sporadic cases and all of their parents. Paper-1396860. The autosomal dominant HPD/DRD is caused by mutations in the gene coding GTP cyclohydrolase I ( GCH I), the enzyme that catalyzes the first step in the biosynthesis of tetrahydrobiopterin. Paper-10331203. The mutated GCH proteins interacted with the wild-type GCH protein; the inclusion bodies were positive for lysosomal marker LAMP1, soluble in 2% SDS, and were not ubiquitinated. Paper-12747043. We found a complete deletion of GCH1 in affected members of family 1, and partial deletions in affected individuals of family 2 ( exons 4-6) and of family 3 ( exons 2-6). Paper-13095102. The GCH1 activity that was expressed in mononuclear blood cells was almost half the normal value (usually 2-20% of the normal value (39.0+/-9.2pmol/ml) in patients with HPD/DRD). Paper-12315999. 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. Paper-344951. X-linked recessive dystonia-parkinsonism (XDP, DYT3), endemic in the Panay island, the Philippines, is characterized by the clinical onset with dystonia followed by parkinsonism. Paper-11122168. We suggest that GTPCH expression is the primary regulator of BH4 levels, and changes in GTPCH or BH4 are not necessarily accompanied by changes in GFRP expression. Paper-13760894. These cells were stably co-transfected to express a human eNOS-green fluorescent protein fusion protein, selecting clones expressing either low ( GCH/eNOS-LOW) or high ( GCH/eNOS-HIGH) levels. Paper-13563266. METHODS AND RESULTS: We measured the mRNA levels of GTP cyclohydrolase I ( GTPCH), the rate-limiting enzyme in the first step of de novo BH4 synthesis, by real-time polymerase chain reaction. Paper-9773781. In addition to augmenting eNOS expression, statins potentiate GTPCH gene expression and BH4 synthesis, thereby increasing NO production and preventing relative shortages of BH4. Paper-9773781. SPR activity was relatively high compared with the activity of GTP cyclohydrolase I ( GCH), the rate-limiting biosynthetic enzyme of BH4, and was more widely distributed than GCH activity. Paper-9281295. Knockdown of either DHFR or GTPCH1 attenuated vascular endothelial growth factor (VEGF)-induced eNOS activity and NO production; these effects were recovered by supplementation with BH4. Paper-13748668. Quantitative comparison of the truncated-subunit mRNA and the wild-type one implied that differential splicing regulates the GTP-CH-I enzyme activity, leading to the clinical variations in HPD/DRD. Paper-1052897. Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase. Paper-12200833. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Paper-13855836. Retrovirus-mediated double transduction of the GTPCH and PTPS genes allows 6-pyruvoyltetrahydropterin synthase-deficient human fibroblasts to synthesize and release tetrahydrobiopterin. Paper-1470574. We studied 22 families with a phenotype of levodopa-responsive dystonia by sequencing the six coding exons, the 5'-untranslated region and the exon-intron boundaries of the GTPCH I gene. Paper-8459753. GCH1 isthe rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin (BH4), the cofactor for tyrosine hydroxylase ( TH), which is the first and rate-limiting enzyme of DA synthesis. Paper-2118431. Guanosine triphosphate (GTP) cyclohydrolase I ( GCH) is the first and rate-limiting enzyme for biosynthesis of tetrahydrobiopterin, the cofactor of tyrosine hydroxylase ( TH). Paper-11589777. We investigated the capacity of gene transfer of guanosine triphosphate (GTP) cyclohydrolase I ( GTPCH), the rate-limiting enzyme for BH4 biosynthesis, to supply cofactor for iNOS activity. Paper-643862. DHFR but not GTPCH1 knockdown inhibited VEGF- induced dephosphorylation of eNOS at the inhibitory site serine 116; these effects were recovered by supplementation with BH4. Paper-13748668. GTP cyclohydrolase I ( GCH-1) is the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin, an essential cofactor for nitric oxide synthase and aromatic amino acid hydroxylase. Paper-13827235. The penetrance for dystonia is incomplete, but both clinically affected and non-manifesting carriers of the DYT1 mutation exhibit impaired motor learning and evidence of altered motor plasticity. Paper-13955168. It is assumed that brain biopterin and dopamine loss should not be as severe in asymptomatic dopa-responsive dystonia caused by GCH1 mutations as it is in symptomatic dopa-responsive dystonia. Paper-9507521. The concomitant induction of AS and GTPCH with that of iNOS suggests that they may be important modulators of arthritis, and that they may represent novel targets for modulation of disease activity. Paper-9735392. Hereditary progressive dystonia with marked diurnal fluctuation ( HPD; dopa-responsive dystonia, DRD) have been recently found to be caused by a genetic defect in the GTP cyclohydrolase I ( GCH1) gene. Paper-1936177. The DA delivery strategy, on the other hand, aims at triple transduction of the TH, GCH1 and aromatic amino-acid decarboxylase ( AADC) enzymes, and thereby provide a higher rate of conversion of DOPA to DA. Paper-13181882. Tetrahydrobiopterin ( BH4) is synthesized from guanosine triphosphate (GTP) by GTP cyclohydrolase I ( GCH), 6-pyruvoyltetrahydropterin synthase ( PTS), and sepiapterin reductase ( SPD). Paper-1860718. 