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

We performed a clinical and molecular genetic analysis in members of five families with dopa-responsive dystonia. Four mutations were detected in the gene GCH1 that codes for GTP cyclohydrolase I. Two of these mutations, a delG309 in exon 1 and a C544T transition in exon 5, have not been described before. They result in inactivation of the enzyme by truncation. The remaining two mutations, both A to G transitions, a(-2)g in intron 1 and a(-2)g in intron 2, cause truncation by abnormal splicing. The genotype of family members was correlated to their clinical phenotype (obtained before molecular analysis). Clinical symptoms observed in the families included generalized and focal dystonia, abnormal gait, and subtle signs such as an abnormal writing test. High penetrance (0.8-1.0) was observed in four of five families if minor symptoms and signs were considered. A given mutation was more likely to cause symptoms in females than in males, thus confirming the well-established higher incidence of dopa-responsive dystonia in females than in males.
 ...
PMID:High penetrance and pronounced variation in expressivity of GCH1 mutations in five families with dopa-responsive dystonia. 958 58

Any model for the physiology of dystonia must be able to explain how dystonia can be produced in various circumstances. Brain lesions can cause dystonia; responsible sites include the basal ganglia, brainstem, and thalamus, but the most common site is the putamen. Dystonia can be hereditary, and genetic linkage has been found for both generalized and focal dystonia. The only genetic dystonia for which the gene product is known is Segawa disease, a hereditary progressive dystonia with marked diurnal fluctuation. The defect is in guanosine triphosphate cyclohydrolase I, a gene that makes a cofactor for the synthesis of dopamine, which explains why this form of dystonia should be amenable to treatment with levodopa. Another example of dystonia in which a disorder of dopamine pharmacology appears responsible is the dystonia occurring in Parkinson disease, either spontaneously or as a result of treatment. Curiously, the dystonia occurs at both peak and trough dopamine levels.
 ...
PMID:The neurophysiology of dystonia. 960 16

The clinical distinction between dopa-responsive dystonia (DRD) and juvenile Parkinson's disease JPD) can pose a diagnostic challenge. Both conditions are dopa responsive. However, long-term L-dopa benefit is very different between the two. The difference in the prognosis is due to presence or absence of nigral cell loss. In JPD, there is degenerative nigral cell loss, whereas there are enzymatic defects in dopamine synthesis without cell loss in DRD. Mutations have been found in the GTP cyclohydrolase I (GCH-I) and tyrosine hydroxylase genes in DRD. As the discovered mutations are multiple and more are expected to be found, it is difficult to confirm or exclude DRD by mutation studies. Measurement of cerebrospinal fluid (CSF) neopterin will detect DRD from mutations in the GCH-I gene but not from mutations in tyrosine hydroxylase. The dopamine transporter (DAT) is a protein in the dopaminergic nerve terminals. (1R)-2beta-Carbomethoxy-3beta-(4-[123I]iodophenyl)tropane ([123I]beta-CIT) is a ligand for the DAT, and it was shown to be a useful nuclear imaging marker for neurons that degenerate in Parkinson's disease (PD). As DRD was shown to have a normal DAT without nigral cell loss in a postmortem study, we predicted that the DAT measured in vivo by nuclear imaging will be normal in DRD and will differentiate DRD from JPD. Therefore, we performed [123I]beta-CIT single-photon emission computed tomography ([123I]beta-CIT SPECT) in clinically diagnosed DRD, PD, and JPD, and examined whether DAT imaging can differentiate DRD from PD and JPD. We then examined whether DAT imaging can provide a screening tool for molecular genetic studies, by studying mutations in the candidate gene GCH-I and measuring CSF neopterin. Five females (4 from two families, and 1 sporadic) were diagnosed as DRD based on early-onset foot dystonia and progressive parkinsonism beginning at ages 7 to 12. All patients were functioning normally on L-dopa 100 to 250 mg/day for up to 8 years. SPECT imaging was obtained after intravenous injection of [123I]beta-CIT; 15 healthy volunteers served as normal control, and 6 PD and 1 JPD as disease controls. [123I]beta-CIT striatal binding was normal in DRD, whereas it was markedly decreased in PD and JPD. Gene analysis showed a novel nonsense mutation in the GCH-I gene in one family. No mutation was found in the other family or in the sporadic case. CSF neopterin was markedly decreased in the 4 tested patients. [123I]beta-CIT SPECT is a sensitive method for probing the integrity of nigrostriatal dopaminergic nerve terminals. A normal striatal DAT in a parkinsonian patient is evidence for a nondegenerative cause of parkinsonism and differentiates DRD from JPD. Finding a new mutation in one family and failure to demonstrate mutations in the putative gene in other cases supports the usefulness of DAT imaging in diagnosing DRD.
 ...
PMID:Dopamine transporter density measured by [123I]beta-CIT single-photon emission computed tomography is normal in dopa-responsive dystonia. 962 49

