GABRB3 Research Articles

High Expression of GABAA Receptor β Subunit Genes Is Associated with Longer Overall Survival in Medulloblastoma.

Background/Objectives: Most of the rapid inhibitory neurotransmission in the brain is mediated through activation of the γ-aminobutyric acid (GABA) type A (GABAA) receptor, which is a ligand-gated ion channel. GABAA receptor activation via GABA binding allows for an intracellular influx of Cl- ions, thus inducing cellular hyperpolarization. Each GABAA receptor consists of a combination of five subunits, and several subunits have been proposed as biomarkers and therapeutic targets in cancer. Here, we show the expression of genes encoding β subunits of the GABAA receptor, namely GABRB1, GABRB2, and GABRB3, across the four different molecular subgroups of medulloblastoma (MB), which is the most common malignant pediatric brain tumor. We also show the associations of GABAA receptor β subunits with MB patients' overall survival (OS). Methods: The expression of genes encoding GABAA receptor β subunits was analyzed using a previously described dataset comprising 763 MB tumor samples. Patients were classified into high- and low-gene-expression groups, and the Kaplan-Meier estimate was used to examine the relationship between gene expression levels and patient OS. Results: High GABRB1 expression was associated with better OS within each of the four molecular subgroups. The GABRB2 gene showed higher transcript levels in Group 3 MB compared to all other subgroups, and high expression was associated with better prognosis in Group 3 tumors. GABRB3 expression was significantly higher in Group 3 and Group 4 MB, and high expression of GABRB3 genes was associated with longer OS in the sonic hedgehog (SHH) subgroup. The high expression of GABRB1, GABRB2, and GABRB3 is associated with longer patient OS in a subgroup-specific manner. Conclusions: These results indicate a role for GABAA receptors containing β subunits in influencing MB progression.

Influence of Chronic Social Stress on the Expression of Genes Associated with Neurotransmitter Systems in the Hypothalamus of Male Mice

Chronic social stress caused by repeated negative experiences in agonistic interactions induces depressive-like behavior in male mice. The aim of the study was to study changes in the expression of genes encoding proteins involved in the metabolism, reception, and transport of catecholamines, opioids, glutamate, and GABA under the influence of chronic stress. Hypothalamic samples were sequenced using RNA-Seq. It was shown that the expression of the catecholaminergic genes Adra1b, Adrbk1, Comtd1, Ppp1r1b, Sncb, Sncg, and Th in depressed animals is increased, while the expression of the Maoa and Maob genes is reduced. The expression of the opioidergic and cannabinoidergic genes Pdyn, Penk, Pomc, Pnoc, Ogfr, and Faah was upregulated, while that of the Oprk1, Opcml, Ogfrl1, and Cnr1 genes was downregulated. The expression of the glutamatergic genes Grik3, Grik4, Grik5, Grin1, Grm2, and Grm4 was increased, while the expression of the Gria3, Grik1, Grik2, Grin2a, Grin3a, Grm5, Grm8, and Gad2 genes was reduced. The expression of the GABAergic genes Gabre, Gabbr2, and Slc6a11 was higher, while the expression of the Gabra1, Gabra2, Gabra3, Gabrb2, Gabrb3, Gabrg1, Gabrg2, and Slc6a13 genes was lower in depressed animals. The data suggest that gene products that interact with other neurotransmitter systems (Th, Gad2, Gabra1, Gabrg2, Grin1, and Pdyn) may be of interest as potential targets for pharmacological correction of the consequences of social stress.

