Potential role of GABAA receptor subunit; GABRA6, GABRB2 and GABRR2 gene polymorphisms in epilepsy susceptibility and pharmacotherapy in North Indian population
Introduction
The epilepsies are one of the most common but serious brain disorders which are characterized by an enduring predisposition to generate epileptic seizures [1]. The incidence of epilepsy in developed countries is around 50 per 100,000 people per year, and is higher in infants and elderly people [2]. The epilepsy affects an estimated 60 million people worldwide of all ages [3]. Earlier reports suggest that almost half of all epilepsies have some genetic component which could directly or indirectly modulate seizure phenotype [4]. According to Epilepsy Genetic Association Study database (http://www.epilepsygenes.org/ page/show/EGAD), more than 50 association studies have been performed and genetic variants of several genes such as neuronal sodium channels, potassium channels, and GABA receptors have been found to be associated in variety of epilepsy phenotypes [5]. Recent progress in genetic research in epilepsy mainly concerns two important aspects of the disease-complexity; the genetic etiology and drug therapy [6]. At the present time, GABA receptors have gained concern regarding their role in epilepsy susceptibility and therapeutic response of epilepsy patients undergoing AED treatment [7], [8].
γ-aminobuytric acid (GABA), is the primary inhibitory neurotransmitter in the CNS, which operates primarily via chloride-permeable GABAA receptor channels. From a genetic perspective, all mutations documented to date are localized to GABAA receptors rather than GABAB and GABAC receptors. Structurally, GABAA receptors are pentameric chloride ion channels formed from various combinations of proteins encoded by α (α 1–α 6), β (β 1–β 3), γ (γ 1–γ 3); δ, ε, θ, and ρ (ρ1–ρ3) subunit gene families [9]. Numerous experimental and clinical observations suggest that epilepsy may result from an imbalance in excitatory and inhibitory neurotransmitter systems resulting in decreased net inhibition. Conventional antiepileptic drugs (e.g. barbiturates, benzodiazepines) suppress seizures by increasing GABAA receptor activity, or by inhibition of GABA breakdown (vigabatrin) or reuptake (tiagabin) [10]. It is also hypothesized that, target receptor sites are somehow altered in epileptic brain so that they are much less sensitive to anticonvulsive effects of administered antiepileptic drugs [11].
These receptors are also key therapeutic targets for benzodiazepines, barbiturates, neurosteroids and general anesthetics [12]. Genetic variations in genes encoding GABA receptors have been shown to bring about inter-individual variation in susceptibility to various neurological syndromes including schizopherenia, epilepsy and alcohol-withdrawal syndromes. In our earlier study, we documented influence of susceptibility and drug response in epilepsy [13]. We have shown that genetic polymorphism present at alpha subunit of GABAA receptor GABRA1 IVS11 + 15 A>G is significantly associated with epilepsy susceptibility and drug resistance. However, GABRG2 588 C>T polymorphism was not found to be associated either with epilepsy susceptibility or with drug resistance. As different subunits of GABA receptors have differential role in epilepsy, the present study was designed to evaluate the association of GABAA receptor subunit subtypes; GABRA6 c. 1512 T>C (rs3219151), GABRB2 c. 1412 C>T (rs2229944), and GABRR2 c. IVS2 C>G (rs9362632) gene polymorphisms with epilepsy susceptibility and pharmacotherapy in north Indian epilepsy patients.