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. Paper-1611077. Autosomal dominant GTP cyclohydrolase I (AD GCH 1) deficiency (Segawa disease) is an autosomal dominant dopa responsive dystonia caused by heterozygous mutation of the GCH 1 gene located on 14q22.1-q22. Paper-13670014. These results indicate that human NSC, genetically transduced with TH and GTPCH1 genes, have great potential in clinical utility for cell replacement therapy in patients suffering from Parkinson disease. Paper-12010487. All exons of the torsion dystonia 1, GTP cyclohydrolase 1 and epsilon-sarcoglycan genes were examined in 40 patients by SSCP analysis of PCR products followed by sequencing of variant conformers. Paper-11216787. By immunoelectron microscopy, GCH-labeled cytoplasm and microtubules in the processes were observed ultrastructurally, but no staining was found in the mitochondria, and Golgi apparatus. Paper-918530. This binary effect, PCD activation and inhibition, is due on one hand to GCH- induced activation of the caspases cascade and on the other to the induction of expression of a new gene that we have named GILZ. Paper-8465020. RESULTS: Constitutive SR activity in these cells enabled BH4 biosynthesis by transducing GTPCH and PTPS cDNAs together with a selective marker coupled in a single transcript with two IRES-elements in tandem. Paper-11546010. Doxycycline abolished GTPCH mRNA expression and GTPCH protein, leading to markedly diminished total biopterin levels and a decreased ratio of BH4 to oxidized biopterins in cells expressing eNOS. Paper-13563266. GTP cyclohydrolase 1 ( GCH1) is the rate-limiting enzyme of a metabolic pathway synthesizing tetrahydrobiopterin (BH(4)), the cofactor dimerizing and activating inducible nitric oxide synthase ( NOS-2). Paper-13704414. GTP cyclohydrolase I ( GCH) is the first and rate-limiting enzyme in the biosynthesis of 5,6,7,8-tertahydrobiopterin (BH4), the required cofactor for tyrosine hydroxylase. Paper-10990701. Incubation of isolated C57BL/6J mouse aortas for 18 hours with recombinant human EPO (1 to 50 U/mL) caused a concentration-dependent increase in intracellular BH(4) levels and activity of GTP-cyclohydrolase I. Paper-12841323. Notwithstanding the discovery of GCH1 and TH mutations in autosomal-dominant and autosomal-recessive DRD, respectively, a therapeutic trial with levodopa is still the most practical approach to the diagnosis of DRD. Paper-9738521. Fine mapping by identification of other dystonia families linked to chromosome 20 and sequencing of candidate genes in the refined interval is required in order to identify the causative gene in DYT17. Paper-13011848. These data suggest that NO increases BH(4) levels through a cAMP/ CREB- mediated increase in GCH1 transcription and that the eNOS uncoupling associated with exogenous NO does not involved reduced BH(4) levels. Paper-13896489. However, only rhSOD restored eNOS function, increased tetrahydrobiopterin (BH(4)), a critical cofactor for eNOS function, and restored GTP cyclohydrolase I expression in isolated vessels and lungs from PPHN lambs. Paper-13479945. These changes, which may be present to different degrees in the DYT1 and DYT6 genotypes, are likely to represent susceptibility factors for the development of clinical manifestations in mutation carriers. Paper-13841874. We here report a Korean family affected with HPD/DRD due to a novel missense mutation of the GCH I gene (T-->G mutation in exon 2), Met 137 Arg, which may change the conformation of the binding site of GCH I. Paper-10331203. These data implicate both NF-kappaB and Stat1 in endothelial cell cytokine- stimulated GTPCH I induction and highlight the role of Stat3 in modulating Stat1-supported gene transcription. Paper-10788016. METHODS AND RESULTS: Using RT-PCR and northern blot technique, coexpression of GFRP and GTPCH I could be demonstrated in a number of different tissues such as endothelial cells and peripheral blood cells. Paper-9896940. Genetic variation in GCH1 underlies important differences in endogenous BH4 availability and is a determinant of eNOS coupling, vascular redox state, and endothelial function in human