Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported four different mutations in the coding region of GTP cyclohydrolase I (GCH-I) gene in patients with hereditary progressive dystonia with marked diurnal fluctuation (HPD). We found two independent new mutations (leucine 79 proline and a deletion in exon 4) in patients with HPD. We also found four families of HPD without any mutations in the coding region of GCH-I gene.
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PMID:GTP cyclohydrolase I gene in hereditary progressive dystonia with marked diurnal fluctuation. 750 Dec 55

We report a novel mutation at a splice site in the GTP cyclohydrolase I gene in a Japanese family with hereditary progressive dystonia with marked diurnal fluctuation (HPD)/dopa responsive dystonia (DRD). Reverse transcriptase-initiated PCR (RT-PCR) of lymphocyte mRNA showed both normal and small size fragments in the HPD patient and his asymptomatic mother. Sequence analysis revealed that skip splicing of exon 1 to exon 3 occurred in the small fragment. The patient and his mother were heterozygous for G --> C substitution at conserved consensus sequence GT at 5' end of the intron 2. Quantitative RT-PCR showed that the expression of normal GTP cyclohydrolase I mRNA decreased in their lymphocytes, while the HPD patient had more expression of mutant GTP cyclohydrolase I mRNA than his asymptomatic mother.
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PMID:Exon skipping caused by a base substitution at a splice site in the GTP cyclohydrolase I gene in a Japanese family with hereditary progressive dystonia dopa responsive dystonia. 754 25

The past 18 months have seen significant advances in our understanding of dopa(dihydroxyphenylalanine)-responsive dystonia. Clinical investigations have broadened the spectrum of disease with particular attention manifestations in infancy. Pathophysiological investigations have revealed features that distinguish dopa-responsive dystonia from childhood-onset parkinsonism. A pathological study has confirmed the 'developmental' nature of the disease. Finally, mutations causing the autosomal dominant form of dopa-responsive dystonia have been identified in the gene coding for GTP cyclohydrolase I. Mutations in tyrosine hydroxylase have been identified in two brothers and put forward as evidence of an autosomal recessive form of the disease.
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PMID:Dopa-responsive dystonia. 758 48

GTP cyclohydrolase I activity in mononuclear blood cells from patients with juvenile parkinsonism (JP) was found to be normal compared to healthy controls. The normal activity in JP contrasts strongly with the decreased activity of 2-20% normal levels in hereditary progressive dystonia with marked diurnal fluctuation (HPD) or dopa responsive dystonia (DRD). The result indicates that the decreased dopamine level in the basal ganglia in JP is not due to decreased activity of GTP cyclohydrolase I, the enzyme for the biosynthesis of the tetrahydrobiopterin cofactor of tyrosine hydroxylase (TH), and the enzyme activity in mononuclear blood cells could be a reliable method for differential diagnosis between JP and HPD/DRD.
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PMID:GTP cyclohydrolase I activity in mononuclear blood cells in juvenile parkinsonism. 764 24

GTP cyclohydrolase I is the first and rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin in mammals. Previously, we reported three species of human GTP cyclohydrolase I cDNA in a human liver cDNA library (Togari, A., Ichinose, H., Matsumoto, S., Fujita, K., and Nagatsu, T. (1992) Biochem. Biophys. Res. Commun. 187, 359-365). Furthermore, very recently, we found that the GTP cyclohydrolase I gene is causative for hereditary progressive dystonia with marked diurnal fluctuation, also known as DOPA-responsive dystonia (Ichinose, H., Ohye, T., Takahashi, E., Seki, N., Hori, T., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji, S., Fujita, K., and Nagatsu, T. (1994) Nature Genetics 8, 236-242). To clarify the mechanisms that regulate transcription of the GTP cyclohydrolase I gene and to generate multiple species of mRNA, we isolated genomic DNA clones for the human and mouse GTP cyclohydrolase I genes. Structural analysis of the isolated clones revealed that the GTP cyclohydrolase I gene is encoded by a single copy gene and is composed of six exons spanning approximately 30 kilobases. We sequenced all exon/intron boundaries of the human and mouse genes. Structural analysis also demonstrated that the heterogeneity of GTP cyclohydrolase I mRNA is caused by an alternative usage of the splicing acceptor site at the sixth exon. The transcription start site of the mouse GTP cyclohydrolase I gene and the 5'-flanking sequences of the mouse and human genes were determined. We performed regional mapping of the mouse gene by fluorescence in situ hybridization, and the mouse GTP cyclohydrolase I gene was assigned to region C2-3 of mouse chromosome 14. We identified missense mutations in patients with GTP cyclohydrolase I deficiency and expressed mutated enzymes in Escherichia coli to confirm alterations in the enzyme activity.
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PMID:Characterization of mouse and human GTP cyclohydrolase I genes. Mutations in patients with GTP cyclohydrolase I deficiency. 773 Mar 9