Section snippets
Study population
Epilepsy patients were enrolled from the outpatient department (OPD) of the Neurology attending the clinics of Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), and Chhatrapati Shahuji Maharaj Medical University (CSMMU), Lucknow, India. The patients were diagnosed and classified by experienced neurologists. The clinical profile of drug responsive and drug resistant epilepsy patients were based on hospital investigations. Exclusion criteria included severe adverse drug
Results
The mean age ± SD of patients with epilepsy was 24.25 ± 11.65. Among all the patients with epilepsy, 73.1% (293/401) were male and 26.9% (108/401) were female. Patients were also categorized on the basis of their drug response status. The mean age of the drug resistant patients was 23.61 ± 11.73 years versus drug responsive patients was 24.52 ± 11.31 years. Mean age of onset for seizures in drug resistant patients was 14.68 ± 10.24 years versus drug responsive patients was 17.09 ± 10.51 years. We were not able
Discussion
Alterations in GABAA receptor subtypes differing in subunit expression and composition in epilepsy are well documented in humans [18] and in animal models [19], [20], [21], [22], [23]. In the present study, we elucidated the association among potentially functional genetic variants of three different subunits of the GABAA receptors; GABRA6 c. 1512 T>C at 3′UTR region, GABRB2 c. 1412 C>T at exon 11, and an intronic GABRR2 c. IVS2 C>G gene polymorphism with disease susceptibility and drug
Acknowledgments
The study was supported by a grant received from the Department of Biotechnology (DBT) and fellowships provided by CSIR and DST, Government of India, New Delhi. We thankfully acknowledge support from Dr. NJ Gogtay, KEM hospital Mumbai, for drug level assays.
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GABRB2, a key player in neuropsychiatric disorders and beyond
2022, GeneCitation Excerpt :The disease can be caused by structural, neoplastic, autoimmune, and genetic causes where genetic factors contribute to the majority of epilepsies (Thomas and Berkovic, 2014). Association of a silent mutation of Ala 398 in GABRB2 with epilepsy susceptibility was reported in the North Indian population (p < 0.05; OR > 1.3) (Buckley et al., 2006; Kumari et al., 2011). However, another study that examined 279 prime candidate genes from European and Australian samples did not find any association between GABRB2 and epilepsy (Cavalleri et al., 2007).
GABRA1 and GABRA6 gene mutations in idiopathic generalized epilepsy patients
2021, SeizureCitation Excerpt :Similarly, a study conducted by Kumari et al. on 410 North Indian patients with epilepsy (73% male and 27% female; 40% are IGE patients) found that 1512C>T mutation in rs3219151 poses a major risk in the development of epilepsy. The global frequency distribution data showed that the frequency of the mutation in our study (0.53) is comparable to that of the European (0.64), Scottish (0.49), and Indian populations (0.44) [39]. This polymorphismwas also observed to be associated with disorders such as alcoholism, anxiety, and depression [40–42].
GABRG2 Deletion Linked to Genetic Epilepsy with Febrile Seizures Plus Affects the Expression of GABA<inf>A</inf> Receptor Subunits and Other Genes at Different Temperatures
2020, NeuroscienceCitation Excerpt :Sanger sequencing has identified a GABRB1 (c.860C>T) missense change (Lien et al., 2016) in an adult patient with refractory epilepsy and severe developmental delay. In the North Indian population, the GABRB2 c. 1412C>T polymorphism conferred a high susceptibility risk for epilepsy in its CT and TT genotypes and T allele variant (Kumari et al., 2011). Whole-exome sequencing revealed a de novo heterozygous missense variant in exon 4 of GABRB2 (c.236T>C; p.M79T) in a patient with epilepsy (Srivastava et al., 2014).
Association between GABA(A) receptor subunit polymorphisms and autism spectrum disorder (ASD)
2015, Psychiatry ResearchCitation Excerpt :Quantitative autoradiographic studies indicated a downregulation of GABAergic function in ASD patients with seizures (Blatt et al., 2001), and an animal model of autism has shown that both pre- and post-synaptic inhibitory transmission is impaired (Banerjee et al., 2013). Evidence for synergy between markers in GABA(A) receptor (GABAR) subunits β3 (chromosome 15) and δ (chromosome 1) has recently been reported suggesting gene–gene interaction across chromosomes associated with increased risk for autism (Sesarini et al., 2014), whereas polymorphisms in GABAR subunits have also been associated with epilepsy (Kumari et al., 2011). In the present study, we analyzed an expanded sample of Argentinean ASD patients and extended the study of polymorphisms in GABAR subunit genes, evaluating their contribution to ASD independently and/or through complex interactions between genes.
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2014, Handbook of Pharmacogenomics and Stratified Medicine