vascular disease. Paper-12868661. The activity of GTP cyclohydrolase I (GTPCH-I), the first enzyme in BH4 biosynthesis, is controlled by protein levels, posttranslational modifications and interaction with GTPCH-I feedback regulatory protein ( GFRP). Paper-11481592. Among the six uniquely regulated genes reported for tularemia patients as being part of the alarm signal gene cluster, five, namely caspase 1, PSME2, TAP-1, GBP1, and GCH1, were induced in vitro. Paper-12953720. Similarly, LPS also induced GTPCH and NOS2 gene expression at 3 and 6 h, and cotreatment of NAMDA repressed the induction with parallel reduction of nitrite, an oxidative metabolite of nitric oxide. Paper-8832774. The present observation suggests that L-dopa is not produced in the cells immunoreactive for TH but not for GCH, and that TH in these cells which lack GCH may have an unidentified role other than dopa synthesis. Paper-11589777. In the present study, the GTP-CH-I gene and the clinical features of eight HPD/DRD patients from six families were analysed to determine the correlations between clinical expression and the mutations in the GTP-CH-I gene. Paper-1405575. Transcription of the human GTPCH gene in human SK-N-BE(2)M17 cells is thus enhanced by cAMP acting through regulatory elements located in the proximal promoter and may involve the transcription factors NF-Y and ATF-2. Paper-9090897. Is phenotypic variation of hereditary progressive dystonia with marked diurnal fluctuation/dopa-responsive dystonia ( HPD/DRD) caused by the difference of the locus of mutation on the GTP cyclohydrolase 1 ( GCH-1) gene? Paper-10212312. The stimulatory effect of EPO on vascular GTP-cyclohydrolase I activity, BH(4) production, and phosphorylation of endothelial NO synthase was also detected in vivo in mice treated with recombinant human EPO. Paper-12841323. METHODS: The exons, exon-intron junctions, and an indispensable part of the 5' flanking region of the GTP-CH-I gene were sequenced in the eight clinically diagnosed patients with HPD/DRD and their asymptomatic parents. Paper-1405575. The pteridine cofactor tetrahydrobiopterin (BH(4)) is a critical determinant of endothelial NOS ( eNOS) activity and coupling, and GTP cyclohydrolase I ( GCH1) is the rate-limiting enzyme in its generation. Paper-13896489. EMSA analysis revealed an increase in the binding of CREB during E2 treatment and mutation of the cAMP response element in the GCH1 promoter attenuated the E2-mediated increase in transcription. Paper-13785616. Furthermore, we looked for the influence of phenylalanine that is known to reverse BH(4)-mediated feedback inhibition of GTPCH I, and of immunostimulation with interferon gamma on the expression of GTPCH I and GFRP. Paper-9896940. GFRP overexpression and knockdown in tet-GCH cells did not alter GTPCH activity or BH4 levels, and GTPCH-specific knockdown in sEnd.1 endothelial cells had no effect on GFRP protein. Paper-13760894. TorsinA is an AAA(+) protein located predominantly in the lumen of the endoplasmic reticulum ( ER) and nuclear envelope responsible for early onset torsion dystonia ( DYT1). Paper-13201772. Surprisingly, although TNF-alpha increased BH(4) synthesis and GTPCH activity, neither BH(4) nor GTPCH expression was affected by C(2)-ceramide or sphingomyelinase in IFN-gamma- and interleukin-1beta-stimulated cells. Paper-8492900. METHODS: A human GTPCH expression plasmid (pCIS- GTPCH) was transfected into rat aortic SMC (RAOSMC) and BH4-deficient NIH3T3 cells engineered to stably express human iNOS (3T3- iNOS). Paper-643862. BACKGROUND: Carriers of a particular haplotype of the GTP cyclohydrolase gene ( GCH1) had less pain after surgery for chronic lumbar radiculopathy and a decreased sensitivity to some experimental mechanical pain stimuli. Paper-12930899. RESULTS: Inducible NOS, AS, and GTPCH mRNA was found in all study groups; however, only iNOS mRNA showed a clear increase in 4-week-old Tg197 h-TNF-alpha transgenics in comparison to age matched wild-type controls. Paper-9735392. OBJECTIVES: To investigate the hypothesis that GTP cyclohydrolase I ( GCH1) mutations are responsible for the phenotype of highly anticholinergic responsive dystonia in patients with apparent primary torsion dystonia. Paper-1194501. 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. Paper-9322950. Similarly, in isolated peritoneal macrophages, roscovitine strongly inhibited (.)NO production, iNOS, and COX-2 upregulation, activation of NFkappaB, and induction of GCH-1 by LPS. Paper-13975431. Northern blot analysis revealed a single GTPCH mRNA transcript that was confirmed by RNase protection assay to encode for Type 1 GTPCH; no alternatively spliced forms of GTPCH mRNA were detected with this assay. Paper-9090897. Importantly, a 2-fold increase in GTPCH I activity was detected in the aortas of caveolin-1-deficient mice, suggesting that caveolin-1 may be involved in the control of GTPCH I enzymatic activity. Paper-13586072. Constitutively active mutants of activating transcription factor 2 ( ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Paper-11175307. 