γ-Aminobutyric acid type A receptor β1 subunit gene polymorphisms are associated with the sedative and amnesic effects of midazolam

Midazolam is widely used for intravenous sedation. However, wide interindividual variability is seen in the sensitivity to midazolam. The association between genetic factors and interindividual differences in midazolam sensitivity remains unclear. The present study explored the association between common genetic variants and sedative and amnesic effects of midazolam. This prospective study included patients who were scheduled to undergo dental procedures under intravenous sedation. The sedative effect was evaluated using the Ramsay sedation scale 5 min after midazolam (0.05 mg/kg) administration. We employed two parallel approaches in this study: genome-wide approach and candidate gene approach. The γ-aminobutyric acid type A receptor subunit genes were selected as candidate genes. Multivariate linear regression analyses were performed to investigate the association between the Ramsay sedation scale and genetic variants. We also analyzed the association between the presence of anterograde amnesia and genetic variants using multivariate binominal logistic regression analyses. The analyses were adjusted for potential confounding factors. A total of 191 patients were included in the analyses. In the genome-wide association analyses, no significant association was found between the genetic variants and Ramsay scores. In the candidate gene analyses, the rs73247636 (dominant model: β = 0.72 [95% confidence interval, 0.34 to 1.10], P < 0.001) and rs56278524 (dominant model: β = 0.73 [0.37 to 1.10], P < 0.001) polymorphisms of the GABRB1 gene were significantly associated with Ramsay scores. Additionally, the rs73247636 (dominant model: odds ratio [OR] = 8.39 [2.36 to 29.85], P = 0.001) and rs56278524 (dominant model: OR = 15.26 [3.42 to 68.07], P < 0.001) polymorphisms were also significantly associated with the presence of anterograde amnesia. The rs73247636 and rs56278524 single-nucleotide polymorphisms of GABRB1 were associated with the sedative and amnesic effects of midazolam.

In silico analysis of missense SNPs in GABRA1, GABRB1, and GABRB3 genes associated with some diseases in neurodevelopmental disorders

BackgroundNeurodevelopmental disorders are disorders that are generally seen in the early developmental period of an individual's life and involve more than one disease that causes disruptions in the central nervous system. These disorders can be given as examples of diseases such as autism, mental retardation, some epileptic disorders, communication disorders, and mental retardation. The aim of this study is to determine the possible harmful effects of missense single nucleotide polymorphisms (SNPs) in the GABRA1, GABRB1, and GABRB3 genes, which are associated with neurodevelopmental disorders, on the structure and stabilization of the protein, using in silico methods. Software tools SIFT, PolyPhen-2 HumVar, PolyPhen-2 HumDiv, PROVEAN, SNAP2, PHD-SNP, SNP&GO, PANTHER, and Meta-SNP were used to predict harmful SNPs. I-Mutant and MUpro software tools were used to predict the effects of predicted harmful SNPs on protein stabilization. The STRING software tool was used for protein–protein interactions, the GeneMANIA software tool for gene–gene interactions, and the Project HOPE software tool for three-dimensional modeling examples.ResultsAs a result of the bioinformatics analysis, rs121434579, rs139163545, and rs267600530 in the GABRA1 gene; rs74608570, rs75612351, rs78815529 in the GABRB1 gene, and rs7819600779, rs1719850690, rs7819600779, rs171985060690, rs7819600779, rs1719850600779, rs149963014 in the GABRB3 gene were predicted as harmful SNPs.ConclusionsIn this study, protein structure, function, and stabilization of SNPs known to cause amino acid substitutions in GABRA1, GABRB1, and GABRB3 genes associated with some diseases in neurodevelopmental disorders were investigated using bioinformatics tools. As a result of the results obtained in our study, it is thought that it will benefit experimental studies and bioinformatics studies.

Correlations of receptor desensitization of gain-of-function GABRB3 variants with clinical severity.