Recombinant rat liver GTP cyclohydrolase I has been prepared by heterologous gene expression in Escherichia coli and characterized by biochemical and biophysical methods. Correlation averaged electron micrograph images of preferentially oriented enzyme particles revealed a fivefold rotational symmetry of the doughnut-shaped views with an average particle diameter of 10 nm. Analytical ultracentrifugation and quantitative scanning transmission electron microscopy yielded average molecular masses of 270 kDa and 275 kDa, respectively. Like the Escherichia coli homolog, these findings suggest that the active enzyme forms a homodecameric protein complex consisting of two fivefold symmetric pentameric rings associated face-to-face. Examination of the amino acid sequence combined with calcium-binding experiments and mutational analysis revealed a high-affinity, EF-hand-like calcium-binding loop motif in eukaryotic enzyme species, which is absent in bacteria. Intrinsic fluorescence measurements yielded an approximate dissociation constant of 10 nM for calcium and no significant binding of magnesium. Interestingly, a loss of calcium-binding capacity observed for two rationally designed mutations within the presumed calcium-binding loop of the rat GTP cyclohydrolase I yielded a 45% decrease in enzyme activity. This finding suggests that failure of calcium binding may be the consequence of a mutation recently identified in the causative GTP cyclohydrolase I gene of patients suffering from dopa responsive dystonia.
 ...
PMID:Rat GTP cyclohydrolase I is a homodecameric protein complex containing high-affinity calcium-binding sites. 963 9

Hereditary progressive dystonia (HPD) is caused by the mutant gene encoding GTP cyclohydrolase I (GCH). The clinical presentation of this disease varies considerably, and many cases appear to be sporadic. We have previously proposed that this clinical variation may be due to differential expression of the mutant and normal GCH mRNA, presumably at the protein level. To provide support for this proposal, we studied a new Japanese family with HPD, in which 2 members were heterozygous for an exon-skipping mutation. This mutation produced truncated GCH, which shared 180-amino acid residues at the amino terminus of the normal enzyme (GCH180). An affected heterozygote had a higher mutant/normal mRNA ratio than an unaffected heterozygote, consistent with our previous finding in the HPD family with GCH114. A further study, using coexpression of the mutant with wild-type GCH in COS-7 cells, showed that three mutant GCHs inactivated the normal enzyme. GCH114 was most effective in enzyme inactivation, which was followed by GCH180 and a normally occurring mutant GCH209. These results suggested that the dominant negative effect of a mutant GCH on the normal enzyme might be one of the molecular mechanisms determining the heterogeneity of clinical phenotypes of HPD.
 ...
PMID:Dominant negative effect of GTP cyclohydrolase I mutations in dopa-responsive hereditary progressive dystonia. 974 3

A family with a dominant form of partial GTP cyclohydrolase deficiency is described. Clinical severity varied from mild involvement with complete responsiveness to levodopa to severe dystonia precluding any voluntary activity including talking, progressive contractures, and only partial responsiveness to levodopa. Although there are several possible reasons for intrafamilial variability, any patient with dystonia, the cause of which is not clearly identified, should receive a trial of levodopa.
 ...
PMID:GTP cyclohydrolase deficiency; intrafamilial variation in clinical phenotype, including levodopa responsiveness. 988 60

