Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A positive family history is present in many patients with essential tremor (ET), but twin studies and segregation analysis have suggested that ET is not entirely a genetic disorder. Two genetic loci have been identified in autosomal dominant (AD) ET and polymorphisms in the DRD3 and HS1-BP3 genes have been proposed as the possible susceptibility factors for ET. There is also evidence for further genetic heterogeneity. We evaluated 4 unrelated large kindreds with ET with an apparent AD mode of transmission. Each kindred spanned at least 3 generations and contained at least 13 living affected subjects who met criteria for definitive ET. None of the pedigrees had evidence for inheritance of ET from both parents. Known genetic ET loci were excluded in these families. We detected a preferential transmission of ET in every kindred and the proportion of affected offspring varied from 75% to 90% (P < 0.05) in the generations with complete ascertainment. Our data indicate that non-Mendelian preferential transmission of an affected allele is a feature in many ET kindreds with multiple affected members and an apparent AD mode of inheritance. ET may have a complex etiology. Additional genetic models need to be considered, including an interaction of susceptibility genes and environmental risk factors.
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PMID:Familial essential tremor with apparent autosomal dominant inheritance: should we also consider other inheritance modes? 1672 53

Familial essential tremor (ET), the most common inherited movement disorder, is generally transmitted as an autosomal dominant trait. A genome-wide scan for ET revealed one major locus on chromosome 3q13. Here, we report that the Ser9Gly variant in the dopamine D(3) receptor gene (DRD3), localized on 3q13.3, is associated and cosegregates with familial ET in 23 out of 30 French families. Sequencing revealed no other nonsynonymous variants in the DRD3-coding sequence and in the first 871 bp of the 5' flanking region. Moreover, Gly-9 homozygous patients presented with more severe and/or earlier onset forms of the disease than heterozygotes. A replication study comparing 276 patients with ET and 184 normal controls confirmed the association of the Gly-9 variant with risk and age-at-onset of ET. In human embryonic kidney (HEK) 293-transfected cells, the Gly-9 variant did not differ from the Ser-9 variant with respect to glycosylation and to anterograde and retrograde trafficking, but dopamine had an affinity that was four to five times higher. With the Gly-9 variant, the dopamine-mediated cAMP response was increased, and the mitogen-associated protein kinase (MAPK) signal was prolonged, as compared with the Ser-9 variant. The gain-of-function produced by the Gly-9 variant may explain why drugs active against tremor in Parkinson's disease (PD) are usually not effective in the treatment of ET and suggests that DRD3 partial agonists or antagonists should be considered as novel therapeutic options for patients with ET.
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PMID:A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor. 1680 26

We studied the association between polymorphisms of genes coding for dopamine D(2) (DRD2), dopamine D(3) (DRD3), serotonin 2(a) (HTR2A), and serotonin 2(c) (HTR2C) receptors and Antipsychotic-Induced Parkinsonism (AIP), rigidity, bradykinesia, and rest-tremor in African-Caribbeans treated with antipsychotics. Polymorphisms of DRD2 (-141CIns/Del, TaqIA, 957C > T), DRD3 (Ser9Gly), HTR2A (-1438A > G, 102T > C, His452Tyr), and HTR2C (-759C > T, Cys23Ser) genes were determined according to standard protocols. The Unified Parkinson Disease Rating Scale was used for the measurement of AIP, rigidity, bradykinesia, and rest-tremor. Chi-squared or Fisher's exact tests were applied for the association analyses. The t-test was applied for continuous data. Ninety nine males and 27 females met the inclusion criteria (Schizophr Res 1996, 19:195). In males, but not in females, there were significant associations between -141CDel-allele carriership (DRD2) and rigidity (Fisher's Exact Test: P = 0.021) and between 23Ser-allele carriership (HTR2C) and bradykinesia (P = 0.026, chi(2) = 5.0) or AIP (P = 0.008, chi(2) = 7.1). Rest-tremor was not associated with any of the polymorphisms studied. Analyses of the age, chlorpromazine equivalents, benztropine equivalents, the number of patients using anticholinergic medication, and the utilization patterns of the antipsychotic medication did not show statistically significant differences between patients with and without AIP, rigidity, bradykinesia, rest-tremor. Conducting the analysis without gender stratification did not affect our findings considerably, except for the association between bradykinesia and 23Ser-allele which failed to reach statistical significance in the total sample (P = 0.0646, chi(2) = 3.41). Since AIPs subsymptoms (rigidity, bradykinesia, and rest-tremor) may differ pharmacogenetically, our data strongly support symptom-specific analysis of AIP. However, further research is warranted to confirm our findings.
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PMID:Pharmacogenetics of parkinsonism, rigidity, rest tremor, and bradykinesia in African-Caribbean inpatients: differences in association with dopamine and serotonin receptors. 1838 1