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. Paper-1194501. When we investigated the potential mediators of this reduction, we discovered that mRNA and protein levels of MCP-1 ( CCL2) but not RANTES ( CCL5) were significantly reduced in GCH/ApoE-KO aortic tissue. Paper-12954365. Enterokinase digestion of recombinant Nocardia GCH, and in-gel digestion of Nocardia GCH and recombinant GCH followed by MALDI-TOF-MS analysis, confirmed that the actual subunit size of the enzyme was 24.5kDa. Paper-10423294. In contrast, affected individuals from the excluded families had a later age of onset (46.9 years vs. 16.1 years in the DYT6), and the dystonia was both more likely to be of focal distribution and begin in the cervical muscles. Paper-13401405. 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. Paper-2118431. Reverse-transcription/limiting-dilution polymerase chain reaction analysis showed that in response to IFN/ TNF/ IL-1, mRNA abundance of GTPCH and PTPS was increased approximately 64-fold and 10-fold, respectively. Paper-1611077. Immunohistochemistry using anti-MAC-3 and MAC-1 antibody staining revealed a marked reduction in vein graft macrophage content, as did RT-PCR expression of macrophage marker CD68 mRNA levels in GCH/ApoE-KO mice. Paper-12954365. GCH1 mRNA was abundant in the trophectoderm and endoderm of conceptuses between Days 13 and 15 of pregnancy and then decreased thereafter, whereas ODC1 mRNA abundance increased in conceptuses between Days 13 and 18 of pregnancy. Paper-13856970. Sensory function, particularly in the somatosensory domain, has been shown to be compromised in patients with primary dystonia, both in adult onset focal dystonia and in genetically characterized DYT1 dystonia. Paper-13910794. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later. Paper-13855836. Furthermore, torsinA, that is mutated in DYT1 dystonia, a rare type of primary dystonia, binds to and promotes the degradation of epsilon-sarcoglycan mutants when both proteins are co-expressed. Paper-12451501. OBJECTIVE: To investigate the range of clinical features to correlate genotypic and phenotypic manifestations in hereditary progressive and/or levodopa-responsive dystonia due to a defect in the guanosine triphosphate-cyclohydrolase ( GCH1) gene. Paper-8951152. Mitogen stimulation induced expression of IFN-gamma, GTP cyclohydrolase I (GCH-I), and indoleamine (2,3)-dioxygenase ( IDO) resulting in enhanced neopterin formation and tryptophan degradation by HIV-infected and control PBMCs. Paper-13487160. METHODS AND RESULTS: Real-time polymerase chain reaction revealed a 4-fold induction of PTPS and a 300-fold induction of GTPCH expression by interleukin (IL)-1beta/tumor necrosis factor-alpha/interferon-gamma, mainly through de novo transcription. Paper-10116955. A constitutively active mutant of the cAMP response element binding ( CREB) protein strongly stimulated GTP cyclohydrolase I promoter activity, indicating that the CRE in the context of the GTP cyclohydrolase I gene is functional. Paper-11175307. In contrast, cells which secreted little hCG, such as SCH, ENAMI-1, and GCH-1, showed no response to the growth inhibitory action of 2 X 10(-8)M MTX and the 3H-thymidine uptake was not reduced by treatment with MTX at doses of up to 10(-4)M for 48 hours. Paper-4347917. Quantitative regulation of intracellular endothelial nitric-oxide synthase ( eNOS) coupling by both tetrahydrobiopterin- eNOS stoichiometry and biopterin redox status: insights from cells with tet-regulated GTP cyclohydrolase I expression. Paper-13563266. Dopa-responsive dystonia (DRD) is an inherited metabolic disorder now classified as DYT5 with two different biochemical defects: autosomal dominant GTP cyclohydrolase 1 ( GCH1) deficiency or autosomal recessive tyrosine hydroxylase deficiency. Paper-13457760. Freshly isolated platelets from healthy volunteers show functional BH4 synthesis, as evidenced by the presence of mRNA species and enzymatic activity of GTP cyclohydrolase I ( GTPCH), 6-pyruvoyl tetrahydropterin synthase, and sepiapterin reductase. Paper-10453812. To determine whether reduced striatal D2 receptor binding reported in patients with idiopathic torsion dystonia is associated with the genotype, the authors used PET and [11C]-raclopride to assess non-manifesting carriers of the DYT1 