Gaba transporterSLC6A11gene polymorphism associated with tardive dyskinesia

Son, Woo Young; Lee, Heon Jeong; Yoon, Ho Kyoung; Na, Kyoung-Sae; Park, Young Min; Yang, Hee Jung; Choi, Jung Eun; An, Hyonggin; Seo, Han Kyu

doi:10.3109/08039488.2013.780260

Cited by 24 publications

(9 citation statements)

References 25 publications

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“…This study was approved by the Ethics Committee of the Korea University Hospital (06-2594), and all the participants provided written informed consent. Other characteristics of these subjects have been previously reported [ 11 - 15 ].…”

Section: Methodsmentioning

confidence: 89%

Association between the IL10 rs1800896 Polymorphism and Tardive Dyskinesia in Schizophrenia

Choi

Choo

Lee

et al. 2020

Psychiatry Investig

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Objective Interleukin-10 (IL-10) is a major immunoregulatory cytokine and its gene plays a fundamental role in anti-inflammatory and immunosuppressive activity. This study aimed to examine the association between the IL10 gene promoter -1082G/A polymorphism (rs1800896) and tardive dyskinesia (TD) in schizophrenia.Methods Two hundred and eighty unrelated Korean schizophrenic patients participated in this study (105 TD and 175 non-TD patients). TD was diagnosed using the Research Diagnostic Criteria for TD and Abnormal Involuntary Movement Scale (AIMS). Genotyping was performed by RT-PCR and high-resolution melting curve analysis.Results The distributions of genotypic frequencies did not differ between patients with and without TD (χ2=4.33, p=0.115). However, allelic frequencies of the two groups were different (χ2=4.45, p=0.035); the A allele frequency was higher in TD. The total AIMS scores of the three genotypes were not different (F=1.33, p=0.266). However, the total AIMS scores of the A allele carrier and the A allele non-carrier were significantly different (t=5.79, p<0.001). Logistic regression analaysis showed that IL10 -1082G/A genotype significantly predicts presence of TD (p=0.045) after adjusting for covariates such as age and treatment duration.Conclusion This finding suggests that the A allele of rs1800896 may be associated with TD development following a low IL-10 function.

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Section: Methodsmentioning

confidence: 89%

Association between the IL10 rs1800896 Polymorphism and Tardive Dyskinesia in Schizophrenia

Choi

Choo

Lee

et al. 2020

Psychiatry Investig

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“…Allelic mutation represses SLC6A2 transcription [132] and confers to ADHD (attention-deficit hyperactivity disorder) [133]. Slc6a11 encodes GABA transporter 3, polymorphism of the gene increased the susceptibility to the tardive dyskinesia, an involuntary neurological movement disorder [134]. Slc6a15 functions as a brain transporter that facilitate the uptake of proline and leucine [135,136].…”