The genetic causes of essential tremor (ET) seem to be heterogeneous. Recently, ET has been found associated with a functional variant (Ser9Gly) of the dopamine D(3) receptor (DRD3), located in the ETM1 locus on chromosome 3q13.3 described for the first time in 1997. We examined this variant in three different populations from Germany, Denmark and France. We undertook an association study of the Ser9Gly variant in 202 cases with a familial history from unrelated families with ET, 97 cases with isolated non-familial ET and 528 healthy controls. In addition, linkage and segregation analyses were carried out in 22 ET families. The distribution of genotypes and allele frequencies showed no significant differences in the whole sample and in a subanalysis of familial and sporadic cases. Age at onset of tremor, tremor duration and tremor severity did not show an association with the genotype. In addition, the DRD3 variant was not found linked to the disease in a subset of informative ET families. We did not find a significant association of the DRD3 variant with ET nor linkage to the DRD3 receptor in German, Danish and French ET patients and families, suggesting that it is unlikely to be a causal factor for ET.
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PMID:Dopamine receptor D3 gene and essential tremor in large series of German, Danish and French patients. 1909 71

A common subset of genetic risk factors for Parkinson's disease (PD) and essential tremor (ET) has been postulated. Recently, an association between the dopamine D(3) receptor (DRD3) Ser9Gly polymorphism and ET has been reported. We studied whether PD tremor is influenced by Ser9Gly in a genetic association study based on the gene bank of the German Competence Network on Parkinson's disease. The study included analyses of motor predominance (mixed, hypokinetic, and tremor), and tremor type (resting, postural, and action). We did not identify any effect of DRD3 Ser9Gly on tremor in PD, even when regarding various symptom combinations to avoid missing a weak effect on the phenotype. Additional studies incorporating symptoms at disease onset, and grading of tremor response to dopaminergic therapy, are warranted.
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PMID:Tremor in Parkinson's disease is not associated with the DRD3 Ser9Gly polymorphism. 2043 88

The dopamine receptor gene DRD3 and in particular the single nucleotide polymorphism Ser9Gly has been extensively investigated and found to have potential association with a wide variety of conditions. These include essential tremor, unipolar and bipolar depression, as well as a loose association with schizophrenia. Evaluation of (1) these known associations with DRD3, (2) the recent finding of Costas and colleagues that a haplotype containing Ser-9 is associated with protection from schizophrenia, and (3) an extant trait model of personality, leads to the hypothesis that an allele DRD3/Ser codes for trait aggression by Mendelian recessive inheritance. The implications of this hypothesis are that (1) DRD3 is a pleiotropic gene having allelic polymorphism related to both behavior and disease, and (2) models of personality based on genetic traits hold promise. In the area of schizophrenia, the hypothesis implies that schizophrenic patients can be divided into two broad classes: those having genotype DRD3/Ser/Ser and those who lack this homozygosity. The hypothesis of the association of DRD3 with trait aggression could be readily evaluated by testing groups of healthy individuals by personality inventory focused on aggression and by biochemical assay of neurotransmitter levels.
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PMID:Dopamine receptor DRD3 codes for trait aggression as Mendelian recessive. 2196 56