mutation. Paper-11302224. Transfection of pcDNA-Hsp27-S3D, a phosphorylation-mimicry Hsp27 mutant, was more effective at the mutated GCH proteins than transfection with pcDNA-Hsp27, but okadaic acid, a phosphatase inhibitor, enhanced the effect of pcDNA-Hsp27. Paper-12747043. The search for mutations in genes coding for components of the biopterin pathway other than GTPCH1 revealed a mutation in the gene coding for sepiapterin reductase ( SPR) in 1 of 95 patients with GCH1-negative dopa-responsive dystonia (DRD). Paper-11424516. We investigated the induction of iNOS together with argininosuccinate synthase (AS) and GTP cyclohydrolase I ( GTPCH), 2 of the rate-limiting enzymes for high output NO generation, in the Tg197 h-TNF-alpha transgenic model of arthritis. Paper-9735392. METHODS: In four human choriocarcinoma cell lines, GCH-1, GCH-1m, NUC-1 and SCH, the expression of HGF and c-MET was analyzed by RT-PCR and Western blotting using anti-c-MET antibody and antiphosphotyrosine antibody. Paper-8588584. Now, we have developed a simple, fast, and reliable method to assay the activities of TH and AADC and have provided the possibility of ex vivo gene therapy for PD by genetically modifying cells with separate hTH, hGCH1, and hAADC genes. Paper-11155660. In the presence of IFN-gamma, TNF-alpha increased GTPCH I mRNA in a manner dependent on nuclear factor-kappaB ( NF-kappaB), as this effect was abrogated by overexpression of a dominant-negative IkappaB construct. Paper-10788016. 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. Paper-1021297. This chapter describes the detailed methods that utilize the drinking water of rats to develop models of nitric oxide synthase ( NOS) inhibition-induced, guanosine triphosphate cyclohydrolase ( GTPCH) inhibition-induced, and glucocorticoid-induced hypertension. Paper-13454627. In the present study, we also found that DAHP significantly suppressed the accumulation of cytokine-induced NF-kappaB ( p65) in the nucleus as well as the mRNA levels of VCAM-1 and GTP cyclohydrolase I ( GTPCH), the rate-limiting enzyme of BH(4) synthesis. Paper-12821351. CONCLUSIONS: Certain progestins, including MPA, attenuate the 17beta-E-induced NO-mediated inhibition of platelet aggregation by endothelial cells through preventing both eNOS and GTPCH I expression most likely via activation of glucocorticoid receptors. Paper-13674061. In all cell lines (Bewo, GCH-1, GCH-2, SCH, JAR, JEG-3, NUC-1 and HCCM-5), no p53 gene abnormality was detected by using Southern blotting. p53 mRNA of the expected size was detected in all cell lines tested by Northern blotting. Paper-152502. 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. Paper-1021297. The expression of other enzymes involved in BH(4) biosynthesis, including aldose reductase ( AKR1B1), carbonyl reductase ( CBR1 and CBR3), GTP-cyclohydrolase I ( GCH1), and 6-pyruvoyltetrahydrobiopterin ( PTS), was also examined. Paper-13136535. Mutations in the GTP-cyclohydrolase I ( GCH) gene have been identified as a cause of two disorders: autosomal dominant hereditary progressive dystonia/dopa-responsive dystonia ( HPD/DRD) and autosomal recessive GCH-deficient hyperphenylalaninemia (HPA). Paper-1483111. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH ( tyrosine hydroxylase) or SPR ( sepiapterin reductase) genes. Paper-13855836. Endothelial NO synthase ( eNOS) and GTP cyclohydrolase I ( GTPCH I) mRNA expression was assessed by RT-PCR, eNOS protein by Western blotting, NO formation by electron spin resonance spectroscopy, and platelet aggregation by an aggregometer. Paper-13674061. Guanosine 5'-triphosphate cyclohydrolase I ( GCH) mutants (H144P and T186K) associated with dominant dopa-responsive dystonia were enzymatically inactive and inhibited the normal enzyme, suggesting that GCH activity in a heterozygote was <50% of control. Paper-1707079. 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. Paper-12010487. The objective of this study was to narrow the DYT6 region, clinically characterize DYT6 dystonia in a larger cohort, and to determine whether DYT6 is associated with dystonia in newly ascertained multiplex families. Paper-13401405. Predominant cranial-cervical involvement of dystonia occurred in this family, which has also been described in patients with idiopathic torsion dystonia linked to the DYT6 region on chromosome 8 and is a rare finding in DYT1 dystonia. Paper-11091640. 