Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopaminergic pathophysiology is important in several psychiatric illnesses. The recently cloned D4 dopamine receptor gene (DRD4) shows considerable homology to the D2 and D3 dopamine receptors (DRD2 and DRD3); pharmacologically, its affinity for the atypical antipsychotic clozapine is much higher than that of these other dopamine receptors. Probe pB28 for this locus recognizes an informative HincII polymorphism. We typed this polymorphism on several large reference families (a total of about 271 individuals) to place DRD4 in the genetic linkage map. Pairwise linkage analysis (using ILINK) provided evidence for close linkage to the distal 11p loci tyrosine hydroxylase (TH) and the Harvey ras oncogene (HRAS). We used our version of LINKMAP adapted to run under distributed parallel processing (Linda-LINKMAP) for an analysis moving DRD4 across a fixed map with HRAS set 3.8 cM distal to TH. This localized DRD4 close to HRAS, with no crossovers observed between those loci and a maximum lod score of 19.9 (2 cM distal to HRAS). The one LOD unit support interval extends from about 1 cM proximal to HRAS to 8 cM distal to HRAS. Crossovers identified in one kindred place DRD4 distal to TH, providing further evidence for its location close to HRAS, making DRD4 one of the most telomeric of 11p markers. (This also places DRD4 in band 11p15.5.)
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PMID:The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS. 134 74

Genetic linkage between manic depression and DNA markers on the short arm of chromosome 11 was first reported in 1987 but not supported by further analyses. However, genetic markers at the tyrosine hydroxylase (TH) gene located within this region have been reported to show allelic association with the affective disorder phenotype. We present the results of a linkage analysis using polymorphic DNA segments within the TH gene and the nearby dopamine D4 receptor (DRD4) gene in 6 families multiply affected with affective disorder. Small positive Lod scores were obtained in 2 of 6 pedigrees with the TH polymorphism which may be indicative of genetic heterogeneity.
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PMID:Linkage between tyrosine hydroxylase gene and affective disorder cannot be excluded in two of six pedigrees. 790 43

The candidate genes tyrosine hydroxylase (TH) and the dopamine D4 receptor gene (DRD4) are both located in the 11p15.5 region, thus creating strong interest in this region for genetic studies of bipolar affective disorder. It is conceivable that disregulation of the dopamine system could arise from genetic defects in DRD4 or TH, which in turn may lead to susceptibility to this disorder. We have begun our search for an autosomal linkage to bipolar affective disorder in the Old Order Amish (OOA110) with the 48 bp coding region polymorphism for DRD4. A small positive lod score of 1.16 was determined. A new polymerase chain reaction-based tetranucleotide repeat marker for the TH gene was investigated, and also had a small positive lod score of 0.63 at theta = 0.10. This finding replicates the small positive (lod = 0.42) RFLP results of Pakstis et al, (1991a). These two new markers were not able to provide statistically significant results, however their role as modifier genes in the pathogenesis of affective disorders cannot be excluded. Future studies that include the sequence variants within the 48 bp motif of the DRD4 coding region polymorphism, and possibly alternate definitions of the affective disorder phenotype, may provide more definitive answers.
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PMID:Analysis of new D4 dopamine receptor (DRD4) coding region variants and TH microsatellite in the Old Order Amish family (OOA110). 791 60

The discovery of a functional polymorphism within the dopamine D4 receptor gene (DRD4) has not only strengthened the hypotheses implicating DRD4 in the etiology of neuropyschiatric disorders, but also provided a genetic marker for testing these hypotheses. The possibility of the dopamine D4 receptor as a candidate gene for schizophrenia was investigated in a large Swedish kindred segregating for schizophrenia. Linkage to schizophrenia was tested by linkage analyses of 6 polymorphic markers (at 4 loci) in chromosome 11p15.5 including the dopamine D4 receptor (DRD4) and the tyrosine hydroxylase (TH) loci. Schizophrenia was excluded from close linkage to the DRD4 locus using two of the polymorphisms located within the dopamine D4 receptor gene. The first DRD4 polymorphism consists of variation in the number of a 48 bp imperfect direct repeat in the third exon; the second consists of a variable number of repeated G nucleotides in the first intron. In addition, some of the individuals homozygous for four or seven copies of 48 bp repeat alleles were tested for previously reported sequence variation among repeats. No single haplotype of the DRD4 alleles or haplotype of other markers in chromosome 11p15.5 was found to be common to the schizophrenic individuals in this family. Therefore, we find no evidence for linkage of the D4 receptor, or this region of 11p15.5, with genetic susceptibility to schizophrenia in this kindred.
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PMID:Alleles at the dopamine D4 receptor locus do not contribute to the genetic susceptibility to schizophrenia in a large Swedish kindred. 813 5

Gilles de la Tourette Syndrome (TS) is neuropsychiatric disorder characterized by both motor and vocal tics affecting approximately 1/10,000 females and 1/2000 males. Because of the success of neuroleptics and other agents interacting with the dopaminergic system in the suppression of tics, a defect in the dopamine system has been hypothesized in the etiology of TS. In this paper we test the hypothesis that the dopamine D4 receptor (DRD4) is linked to the genetic susceptibility to TS in five families. We tested three polymorphisms in the DRD4 gene and a polymorphism in the closely linked locus, tyrosine hydroxylase (TH). We found no evidence for linkage of DRD4 or TH to TS using an autosomal dominant model with reduced penetrance or using non-parametric methods. The presence of a mutation that results in a truncated non-functional D4 receptor protein was also tested for, but was not observed in these families.
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PMID:No evidence for a major gene effect of the dopamine D4 receptor gene in the susceptibility to Gilles de la Tourette syndrome in five Canadian families. 872 47