Essential tremor (ET) is a prevalent condition manifesting with progressive action tremor. Although ET was traditionally viewed as a sporadic disease, a significant proportion of cases report a positive family history of tremor. Autosomal dominant inheritance can be demonstrated in many families. Previously, genome-wide linkage studies in families mapped three loci for ET, hereditary essential tremor-1 (ETM1), ETM2 and ETM3. However, no causal mutation has been replicated in candidate genes within these loci, including dopamine D3 receptor (DRD3) and HS1-binding protein 3 (HS1BP3). Recently, the first genome-wide association study in ET followed by replication studies conducted in diverse populations identified a significant association between the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) SNP rs9652490 and risk for ET Although further novel variants were indentified in LINGO1 and its paralog LINGO2 that may be associated with risk for ET, the pathogenic mechanisms involved remain elusive. Given the possibility that ET as a complex trait may be influenced by the combined effects of rare variants, novel high-throughput technologies sequencing all exons across the genome (exome sequencing) or the whole genome (genome sequencing) may become crucial in understanding/deciphering the genetic background of ET.
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PMID:Genetics of essential tremor. 2216 13

The dopamine D3 receptor (DRD3) Ser9Gly variant has attracted more attention since the variant was observed to be associated with risk of essential tremor (ET). A number of association studies concerning the DRD3 Ser9Gly variant and ET susceptibility have been conducted in various populations. However, some results were contradictory. To derive a more precise estimation of the relationship between the DRD3 Ser9Gly variant and the genetic risk of ET, we performed a comprehensive meta-analysis which included seven case-control studies. The meta-analysis was conducted in four genetic models: dominant, recessive, heterozygous, and homozygous. The odds ratio and 95% confidence intervals were used as the measure of association. The combined results of overall analysis showed a lack of association of the DRD3 Ser9Gly variant and ET, regardless of the genetic model of Ser9Gly. Publication bias and heterogeneity were absent in most analyses. In conclusion, the present meta-analysis does not support the notion that the DRD3 Ser9Gly variant is a genetic risk factor for ET.
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PMID:Meta-analysis of the influence of DRD3 Ser9Gly variant on susceptibility for essential tremor. 2405 3

The response to dopaminergic treatment in Parkinson's disease depends on many clinical and genetic factors. The very common motor fluctuations (MF) and dyskinesia affect approximately half of patients after 5 years of treatment with levodopa. We did an evaluation of a combined effect of 16 clinical parameters and 34 single nucleotide polymorphisms to build clinical and clinical-pharmacogenetic models for prediction of time to occurrence of motor complications and to compare their predictive abilities. In total, 220 Parkinson's disease patients were included in the analysis. Their demographic, clinical, and genotype data were obtained. The combined effect of clinical and genetic factors was assessed using The Least Absolute Shrinkage and Selection Operator penalized regression in the Cox proportional hazards model. Clinical and clinical-pharmacogenetic models were constructed. The predictive capacity of the models was evaluated with the cross-validated area under time-dependent receiver operating characteristic curve. Clinical-pharmacogenetic model included age at diagnosis (HR = 0.99), time from diagnosis to initiation of levodopa treatment (HR = 1.24), COMT rs165815 (HR = 0.90), DRD3 rs6280 (HR = 1.03), and BIRC5 rs9904341 (HR = 0.95) as predictive factors for time to occurrence of MF. Furthermore, clinical-pharmacogenetic model for prediction of time to occurrence of dyskinesia included female sex (HR = 1.07), age at diagnosis (HR = 0.97), tremor-predominant Parkinson's disease (HR = 0.88), beta-blockers (HR = 0.95), alcohol consumption (HR = 0.99), time from diagnosis to initiation of levodopa treatment (HR = 1.15), CAT rs1001179 (HR = 1.27), SOD2 rs4880 (HR = 0.95), NOS1 rs2293054 (HR = 0.99), COMT rs165815 (HR = 0.92), and SLC22A1 rs628031 (HR = 0.80). Areas under the curves for clinical and clinical-pharmacogenetic models for MF after 5 years of levodopa treatment were 0.68 and 0.70, respectively. Areas under the curves for clinical and clinical-pharmacogenetic models for dyskinesia after 5 years of levodopa treatment were 0.71 and 0.68, respectively. These results show that clinical-pharmacogenetic models do not have better ability to predict time to occurrence of motor complications in comparison to the clinical ones despite the significance of several polymorphisms. Models could be improved by a larger sample size and by additional polymorphisms, epigenetic predictors or serum biomarkers.
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PMID:Clinical-Pharmacogenetic Predictive Models for Time to Occurrence of Levodopa Related Motor Complications in Parkinson's Disease. 3115 12