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). Paper-12004980. Quantitative analysis of cellular BH4 versus superoxide production between GCH/eNOS-LOW and GCH/eNOS-HIGH cells revealed a striking linear relationship between eNOS protein and cellular BH4 stoichiometry, with eNOS uncoupling at eNOS:BH4 molar ratio >1. Paper-13563266. We systematically examined familial Amish-Mennonite dystonia cases, identifying five additional members from the original families, as well as three other multiplex Amish-Mennonite families, and evaluated the known DYT6 haplotype and recombination events. Paper-13401405. Our data indicate that 17beta-estradiol ( E2) increases GCH1 transcription in a dose- and time-dependent manner, whereas estrogen receptor antagonism or NO synthase inhibition attenuated E2- stimulated GCH1 expression. Paper-13785616. METHODS: We used 4 and 8-week-old Tg197 h-TNF-alpha transgenic mice and wild-type CBA C57B1/6 control mice to investigate the expression of iNOS with respect to that of AS, GTPCH, and 3-nitrotyrosine by quantitative RT-PCR and immunocytochemistry. Paper-9735392. GTPCH activity and intracellular biopterins were assessed as a measure of successful transfection, and the capacity of GTPCH to reconstitute iNOS activity was used to determine whether BH4 was made available to the iNOS protein. Paper-643862. GCH1 protein was localized primarily in the nuclei of trophectoderm and endoderm, and its abundance decreased after Day 14 of pregnancy, whereas ODC1 protein was more abundant in the trophectoderm than in the endoderm between Days 13 and 18 of pregnancy. Paper-13856970. In this in vitro study, the modulatory effect of resveratrol on two interferon-gamma-mediated pathways, the degradation of tryptophan by the enzyme indoleamine 2,3-dioxygenase, and the production of neopterin by activation of the GTP-cyclohydrolase I, was tested. Paper-11536363. 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. Paper-1860718. 4. In juvenile parkinsonism and Parkinson's disease, which have dopamine deficiency in the basal ganglia as HPD/DRD, the GCH gene may be normal, and the molecular mechanism of the dopamine deficiency in the basal ganglia is different from that in HPD/DRD. Paper-1849900. Interferon-gamma (IFN-gamma) induced endothelial cell GTPCH I protein and BH4 modestly, whereas high-level induction required combinations of IFN-gamma and tumor necrosis factor-alpha ( TNF-alpha). Paper-10788016. Amantadine suppressed severe levodopa-induced choreic dyskinesia, which developed at initiation of levodopa therapy, in two siblings manifesting dystonia with motor delay phenotype of GTP cyclohydrolase I deficiency caused by compound heterozygous GCH1 mutations. Paper-10897826. METHODS: The genes for dopamine synthetic enzymes, tyrosine hydroxylase ( TH), aromatic L-amino acid decarboxylase ( AADC), and GTP cyclohydrolase I ( GCH, an enzyme critical for tetrahydrobiopterin synthesis) were contransduced into 293 cells with separate AAV vectors. Paper-8896469. When Hsp27 was expressed together with the GCH mutants, Hsp27 expression decreased the formation of inclusion bodies by GCH (as assessed by immunofluorescence) and decreased the amount of insoluble GCH mutant proteins (as assessed by Western blot). Paper-12747043. These observations suggest that the mutation in the torsinA protein responsible for DYT1 dystonia may interfere with transport or release of DA, but does not alter pre-synaptic transporters or post-synaptic DA receptors. Paper-13337072. The DOPA delivery strategy, based on the co-transduction of tyrosine hydroxylase ( TH), and GTP cyclohydrolase 1 ( GCH1) genes, has been shown to be a powerful approach providing a robust behavioral recovery and reversal of side effects of the pulsatile administration of L-DOPA medication. Paper-13181882. Furthermore, utilizing GCH1 promoter fragments fused to a luciferase reporter gene, we found that GCH1 promoter activity was enhanced by SPNONO in a CREB-dependent manner, and electromobility shift assays revealed an NO-dependent increase in the nuclear binding of CREB. Paper-13896489. 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. Paper-8306872. Using the antiserum against GTP cyclohydrolase I ( GCH), first rate-limiting enzyme of the biosynthesis of tetrahydrobiopterin (BH4), the cofactor for TH, we proved that these TH-only-ir neurons in the wild mice and in the hTHTg mice were not stained with the antiserum against GCH. Paper-1113747. 