Genetic variants associated with developmental and epileptic encephalopathies have been identified in the GABRB3 gene that encodes the β3 subunit of GABAA receptors. Typically, variants alter receptor sensitivity to GABA resulting in either gain- or loss-of-function, which correlates with patient phenotypes. However, it is unclear how another important receptor property, desensitization, contributes to the greater clinical severity of gain-of-function variants. Desensitization properties of 20 gain-of-function GABRB3 variant receptors were evaluated using two-electrode voltage-clamp electrophysiology. The parameters measured included current decay rates and steady-state currents. Selected variants with increased or reduced desensitization were also evaluated using whole-cell electrophysiology in transfected mammalian cell lines. Of the 20 gain-of-function variants assessed, 13 were found to alter receptor desensitization properties. Seven variants reduced desensitization at equilibrium, which acts to worsen gain-of-function traits. Six variants accelerated current decay kinetics, which limits gain-of-function traits. All affected patients displayed severe clinical phenotypes with intellectual disability and difficult-to-treat epilepsy. Nevertheless, variants that reduced desensitization at equilibrium were associated with more severe clinical outcomes. This included younger age of first seizure onset (median 0.5 months), movement disorders (dystonia and dyskinesia), epilepsy of infancy with migrating focal seizures (EIMFS) and risk of early mortality. Variants that accelerated current decay kinetics were associated with slightly milder phenotypes with later seizure onset (median 4 months), unclassifiable developmental and epileptic encephalopathies or Lennox-Gastaut syndrome and no movement disorders. Our study reveals that gain-of-function GABRB3 variants can increase or decrease receptor desensitization properties and that there is a correlation with the degree of disease severity. Variants that reduced the desensitization at equilibrium were clustered in the transmembrane regions that constitute the channel pore and correlated with greater disease severity, while variants that accelerated current decay were clustered in the coupling loops responsible for receptor activation and correlated with lesser severity.

Phenotypes and Clinical Genotypes of Bruxism Patients: A Systematic Review

Background. Bruxism is a phenomenon where psychological and exogenous biological factors act in greater percentage. Several genetic polymorphisms have been described in GABAA receptors, and some have been associated with motor limitations, such as the rs1805057 polymorphism of the GABRB1 gene (GABAA), which found a haplotype associated with a lower limitation in movement in acute pain processes. The aim to identify the clinical phenotypes in bruxism patients. Eligibility criteria were as follows: observational studies, case control studies, odds ratios, bruxism, patients, and a keyword search that included [[bruxism]], OR [[temporomandibular joint disorders]] OR [[sleep bruxism]], OR [[awake bruxism]], OR [[polymorphism]] or [[GABAA]], or [[serotonin]] , using the Boolean operators AND, OR and NOT. Were included 210 identified records in databases; 50 records from other sources; 117 records were deleted after determining they were duplicates; 42 studies were included in qualitative synthesis ; finally, who met inclusion requirements 5 studies were included in synthesis. The comparison of global DNA methylation profiles in patients with bruxism shows a possible genetic influence on their etiology, indicating that patients with HTR2A rs2770304 alleles are at increased risk. the HTR2A rs2770304 allele leads to an increased risk of bruxism.

Studies of Epileptic Encephalopathies with GABRB3 variant

Epilepsy has been accounting for a significant proportion of human population. Estimated 50 millions people or 4 out of 1000 population have been affected by the epilepsy. As one of the categories of epilepsy, Epileptic Encephalopathy has been affecting a certain portion of people, especially among children, from infant to the age of 16. It contributes to severe cognitive and behavioral impairments. In recent studies on the genetic cause of the epileptic encephalopathy, scientists have found the association with GABRB3 gene. This review article is going to introduce an overview of the properties and function of the GABRB3 gene, including the receptor it is located in. Then this article will introduce different types of epileptic encephalopathy, including dravet syndrome, west syndrome, Lennox-gastaut syndrome, and myoclonic astatic epilepsy. And then summarize recent research and studies of patients with different types of epileptic encephalopathy, including the conditions of seizure onset, types of seizure appeared, position of mutation, and the type of mutation.

Characterization of Different Subtypes of Immune Cell Infiltration in Glioblastoma to Aid Immunotherapy.

