Association of GABAA Receptor Gene with Epilepsy Syndromes

Bhat, Musadiq Ahmad; Guru, Sameer Ahmad; Mir, Rashid; Waza, Ajaz Ahmad; Zuberi, Mariyam; Sumi, Mamta P.; Bodeliwala, Shaam; Puri, Vinod; Saxena, Alpana

doi:10.1007/s12031-018-1081-7

Cited by 14 publications

(9 citation statements)

References 36 publications

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“…Crestin expression, however, is reduced, with hypo-methylation of both the neighboring CpG site and associated DMR. Gabra1 , a GABA receptor subunit (Bhat et al, 2018) has decreased expression while the associated DMR is hyper-methylated, demonstrating a relationship between methylation and gene expression. Riox1 and wdr5 , respectively, a histone demethylase and histone methyltransferase (Aravind et al, 2011; Tao et al, 2013), exhibit decreased expression while the endosomal GTPase rab11bb (Clark et al, 2011) has increased expression, but all three are surrounded by a mixture of hyper and hypo-methylated sites ( riox and wdr5 ) and DMRs ( rab11bb ).…”

Section: Resultsmentioning

confidence: 99%

Developmental Dioxin Exposure Alters the Methylome of Adult Male Zebrafish Gonads

et al. 2019

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental toxicant and endocrine disrupting compound with reproductive and developmental effects in humans and model organisms, including zebrafish. Our previous microarray and histological studies found defects in spermatogenesis and fertility of zebrafish in response to acute developmental TCDD exposure. These effects are apparent following exposure during reproductive development, modeling fetal basis of adult-onset disease. Some outcomes of these previous studies (reduced fertility, changes in sex ratio, transcriptomic alterations) are also transgenerational – persisting to unexposed generations – through the male germline. We hypothesized that DNA methylation could be a possible mechanism for these reproductive effects and performed whole genome bisulfite sequencing (WGBS), which identifies whole genome DNA methylation status at the base pair level, on testes of adult zebrafish exposed to TCDD (two separate hour-long exposures to 50 pg/mL TCDD at 3 and 7 weeks post fertilization). In response to TCDD exposure, multiple genes were differentially methylated; many of which are involved in reproductive processes or epigenetic modifications, suggesting a role of DNA methylation in later-life health outcomes. Additionally, several differentially methylated genes corresponded with gene expression changes identified in TCDD-exposed zebrafish testes, indicating a potential link between DNA methylation and gene expression. Ingenuity pathway analysis of WGBS and microarray data revealed genes involved in reproductive processes and development, RNA regulation, the cell cycle, and cellular morphology and development. We conclude that site-specific changes in DNA methylation of adult zebrafish testes occur in response to acute developmental TCDD exposure.

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Section: Resultsmentioning

confidence: 99%

Developmental Dioxin Exposure Alters the Methylome of Adult Male Zebrafish Gonads

et al. 2019

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“…This lowers surface expression of mature protein [ 160 ], in turn reducing GABA evoked chloride currents, leading to neuronal disinhibition by preventing hyperpolarization of membrane [ 161 ]. Studies have shown that R220H variant of GABRD can be a susceptibility allele for JME [ 162 , 163 ]. In contrast, Lenzen et al found no association between the R220H variant and JME among 562 German patients and 664 controls [ 164 ].…”