3. Mutations of GCH result in reductions in GCH activity, BH4, TH activity, and dopamine, causing either recessively inherited GCH deficiency or dominantly inherited hereditary progressive dystonia [ HPD; Segawa's disease; also called dopa-responsive dystonia (DRD)]. Paper-1849900. This study demonstrates that argininosuccinate synthetase and GTP-cyclohydrolase-I, which catalyze rate-limiting steps in the synthesis of iNOS substrate ( arginine) and cofactor ( tetrahydrobiopterin), respectively, are coinduced with iNOS expression in two human tumor cell lines. Paper-533469. We thus established reference values for pterins in blood spots in patients with hyperphenylalaninemia and identified new patients with GTP cyclohydrolase I deficiency, 6-pyruvoyl-tetrahydropterin synthase deficiency, and dihydropteridine reductase deficiency using dried blood spots on filter paper. Paper-11457125. Analysis of the GCH1 promoter fragment responsive to E2 revealed the presence of a cAMP response element, and we found that E2 triggers a rapid but transient elevation of phospho-cAMP response element-binding protein (CREB; <1 h) followed by a second sustained rise after 6 h. Paper-13785616. 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. Paper-11155660. These responses to 17 beta-estradiol required estrogen receptors and specific agonists for estrogen receptor alpha and estrogen receptor beta, 4,4,4,-(4-propil-[1H-pyrazole-1,3,5-triyl)tris-phenol and 2,3-bis[4-hydroxyphenyl]propionitrile respectively, triggered increased GTPCH promoter activity. Paper-12136528. 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. Paper-2118431. We evaluated the influence of gender on penetrance of GTP-cyclohydrolase I ( GCH) gene mutations in hereditary progressive dystonia/dopa-responsive dystonia ( HPD/DRD) and determined whether some apparently sporadic HPD/DRD patients owe their disorder to a de novo mutation of the GCH gene. Paper-1396860. CONCLUSIONS: These findings suggest that GTPCH gene transfer is a valid approach to increase BH4 levels in human endothelial cells, and provide new evidence for the relative importance of different mechanisms underlying BH4-mediated eNOS regulation in intact human endothelial cells. Paper-9533631. The expression of NOS1-3 (synthesis of NO), arginase1 (reduction of L: -arginine), p22phox (active subunit of NADPH oxidase), GTPCH (rate limiting enzyme for tetrahydrobiopterin), SOD1-3 (scavengers of superoxide anions), PRTMT1-3, and DDAH2 (involved in the metabolism of ADMA) was determined. Paper-12129898. METHODS AND RESULTS: Pteridine production, mRNA expression of GTP cyclohydrolase ( GTPCH) and 6-pyruvoyltetrahydropterin synthase ( PTPS) (both key enzymes of BH4 biosynthesis), and PTPS activity were studied in human umbilical vein endothelial cells (HUVECs) exposed to inflammatory cytokines. Paper-1611077. Addition of 2.5-20 nM of 17 beta-estradiol increased GTPCH promoter-driven luciferase activity in the presence of either estrogen receptor alpha or estrogen receptor beta indicating, for the first time, that 17 beta-estradiol can regulate GTPCH gene expression via transcriptional mechanisms. Paper-12136528. To investigate the de novo synthesis of BH4 in the human placenta, the activity of guanosine triphosphate cyclohydrolase I ( GTPCH), 6-pyruvoyltetrahydropterin synthase ( PTPS), and sepiapterin reductase ( SR) in the chorionic tissue during the first, second and third trimester of pregnancy was analyzed. Paper-10341420. Recent advances in the genetics of pain and pain disorders include the discovery of the role of the sodium ion channel SCN9A in neuropathic pain as well as in inability to experience pain, and of GTP cyclohydrolase ( GCH1) in setting the sensitivity to pain in normal individuals and modulating liability to chronic pain. Paper-13244276. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 ( parkin) genes. Paper-13855836. 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). Paper-8446266. Although the physiological relevance of the Aha1- GCH1 interaction requires further study, Aha1 may recruit GCH1 into the endothelial nitric oxide synthase/heat shock protein ( eNOS/ Hsp90) complex to support changes in endothelial nitric oxide production through the local synthesis of BH4. Paper-12004980. Exposure to the three cytokines' mixture (CM-trio) significantly changed, within the 48-72 h required for the induction and activation of GCH1, the levels and identities of some of the 0 h-associated proteins: after 72 h CK-IIalpha tended to dissociate from, whereas MAPK12 and JNK3 were strongly associated with fully active GCH1. Paper-13704414. Furthermore, inhibition of the cAMP-dependent kinase, protein kinase A (PKA) completely abolished the E2- stimulated GCH1 promoter activity, whereas the stimulation of cAMP levels with forskolin increased GCH1 promoter activity, indicating the key role of cAMP in regulating GCH1 promoter activity. Paper-13785616. Hereditary Progressive Dystonia with marked diurnal fluctuation ( HPD) is an autosomally dominantly inherited dystonia which is characterized by marked diurnal fluctuation of symptoms and by marked and sustained response to levodopa associated with mutations in guanosine triphosphate cyclohydrolase ( GCH-1) deficiency gene. Paper-11393041. The