Section: Solute Carrier Genesmentioning

confidence: 99%

Sleep control by TFAP2a and TFAP2b transcription factors in mice

Yang¹

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Sleep is a universal behavior that exists across species. We previously found that deletion of transcription factor APTF-1 induces sleep loss in C. elegans and Drosophila. In mammals, sleep has two states: rapid eye movement sleep (REMS) and non-REM sleep (NREMS), which can be distinguished by EEG spectral power. There are five homologs of APTF-1 in mammals, from Tfap2a to e. However, little is known about whether these homologs, Tfap2a and b, have a conserved role of regulating sleep in animals with a more complex brain. Therefore, I characterized the sleep and wakefulness of Tfap2a and b mutants in mice. Consistent with our previous finding, paralogs of Tfap2a and b control sleep in mice. However, Tfap2a and b control sleep in a bidirectional manner. EEG results showed that Tfap2a +/mice exhibited higher sleep drive, whereas Tfap2b +/mice showed a reduced sleep quality with shortened NREMS amount during baseline recording. As expected, sleep deprivation induced a stronger delta and theta power rebound in Tfap2a mutants, but a weaker response in Tfap2b mutants. This functional divergence was also observed in behaviors beyond sleep. Tfap2b +/mice displayed depression-like behavior while Tfap2a +/mice were hyperactive and showed more resistance to the stressful environment. With the decreased sleep quality, learning and memory were impaired in Tfap2b mutants. In addition, Tfap2b mutants exhibited a slightly shortened circadian period. In summary, Tfap2a and b control sleep in mice as well, but in a bidirectional way. It might support the hypothesis that, as nervous system evolved, the function of Tfap2a and b genes also diverged.GABAergic neurons play a key role promoting sleep. The development of GABAergic neurons is regulated by various transcription factors. However, it is not clear whether or how Tfap2a and b are involved in the expression and function of GABAergic neurons. Here I measured the expression of the genes that control GABA synthesis and transportation in Tfap2a +/and Tfap2b +/mice. Results from qPCR has confirmed a role of Tfap2b, but not TFap2a, in regulating the GABAergic gene expression.However, the role of Tfap2b was complex. The expression of GAD65, GAD67, Vgat was decreased in cortex, brainstem, cerebellum, but increased in striatum. Further, using ISH, a decrease number of the GAD67 expressing GABAergic cells was detected in the parafacial zone, a sleep-promoting center located in the lower brainstem. Since the expression of Tfap2b in brain starts early at developmental stages, E14.5 brains were extracted and analyzed using RNA-seq. Results have revealed various differentially regulated genes from homeobox, Slc family and those related to neurotransmission function. Together with qPCR and ISH results, they provided molecular evidences implying a functional role of GABAergic neurons expressing Tfap2b gene. Next, I characterized the function of GABAergic neurons expressing Tfap2b in sleep in Vgat-Tfap2b -/mice. EEG analysis showed that sleep quantity and intensity were reduced in female Vgat-T...

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“…The role of GABA receptor genes GABRB2 and GABRG3 in TD has been investigated, but no significant associations were reported for the studied polymorphisms. However, gene-gene interactions between GABRB2 , GABRG3 , and SCL6A11 and susceptibility to TD highlighted the importance of the GABA receptor signaling pathway ( Son et al, 2014 ).…”

Section: Pharmacogenomic Studies Focusing On the Association Between Tardive Dyskinesia And Genes Involved In The Pharmacodynamicsmentioning

confidence: 99%

“…The protein encoded by SLC6A11 is a sodium-dependent transporter of GABA from synaptic cleft to surrounding glial cells leading to decreased GABA signaling. A case-control study, which included 180 patients with schizophrenia, 105 of whom experienced TD, identified an association between SLC6A11 rs4684742 and TD ( Son et al, 2014 ) (Summarized in Table 5 ). All of the studies are presented in this chaptercan be found in the Supplementary Table S2 .…”

Section: Pharmacogenomic Studies Focusing On the Association Between Tardive Dyskinesia And Genes Involved In The Pharmacodynamicsmentioning

confidence: 99%

Genetic Factors Associated With Tardive Dyskinesia: From Pre-clinical Models to Clinical Studies

2022

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Tardive dyskinesia is a severe motor adverse event of antipsychotic medication, characterized by involuntary athetoid movements of the trunk, limbs, and/or orofacial areas. It affects two to ten patients under long-term administration of antipsychotics that do not subside for years even after the drug is stopped. Dopamine, serotonin, cannabinoid receptors, oxidative stress, plasticity factors, signaling cascades, as well as CYP isoenzymes and transporters have been associated with tardive dyskinesia (TD) occurrence in terms of genetic variability and metabolic capacity. Besides the factors related to the drug and the dose and patients’ clinical characteristics, a very crucial variable of TD development is individual susceptibility and genetic predisposition. This review summarizes the studies in experimental animal models and clinical studies focusing on the impact of genetic variations on TD occurrence. We identified eight genes emerging from preclinical findings that also reached statistical significance in at least one clinical study. The results of clinical studies are often conflicting and non-conclusive enough to support implementation in clinical practice.

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Gaba transporterSLC6A11gene polymorphism associated with tardive dyskinesia

Abstract: These results suggest that GABA receptor signaling pathway was associated with the increased susceptibility to TD in Korean schizophrenic patients.

Cited by 24 publications

References 25 publications

Association between the IL10 rs1800896 Polymorphism and Tardive Dyskinesia in Schizophrenia

Association between the IL10 rs1800896 Polymorphism and Tardive Dyskinesia in Schizophrenia

Sleep control by TFAP2a and TFAP2b transcription factors in mice

Genetic Factors Associated With Tardive Dyskinesia: From Pre-clinical Models to Clinical Studies

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