Section: Genetic Studies Of Common Epilepsiesmentioning

confidence: 99%

Genetic Landscape of Common Epilepsies: Advancing towards Precision in Treatment

Thakran

Guin

Singh

et al. 2020

IJMS

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Epilepsy, a neurological disease characterized by recurrent seizures, is highly heterogeneous in nature. Based on the prevalence, epilepsy is classified into two types: common and rare epilepsies. Common epilepsies affecting nearly 95% people with epilepsy, comprise generalized epilepsy which encompass idiopathic generalized epilepsy like childhood absence epilepsy, juvenile myoclonic epilepsy, juvenile absence epilepsy and epilepsy with generalized tonic-clonic seizure on awakening and focal epilepsy like temporal lobe epilepsy and cryptogenic focal epilepsy. In 70% of the epilepsy cases, genetic factors are responsible either as single genetic variant in rare epilepsies or multiple genetic variants acting along with different environmental factors as in common epilepsies. Genetic testing and precision treatment have been developed for a few rare epilepsies and is lacking for common epilepsies due to their complex nature of inheritance. Precision medicine for common epilepsies require a panoramic approach that incorporates polygenic background and other non-genetic factors like microbiome, diet, age at disease onset, optimal time for treatment and other lifestyle factors which influence seizure threshold. This review aims to comprehensively present a state-of-art review of all the genes and their genetic variants that are associated with all common epilepsy subtypes. It also encompasses the basis of these genes in the epileptogenesis. Here, we discussed the current status of the common epilepsy genetics and address the clinical application so far on evidence-based markers in prognosis, diagnosis, and treatment management. In addition, we assessed the diagnostic predictability of a few genetic markers used for disease risk prediction in individuals. A combination of deeper endo-phenotyping including pharmaco-response data, electro-clinical imaging, and other clinical measurements along with genetics may be used to diagnose common epilepsies and this marks a step ahead in precision medicine in common epilepsies management.

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“…The γ2 subunit was reported to change the kinetics of GABA A related to channels and to the synaptic and postsynaptic clustering and maintenance. 16 , 17 , 18 , 19 C588T, located in the GABRG2 gene encoding the γ2 subunit, has previously been shown to cause genetic generalized epilepsy (GGE) risk and response to AEDs 20 , 21 , 22 ; however, other results were found to have conflicting results. 23 , 24 , 25 , 26 …”

Section: Introductionmentioning

confidence: 99%

“…The γ2 subunit was reported to change the kinetics of GABA A related to channels and to the synaptic and postsynaptic clustering and maintenance. [16][17][18][19] C588T, located in the GABRG2 gene encoding the γ2 subunit, has previously been shown to cause genetic generalized epilepsy (GGE) risk and response to AEDs [20][21][22] ; however, other results were found to have conflicting results. [23][24][25][26] Here, we aimed to explore whether the GABRG2 C588T polymorphism predicts susceptibility to GGE and to evaluate the role of GABRG2 in epilepsy treatment.…”

Section: Introductionmentioning

confidence: 99%

Analysis of GABRG2 C588T polymorphism in genetic epilepsy and evaluation of GABRG2 in drug treatment

Wang

Zhang

Zhou

et al. 2021

Clinical Translational Sci

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Epilepsy is a common disorder with complex inheritance, and its treatment is very unsatisfactory. An association between the GABRG2 C588T polymorphism and genetic generalized epilepsy has been studied by several genetic association studies. However, these results were inconsistent, and the role of GABRG2 in epilepsy treatment remains unknown. To evaluate the role of GABRG2 in epilepsy, we performed meta-analysis, expression quantitative trait loci analysis, protein-protein interaction analysis, and drug-gene interaction analysis. The combined results indicated that the GABRG2 C588T polymorphism was associated with genetic generalized epilepsy risk under dominant and allelic Accepted ArticleThis article is protected by copyright. All rights reserved models (odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.02-1.54, P = 0.03, I 2 = 0% and OR = 1.21, 95% CI = 1.03-1.42, P= 0.02, I 2 = 20%, respectively). In the Asian population, we also found similar results under dominant and allelic models (OR = 1.93, 95% CI = 1.18-3.16, P = 0.009, I 2 = 0% and OR= 1.69, 95% CI = 1.20-2.37, P = 0.003, I 2 = 11%, respectively). We first found that the GABRG2 C588T polymorphism regulates GABRG2 expression in human brain tissues and that the protein encoded by GABRG2 interacts with targets of approved antiepileptic drugs. Interestingly, we also found that GABRG2 itself interacts with approved antiepileptic drugs. Taken together, the results indicate that the C588T polymorphism might alter the GABA A receptor by modulating GABRG2 gene expression, resulting in increased risk for epilepsy, and that GABRG2 may be a potential therapeutic target for epilepsy.

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Association of GABAA Receptor Gene with Epilepsy Syndromes

Cited by 14 publications

References 36 publications

Developmental Dioxin Exposure Alters the Methylome of Adult Male Zebrafish Gonads

Developmental Dioxin Exposure Alters the Methylome of Adult Male Zebrafish Gonads

Genetic Landscape of Common Epilepsies: Advancing towards Precision in Treatment

Analysis of GABRG2 C588T polymorphism in genetic epilepsy and evaluation of GABRG2 in drug treatment

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