PET imaging protocol used in this study is fully adaptable to humans and thus can serve as an in vivo imaging technique to follow TH + GCH1 gene therapy in PD patients and provide an additional objective measure to a potential clinical trial using rAAV vectors to deliver l-3,4-dihydroxyphenylanaline in the brain. Paper-13603449. Ten DRD families from the Han ethnic group including 14 patients and 28 clinically unaffected relatives were screened for GCH-1, TH and parkin mutations by direct sequencing, semiquantitative polymerase chain reaction ( PCR), polymerase chain reaction-restriction fragment length polymorphism analysis and allele-specific PCR. Paper-13078526. GCH1 protein expression and enzyme activity are minimal in cultured, phenotypically stable, untreated normal adult human astrocytes (NAHA), but are strongly induced, together with NOS-2, by a mixture of three proinflammatory cytokines (IL-1beta, TNF-alpha, and IFN-gamma--the CM-trio) released by microglia under brain-damaging conditions. Paper-13704414. IDO and other IFN-gamma-mediated pathways are strongly induced in patients with HIV infection and are also linked with disease progression: Neopterin formation by GTP-cyclohydrolase I sensitively reflects the stage of the disease, and determination of the pteridine in body fluids is useful to monitor the efficacy of antiretroviral therapy. Paper-13181867. METHODS AND RESULTS: Endothelium-targeted overexpression of GTP cyclohydrolase 1 ( GCH), the rate limiting enzyme in BH4 synthesis, increased levels of tetrahydrobiopterin ( BH4), reduced endothelial superoxide, improved eNOS coupling, and reduced vein graft atherosclerosis in transgenic GCH/ApoE-KO mice compared to ApoE-KO controls. Paper-12954365. We used small interference RNA (siRNA)-mediated "knockdown" GTP cyclohydrolase-1 ( GTPCH1), the rate-limiting enzyme in BH4 biosynthesis, and dihydrofolate reductase ( DHFR), an enzyme-recycling oxidized BH4 ( 7,8-dihydrobiopterin ( BH2)), and studied the effects on eNOS regulation and biopterin metabolism in cultured aortic endothelial cells. Paper-13748668. The activity of GCH was increased up to 5-fold after the NGF treatment, and the increase was repressed by pretreatment with U0126, an MEK1/2 inhibitor, but not with protein kinase A (PKA), phosphoinositide 3-kinase ( PI3K), p38 mitogen- activated protein kinase ( MAPK), and c-Jun NH2-terminal kinase (JNK) inhibitors. Paper-10990701. Using the method, we found though hTH, hGCH1, and hAADC genes were expressed, respectively, they could fulfil the function of DA synthesis by incubating together in vitro, and more DA was synthesized in vitro when hTH, hGCH1, and hAADC genes were expressed together rather than hTH and hAADC genes expressed or hTH expressed. Paper-11155660. These synonyms are used for gene GCH1 (GTP cyclohydrolase 1): HPABH4B, GTP cyclohydrolase I, GTP-CH-I, GTP-CH-1, GTPCH1, GCH, DYT5, DYT14, dystonia 14. These accession numbers are used for gene GCH1: Q9Y4I8 (UNIPROT__AC), Q8IZH9 (UNIPROT__AC), CAA83213 (NCBI_GENBANK__AC), CAA78908 (NCBI_GENBANK__AC). GCH1 is a homologue of SPAC17A5.13 (GTP cyclohydrolase (predicted)) from Schizosaccharomyces pombe. GCH1 is a homologue of Pu (Punch) from Drosophila melanogaster. GCH1 is a homologue of Os04g0662700 (Os04g0662700) from Oryza sativa Japonica Group. GCH1 is a homologue of NCU07774 (GTP cyclohydrolase I) from Neurospora crassa OR74A. GCH1 is a homologue of MGG_09458 (GTP cyclohydrolase I, putative) from Magnaporthe grisea 70-15. GCH1 is a homologue of LOC566510 (similar to GTP cyclohydrolase 1 precursor (GTP cyclohydrolase I) (GTP-CH-I)) from Danio rerio. GCH1 is a homologue of KLLA0A09735g (hypothetical protein) from Kluyveromyces lactis NRRL Y-1140. GCH1 is a homologue of GCH1 (GTP cyclohydrolase 1) from Bos taurus. GCH1 is a homologue of GCH1 (GTP cyclohydrolase 1) from Pan troglodytes. GCH1 is a homologue of GCH1 (GTP cyclohydrolase 1 (dopa-responsive dystonia)) from Gallus gallus. GCH1 is a homologue of GCH1 (GTP cyclohydrolase 1) from Canis lupus familiaris. GCH1 is a homologue of Gch1 (GTP cyclohydrolase 1) from Mus musculus. GCH1 is a homologue of Gch1 (GTP cyclohydrolase 1) from Rattus norvegicus. GCH1 is a homologue of FOL2 (Fol2p) from Saccharomyces cerevisiae. GCH1 is a homologue of cat-4 (abnormal CATecholamine distribution) from Caenorhabditis elegans. GCH1 is a homologue of AT3G07270 (GTP cyclohydrolase I) from Arabidopsis thaliana. GCH1 is a homologue of AGOS_AGR335C (AGR335Cp) from Ashbya gossypii ATCC 10895. GCH1 is a homologue of AgaP_AGAP006441 (AGAP006441-PB) from Anopheles gambiae str. PEST. Important links ! iHOP - Information Hyperlinked over Proteins . Concept & Implementation by Robert Hoffmann.