Glioblastoma multiforme (GBM) has been identified as a frequently occurring adult primary brain cancer that is highly aggressive. Currently, the prognostic outcome for GBM patients is dismal, even with intensive treatment, and the median overall survival (OS) is 14.6 months. Immunotherapy, which is specific at the cellular level and can generate persistent immunosurveillance, is now becoming a promising tool to treat diverse cancers. However, the complicated nature of the tumor microenvironment (TME) makes it challenging to develop anti-GBM immunotherapy because several cell types, cytokines, and signaling pathways are involved in generating the immunosuppressive environment. Novel immunotherapies can illustrate novel tumor-induced immunosuppressive mechanisms. Here, we used unsupervised clustering analysis to identify different subtypes of immune cell infiltration that actuated different prognoses, biological actions, and immunotherapy responses. Gene cluster A, with a hot immune cell infiltration phenotype, had high levels of immune-related genes (IRGs), which were associated with immune pathways including the interferon-gamma response and interferon-alpha response, and had low IDH1 and ATRX mutation frequencies. Gene cluster B, a cold immune cell infiltration subtype, exhibited a high expression of the KCNIP2, SCRT1, CPLX2, JPH3, UNC13A, GABRB3, ARPP21, DLGAP1, NRXN1, DLL3, CA10, MAP2, SEZ6L, GRIA2, and GRIA4 genes and a low expression of immune-related genes, i.e., low levels of immune reactivity. Our study highlighted the complex interplay between immune cell infiltration and genetic mutation in the establishment of the tumor immune phenotype. Gene cluster A was identified as an important subtype with a better prognosis and improved immunotherapy response.

GABRA1 and GABRB2 Polymorphisms are Associated with Propofol Susceptibility.

PurposeTo explore the effect of gene polymorphisms of propofol GABAA receptor and metabolic enzyme on drug susceptibility during the induction period of general anesthesia.Patients and MethodsA total of 294 female patients aged 18–55 years, ASA I–II, who underwent hysteroscopy with intravenous general anesthesia, were included in the study. Anesthesia was induced by continuous intravenous infusion of propofol at 40 mg·kg−1·h−1. Infusion of propofol was ended when both the Modified Observer’s Assessment of Awareness/Sedation scale (MOAA/S scale) decreased to 1 and the BIS index decreased to 60. The time when the MOAA/S scale decreased to 1 and the time when BIS index decreased to 60 was recorded to assess the susceptibility to the sedation effect. The maximum decreased percentage in mean arterial pressure (MAP) within 5 minutes was recorded to assess the susceptibility of cardiovascular response. Venous blood of each patient was collected to identify the presence of genetic variants in the GABRA1, GABRA2, GABRB2, GABRB3, GABRG2, CYP2B6, and UGT1A9 genes using the Sequenom MassARRAY® platform.ResultsAfter receiving propofol infusion, carriers of polymorphic GABRA1 rs4263535 G allele required significantly less time for BIS decreased to 60, while carriers of polymorphic GABRB2 rs3816596 T allele required significantly more time for BIS decreased to 60, carriers of polymorphic GABRA1 rs1157122 C allele and carriers of polymorphic GABRB2 rs76774144 T allele had a significantly less change in MAP.ConclusionGABRB2 rs3816596 and GABRA1 rs4263535 polymorphisms are associated with susceptibility to the sedation effect of propofol. GABRA1 rs1157122 and GABRB2 rs76774144 polymorphisms are associated with the degree of drop in blood pressure after propofol infusion.

GABRB2, a key player in neuropsychiatric disorders and beyond.

The GABA receptors represent the main inhibitory system in the central nervous system that ensure synaptogenesis, neurogenesis, and the regulation of neuronal plasticity and learning. GABAA receptors are pentameric in structure and belong to the Cys-loop superfamily. The GABRB2 gene, located on chromosome 5q34, encodes the β2 subunit that combines with the α and γ subunits to form the major subtype of GABAA receptors, which account for 43% of all GABAA receptors in the mammalian brain. Each subunit probably consists of an extracellular N-terminal domain, four membrane-spanning segments, a large intracellular loop between TM3 and TM4, and an extracellular C-terminal domain. Alternative splicing of the RNA transcript of the GABRB2 gene gives rise at least to four long and short isoforms with dissimilar electrophysiological properties. Furthermore, GABRB2 is imprinted and subjected to epigenetic regulation and positive selection. It has been associated with schizophrenia first in Han Chinese, and subsequently validated in other populations. Gabrb2 knockout mice also exhibited schizophrenia-like behavior and neuroinflammation that were ameliorated by the antipsychotic drug risperidone. GABRB2 was also associated with other neuropsychiatric disorders including bipolar disorder, epilepsy, autism spectrum disorder, Alzheimer's disease, frontotemporal dementia, substance dependence, depression, internet gaming disorder, and premenstrual dysphoric disorder. Recently, it has been postulated that GABRB2 might be a potential marker for different cancer types. As GABRB2 has a pivotal role in the central nervous system and is increasingly recognized to contribute to human diseases, further understanding of its structure and function may expedite the generation of new therapeutic approaches.

