Proposed Schizophrenia-Related Gene Polymorphism: Expression of the Ser9Gly Mutant Human Dopamine D3Receptor with the Semliki Forest Virus System

Lundström, Kenneth; Turpin, Michael P.

doi:10.1006/bbrc.1996.1296

Cited by 227 publications

(130 citation statements)

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“…29 A significantly higher dopamine binding affinity for the Gly9 homozygote than that for the other genotypes was detected in CHO cells doubly infected with the Semliki Forest virus system containing the dopamine D3 receptor gene. 30 In this study, higher Novelty Seeking scores were associated with the C allele of the −521C/T polymorphism. The CAT assay suggested that the C allele is transcriptionally more active than the T allele.…”

Section: Molecular Psychiatrymentioning

confidence: 47%

Identification of a polymorphism in the promoter region of DRD4associated with the human novelty seeking personality trait

et al. 2000

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Section: Molecular Psychiatrymentioning

confidence: 47%

Identification of a polymorphism in the promoter region of DRD4associated with the human novelty seeking personality trait

et al. 2000

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“…31,101,102 In vitro studies indicate that the Gly variants is associated with higher dopamine binding affinity. 161 However, the biological interpretation of this observation is difficult, as the Gly variants was mostly associated with good response in Caucasian patients 101,102,104 and with poor response in Chinese populations, suggesting that linkage disequilibrium (LD) status with another functional polymorphism may explain the different associations with response.…”

Section: Pharmacodynamic Factorsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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“…The high degree of the interspecies variation of this amino acid suggests that it may not be subjected to evolutionary constraint. On the other hand, the receptors encoded by the human ser9 and gly9 alleles are reported to differ in their dopamine affinities, 12 indicating a role for this amino acid in the control of receptor action. The total number of amino acids amounted to 400 in both species.…”

Section: Resultsmentioning

confidence: 99%

“…Although the significance of this substitution in vivo remains unknown, it has been reported that the gly9 receptor in vitro binds dopamine with a seven-fold higher affinity than does the Ser9 receptor. 12 The gly9ser polymorphism has been examined in relation to both schizophrenia and TD. Whereas a possible link to schizophrenia is less clarified, 13 the original study reporting an association between the gly9 receptor and TD 14 has gained substantial support from a considerable number of subsequent studies.…”

Section: Introductionmentioning

confidence: 99%

Cebus apella, a nonhuman primate highly susceptible to neuroleptic side effects, carries the GLY9 dopamine receptor D3 associated with tardive dyskinesia in humans

et al. 2003

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Tardive dyskinesia (TD) is a severe side effect of traditional neuroleptics affecting a considerable number of schizophrenic patients. Accumulating evidence suggests the existence of a genetic disposition to TD and other extra pyramidal symptoms (EPS) most strongly linked to a ser/gly polymorphism in position 9 of the D3 dopamine receptor gene (DRD3). The Cebus apella monkey is the favored animal model to study TD and other EPS because of its high susceptibility to side effects of neuroleptics. We therefore determined the sequence of the DRD3 gene in this species and compared it with that of humans. We found that the highly TD susceptible C. apella monkey (n ¼ 21) carries the gly9/gly9 DRD3 genotype that has been associated with TD in humans. Contrarily, C. apella did not carry the ser23 5HT2C allele that has been reported to increase TD susceptibility in humans.

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Proposed Schizophrenia-Related Gene Polymorphism: Expression of the Ser9Gly Mutant Human Dopamine D3Receptor with the Semliki Forest Virus System

Cited by 227 publications

References 0 publications

Identification of a polymorphism in the promoter region of DRD4associated with the human novelty seeking personality trait

Identification of a polymorphism in the promoter region of DRD4associated with the human novelty seeking personality trait

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Cebus apella, a nonhuman primate highly susceptible to neuroleptic side effects, carries the GLY9 dopamine receptor D3 associated with tardive dyskinesia in humans

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