A NEW CLASSIFICATION: The advent of molecular genetics has led to a total revision of earlier classifications of primary dystonias. LOCUS DYT-1 PRIMARY DYSTONIA: Locus DYT1, situated on chromosome 9, is responsible for the most common phenotypic expression of generalized primary dystonia, Ziehen-Oppenheim disease. This autosomal dominant disease has variable penetration. It has long been recognized that some individuals in families with typical disease only have segmentary, multifocal or even focal dystonia. It has been proven by molecular genetics that the disease can be expressed simply by familial writers cramp with particularly early, and often bilateral, onset. The mutation concerns the torsine A gene, whose function remains to be elucidated. Torsine A is found in the central nervous system, particularly in the dopaminergic neurons of the locus niger. GENERALIZED PRIMARY DYSTONIA UNRELATED TO DYT-1: These dystonias are phenotypically different: younger and more variable age at onset, focal localization early in the disease course generally involving the cervical or cephalic pole, less severe course. Certain forms are linked to chromosome 8 (locus DYT 6). PRIMARY FOCAL OR SEGMENTARY DYSTONIAS: These primary dystonias cause functional or postural disorders and were long considered as sporadic despite rare familial cases suggesting a genetic factor. When searched for systematically, familial cases are found in 20 to 30% of the cases. The dystonia is transmitted by dominant autosomal heredity with reduced penetration. Phenotypically, expression is heterogeneous with a constant frequency of unrecognized or neglected forms and of postural forms. One form is known to be linked to chromosome 18 (locus DYT 7). DOPA-RESPONSIVE DYSTONIA: This class represents 5 to 10% of childhood dystonias. The phenotypic expression is polymorphous but symptoms always improve with very small doses of L-dopa. Both sporadic, and more frequently familial, cases are described. Some forms are recessive, caused by mutation of the gene coding for tyrosine hydroxylase, others are autosomal dominant, often linked to mutation of the gene coding for GTP cyclohydrolase. RAPID ONSET DYSTONIA SYNDROME-PARKINSONISM: This dominant autosomal dystonia is quite exceptional, ... and intriguing.
 ...
PMID:[Genetic dystonia]. 1007 76

Dopa-responsive dystonia (DRD) due to mutant GTP cyclohydrolase I (GCH) shows the considerable heterogeneity of clinical phenotypic expression. To explain the clinical diversity, we studied a Japanese family with a novel mutant GCH (GCH-G90V), where an affected heterozygote had a higher mutant/normal mRNA ratio than an unaffected heterozygote. Coexpression experiments using the mutant with wild-type GCH showed that GCH-G90V inactivated the normal enzyme in a dose-dependent manner, suggesting that the dominant negative effect of a mutant GCH on the normal enzyme might be one of the molecular mechanisms for the clinical heterogeneity of DRD.
 ...
PMID:A novel missense mutant inactivates GTP cyclohydrolase I in dopa-responsive dystonia. 1007 97

1. Catecholamine (dopamine, norepinephrine, and epinephrine) biosynthesis is regulated by tyrosine hydroxylase (TH). TH activity is regulated by the concentration of the cofactor tetrahydrobiopterin (BH4), whose level is regulated by GTP cyclohydrolase I (GCH) activity. Thus, GCH activity indirectly regulates TH activity and catecholamine levels. 2. TH activity in the nigrostriatal dopaminergic neurons is most sensitive to the decrease in BH4. 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)]. 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.
 ...
PMID:Molecular biology of catecholamine-related enzymes in relation to Parkinson's disease. 1007 65

Tetrahydrobiopterin (BH4) is synthesized from guanosine triphosphate (GTP) by GTP cyclohydrolase I (GCH), 6-pyruvoyltetrahydropterin synthase (PTS), and sepiapterin reductase (SPD). GCH is the rate-limiting enzyme. BH4 is a cofactor for three pteridine-requiring monooxygenases that hydroxylate aromatic L-amino acids, i.e., tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and phenylalanine hydroxylase (PAH), as well as for nitric oxide synthase (NOS). The intracellular concentrations of BH4, which are mainly determined by GCH activity, may regulate the activity of TH (an enzyme-synthesizing catecholamines from tyrosine), TPH (an enzyme-synthesizing serotonin and melatonin from tryptophan), PAH (an enzyme required for complete degradation of phenylalanine to tyrosine, finally to CO2 + H2O), and also the activity of NOS (an enzyme forming NO from arginine), Dominantly inherited hereditary progressive dystonia (HPD), also termed DOPA-responsive dystonia (DRD) or Segawa's disease, is a dopamine deficiency in the nigrostriatal dopamine neurons, and is caused by mutations of one allele of the GCH gene. GCH activity and BH4 concentrations in HPD/DRD are estimated to be 2-20% of the normal value. By contrast, recessively inherited GCH deficiency is caused by mutations of both alleles of the GCH gene, and the GCH activity and BH4 concentrations are undetectable. 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. The biosynthesis of dopamine, norepinephrine, epinephrine, serotonin, melatonin, and probably NO by individual pteridine-requiring enzymes may be differentially regulated by the intracellular concentration of BH4, which is mainly determined by GCH activity. Dopamine biosynthesis in different groups of dopamine neurons may be differentially regulated by TH activity, depending on intracellular BH4 concentrations and GCH activity. The nigrostriatal dopamine neurons may be most susceptible to a partial decrease in BH4, causing dopamine deficiency in the striatum and the HPD/DRD phenotype.
 ...
PMID:Regulation of pteridine-requiring enzymes by the cofactor tetrahydrobiopterin. 1032 73


<< Previous 1 2 3 4 5 6 7 8 9 Next >>