GABRB3 mutation as a cause of Ohtahara syndrome: A case report

Ohtahara syndrome (OS) is a rare early infantile epileptic encephalopathy that is characterized by an abnormal electroencephalogram (EEG) and intractable seizures. The patient of this reported case is a 4-month-old male infant delivered by cesarean section with an uneventful antenatal and neonatal period. At 2 months of age, he developed seizures that were refractory to anticonvulsants. Prolonged video EEG showed a characteristic suppression-burst pattern. We report an infant OS associated with heterozygous mutation in the GABRB3 gene.

The neuropathological findings of developmental and epileptic encephalopathy-43 (DEE43) and delineation of a the molecular spectrum of novel case

Developmental and epileptic encephalopathies (DEE) constitute an expanding group of severely disabling and, most frequently, drug-resistant disorders starting in the first year of life. Among them, there is DEE43, caused by dominant mutations in the GABRB3 gene. We present first neuropathological findings in a novel, molecularly confirmed case with the fatal course. The neuropathological analysis revealed co-existing developmental anomalies and retardation of myelination resulting from disturbed early brain growth as well as lesions caused by epileptic hypoxic-ischemic episodes. Developmental anomalies included misplaced neurons in the cerebellar white matter, heterotopic neurons in the cortical molecular layer and in the molecular layer of the hippocampal dentate gyrus, dysmorphic cerebellar dentate nuclei and inferior olivary nuclei in the medulla oblongata. The migrational and maturational disorders leading to the neuronal network dysfunction could be the cause of both the lack of development and the ineffectiveness of antiepileptic treatment in children affected by DEE. Giving the presented neuropathological description and based on the literature, we discuss the pathomechanism of the disease, to improve current understanding of both the lack of development and the ineffectiveness of treatment of affected children.

Clinical Attributes and Electroencephalogram Analysis of Patients With Varying Alpers' Syndrome Genotypes.

Alpers’ syndrome is an early inceptive neurodegenerative disorder with a poor prognosis, characterized by developmental regression, intractable epilepsy, and hepatic dysfunction. Candidate genes, such as POLG, PARS2, CARS2, FARS2, NARS2, and GABRB2 are distinguished and registered following research on large cohorts that portray the clinical phenotype in such patients using expanded access to whole-exome sequencing (WES). In this study, we aimed to better understand the electroencephalogram (EEG) characteristics and clinical phenotype of different genotypes of the Alpers’ syndrome, which are currently insufficiently studied. We conducted a study on seven patients with Alpers’ syndrome who received treatment in Beijing Children’s Hospital and had a detailed clinical EEG. Furthermore, a substantial literature search of the Chinese Biomedical Literature Database, PubMed, and Cochrane Central Register of Controlled Trials EMBASE was also conducted, which revealed a total of 22 reported cases between January 2008 to January 2021. We analyzed 29 cases of Alpers’ syndrome caused by different gene variants, of which 22 cases were related to POLG gene mutation and 7 cases were related to PARS2, CARS2, FARS2, NARS2, and GABRB2 gene mutation, and found that patients with distinctive pathogenic variants exhibited comparable phenotypes and similar EEG patterns. And we defined EEG characteristics found specifically in Alpers’ syndrome. Rhythmic high-amplitude delta with superimposed (poly) spikes (RHADS) is a characteristic EEG finding in the early stages of Alpers’ syndrome and is a kind of epileptic phenomenon, which can provide clues for the early diagnosis of the disease.