Hereditary progressive dystonia with marked diurnal fluctuation (HPD) (also known as dopa responsive dystonia) is a dystonia with onset in childhood that shows a marked response without any side effects to levodopa. Recently the gene for dopa responsive dystonia (DRD) was mapped to chromosome 14q. Here we report that GTP cyclohydrolase I is mapped to 14q22.1-q22.2. The identification of four independent mutations of the gene for GTP cyclohydrolase I in patients with HPD, as well as a marked decrease in the enzyme's activity in mononuclear blood cells, confirms that the GTP cyclohydrolase I gene is a causative gene for HPD/DRD. This is the first report of a causative gene for the inherited dystonias.
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PMID:Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. 787 57

hph-1 mice, which have defective tetrahydrobiopterin biosynthesis due to decreased GTP cyclohydrolase I activity, have been used to investigate the effects of tetrahydrobiopterin deficiency on aromatic L-amino acid monooxygenases and brain monoamine metabolism. Liver tetrahydrobiopterin levels were decreased, and tetrahydrobiopterin deficiency and reduced levels of dopamine, norepinephrine, serotonin, and their metabolites in the brain occurred both pre- and postnatally. Chronic subcutaneous tetrahydrobiopterin elevated brain levels to values higher than those seen in controls but had no effect on monoamine metabolism. In vivo activities of tyrosine hydroxylase and tryptophan hydroxylase were significantly decreased. There was a 30% decrease in the in vitro activity of striatal tyrosine hydroxylase and 50% decrease in liver phenylalanine hydroxylase. Western blotting demonstrated that the lower monooxygenase activities resulted from a reduced absolute amount of tyrosine hydroxylase and phenylalanine hydroxylase protein. The findings suggest involvement of tetrahydrobiopterin in the control of the steady-state concentration of the aromatic L-amino acid monooxygenases. In addition, demonstration of central monoamine changes in the hph-1 mouse make it a possible model system for the investigation of the neuropathological mechanisms in Dopa-responsive dystonia, which has recently been linked with mutations in the gene for GTP cyclohydrolase I.
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PMID:Tetrahydrobiopterin and biogenic amine metabolism in the hph-1 mouse. 876 4

Dopa-responsive dystonia (DRD) was originally described in a series of Japanese patients, but is now increasingly recognized in other countries. Recently the GTP cyclohydrolase I (GTPCH) gene was isolated as the first causative gene for dopa-responsive dystonia (DRD). Mutations were identified in three Japanese families with autosomal dominantly inherited DRD and in one sporadic Japanese patient. Characterisation of the exon-intron boundaries of this gene has now allowed the analysis of mutations at the level of genomic DNA. 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. Only point mutations were found, causing a stop codon in one family and an amino acid change in highly conserved regions of the gene in a further four families and in one sporadic case. None of these mutations were detected more than once and none of the mutations previously described were found in our patients. No mutations were identified in four families and in two sporadic cases.
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PMID:Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity. 885 66

GTP cyclohydrolase I (GTPCH) has recently been identified as the first causative gene for Dopa-responsive dystonia (DRD). DRD typically presents with dystonia in the lower limbs in childhood, but may produce an akinetic-rigid syndrome in middle and old age. We have sequenced the GTPCH gene in 29 Parkinsonian patients without a positive family history for DRD, but who shared at least one feature of the akinetic-rigid presentation of DRD: 23 patients had at least one living relative who also suffered from an akinetic-rigid syndrome; 2 patients had an abnormally mild course of their parkinsonism which was extremely dopa-responsive. DNA was also analysed from 4 brain samples of patients who were clinically diagnosed as suffering from Parkinson's disease, but then did not show any pathological findings at post mortem. No changes in the sequence of the GTPCH gene were detected. We conclude that so far there is no evidence that mutations of the GTPCH gene are responsible for the development of parkinsonism in patients without a positive family history of DRD.
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PMID:The GTP-cyclohydrolase I gene in atypical parkinsonian patients: a clinico-genetic study. 888 Jun 88

We present a new Japanese family with hereditary progressive dystonia with marked diurnal fluctuation/dopa-responsive dystonia. The affected daughter and her asymptomatic father are heterozygous for a novel missense mutation that replaces His by Pro at codon 144 in the GTP cyclohydrolase I gene. Quantitative reverse transcription-polymerase chain reaction revealed a higher ratio of mutant/normal mRNA encoding GTP cyclohydrolase I in the patient. These results demonstrate the importance of mutant mRNA levels for phenotypic variability among cases with the same mutation.
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PMID:Mutant GTP cyclohydrolase I mRNA levels contribute to dopa-responsive dystonia onset. 895 22


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