Monoamine metabolite (MM) levels in lumbar cerebrospinal fluid (CSF) are extensively used as indirect estimates of monoamine turnover in the brain. In this study we investigated genotypes for DNA polymorphisms in the D2 (DRD2), D3 (DRD3), and D4 (DRD4) dopamine receptor and tyrosine hydroxylase (TH) genes and their relationships to CSF MM in healthy volunteers (n = 66). Concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were corrected for back length, a confounding variable. Corrected MM levels were not related to age, gender, height, weight heredity, season or atmospheric pressure at sampling. Individuals with specific DRD2 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations. DRD3 homo- and heterozygotic genotypes had significantly different CSF 5-HIAA levels. DRD4 genotypes were not related to MM concentrations. The results suggest that specific DRD2, DRD3, and TH genotypes participate in the regulation of monoamine turnover in the central nervous system. Accordingly monoamine receptors and synthesizing enzyme genotypes appear to be variance factors influencing MM concentrations in CSF. The relationships found in this study support MM concentrations as markers for monoamine transmission in the human brain.
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PMID:Dopamine-related genes and their relationships to monoamine metabolites in CSF. 891 63

Associations of polymorphic genetic markers at the tyrosine hydroxylase (TH) and dopamine D4 receptor (DRD4) loci were examined in Scandinavian chronic alcoholics (n = 72) and control subjects (n = 67). Patients were divided into subgroups with regard to the presence of parental alcoholism and age of onset. Neither the TH nor the DRD4 allele distributions were significantly different when alcoholic samples were compared with control subjects. However, a tendency to high prevalence for 1 of the 5 TH alleles assayed (TH-K3) was observed in a subsample of 44 alcoholics characterized by late onset when compared with control subjects (27.3% vs. 10.6%, p = 0.041). Results suggest that no major influence on alcoholism is exerted through genes associated with the DRD4 or TH allelic markers examined.
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PMID:Tyrosine hydroxylase and dopamine D4 receptor allelic distribution in Scandinavian chronic alcoholics. 904 70

To identify specific genes affecting vulnerability or resistance, we performed a whole-autosomal genome scan for genetic linkage to alcohol dependence in a Southwestern American Indian tribe. Genotypes at 517 autosomal microsatellite loci and clinical evaluations were available for 152 subjects belonging to extended pedigrees and forming 172 sib-pairs. Highly suggestive evidence for linkage emerged for two genomic regions using two- and multipoint sib-pair regression methods; both regions harbored neurogenetic candidate genes. The best evidence is seen with D11S1984 (nominal P = 0.00007, lod approximately equal to 3.1) on chromosome 11p, in close proximity to the DRD4 dopamine receptor and tyrosine hydroxylase (TH) genes. Good evidence is seen with D4S3242 (nominal P = 0.0002, lod approximately equal to 2.8) on chromosome 4p, near the beta1 GABA receptor gene. Interestingly, three loci in the alcohol dehydrogenase gene cluster on chromosome 4q showed evidence for linkage with two-point analyses, but not multipoint analysis.
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PMID:Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population. 960 7

A systematic search was performed for DNA sequence variation in genes regulating neurotransmitter metabolism in rhesus macaque (Macaca mulatta). These genes included dopamine and serotonin receptors and transporters, and tyrosine hydroxylase. A total of 13 single nucleotide polymorphisms in five different genes were identified, namely: DRD1 (-244T->G), q = 0.45; DRD1 (-179C->T), q = 0.19; DRD1 (-127G->A), q = 0.25; DRD1(-11T->G), q = 0.08; DRD1(-81C->T), q = 0.19; DRD3 (248G->A), q= 0.08; DRD3(341G->C), q = 0.11; DRD3(377A->G), q = 0.19; DRD3 (403C->T; A59V), q= 0.11; DRD4(2608G->A), q= 0.48; HTR1D(-506G->T), q = 0.47; HTR1D(-173C->T), q = 0.47; and HTT(340G->A), q = 0.39. The nucleotide positions listed correspond to the human homologs.
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PMID:DNA sequence polymorphisms in genes involved in the regulation of dopamine and serotonin metabolism in rhesus macaques. 1043 47

To determine the role of genes in the chromosomal regions 11p15 and 4p12 in the development of alcohol dependence, a sample of alcoholics (n = 133) and normal controls (n = 89) were screened using polymorphisms in the dopamine D4 receptor (DRD4), tyrosine hydroxylase (TH), and GABA receptor beta1 (GABRbeta1) genes. Comparison of total alcoholics with normal controls for GABRbeta1 gene was highly significant (p = 0.004). The difference between type II alcoholics and normal controls for the same allele frequencies was also significant (p = 0.029). The allele distributions of the polymorphisms in the DRD4 and TH genes in alcoholics and normal controls were similar and their differences were not significant. Our association studies indicate that the GABRbeta1 gene may play a role in the development of alcoholism. Therefore, it is important to screen a sample of well-characterized alcoholics with functional polymorphisms in all of the GABAalpha receptor subunit genes and determine their relationship with alcoholism phenotypes. Results with TH and DRD4 genes indicate that these two genes may not play major roles in the development of alcoholism.
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PMID:Human chromosomes 11p15 and 4p12 and alcohol dependence: possible association with the GABRB1 gene. 1049 Jul 12


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