Effect of Valerian Extract on GABRB3 Gene MRNA Expression and Sedation in BALB/C Mice

Background: Valerian, also known as Setwall, Baldrianwurzel, or Phu is an herbaceous perennial plant from Europe and Asia, ubiquitously dispersed in almost all countries with a pH of 6-7. Valeriana officinalis is often used to treat sleep disorders, anxiety, fatigue, seizures, epilepsy, and depression as traditional medicine for 2000 years. The main constituent of Valeriana officinalis is Valerenic acid with hydroxyl and acetone group derivatives. Valerenic acid has anxiolytic, tranquilizing, and sleep-inducing effects that have been demonstrated in both animal studies and clinical trials. Valerenic acid inhibits catabolism-enzyme induced breakdown of Gamma-Aminobutyric Acid (GABA) in the brain resulting in sedation. Gamma-aminobutyric acid is the most important brain inhibitory neurotransmitter with key roles in the regulation and function of the central nervous system. The sedative effect of Valerian extract is facilitated by the GABAA receptor β3 subunit. GABRB3 gene is a ligand-gated ion channel that encodes the GABAA receptor β3 subunit. GABRB3 also functions as a receptor for diazepam and other anesthetic drugs (i.e. phenobarbital). Valerian influences the presynaptic component of GABA-ergic neurons that affect the release of synaptic GABA. Valerian also inhibits GABA reuptake and GABA catabolism by inhibiting the enzyme GABA transaminase. On that basis, this study aims to determine the effect of valerian extract on GABRB3 gene mRNA expression and sedative effect in BALB/c mice. Objective: This is an experimental study using an animal model, with a posttest-only control group design to determine the effect of Valerian extract on GABRB3 gene mRNA expression and sedative effect in BALB/c mice. Methods: Twenty selected BALB/c mice were randomly allocated into four groups; each group consisting of 5 mice. Group A (negative control) was given 5 ml of aqua dest (distilled water). Group B (positive control) was given 0.025 mg/10 g of diazepam. Group C (treatment group 1) was given 2.5 mg/10 g of Valerian extract, and group D (treatment group 2) was given 5 mg/10 g of Valerian extract. The drugs were administered for seven days through a gastric gavage. Rotarod test was performed on the seventh day. A blood sample of 1 ml was taken on the first day before drug administration and after the rotarod test on the seventh day to be analyzed using RT-PCR. Results: GABRB3 gene mRNA expression showed a significant increase in group B, C, and D (p &lt;0.0001). There was a significant difference between group C and D. The examination of motor coordination functions (Rotarod test) showed a significant difference (p&lt;0.05) between group A and group B, between group A and group C, and between group A and group D. There was no significant difference between group B and both group C and D. Conclusions: GABRB3 gene mRNA expression was increased significantly after the administration of Valerian extract. Based on the Rotarod test, Valerian extract and Diazepam had a clinically similar sedation effect. A higher dose of Valerian extract does not yield a higher level of GABRB3 gene mRNA expression nor sedative effects.

Relationship between GABRB2 gene polymorphisms and schizophrenia susceptibility: a case-control study and in silico analyses

Purpose Converging evidence has recently established the significance of γ-aminobutyric acid neurotransmitter (GABA) system in the development of schizophrenia (SCZ). We aimed to determine the association of two markers of the GABAA receptor β2 subunit gene (GABRB2), rs12187676 G/C and rs1816072 T/C, with the risk of SCZ in Iranian population. Materials and methods In this case-control study, 190 patients with SCZ and 200 healthy controls were recruited from December 2018 to February 2020. Genotyping was done using the Tetra-ARMS-PCR technique. In silico analyses were performed to determine the potential effects of the variants. Results The C allele and genotypes of codominant CC vs.TT and CT vs.TT, dominant TT vs. TC + CC, recessive TT + TC vs. CC of rs1816072 polymorphism, as well as codominant CC vs. GG and recessive GG + GC vs. CC genetic models of rs12187676 polymorphism were significantly associated with SCZ susceptibility. Compared to the TC/GC model, we have found that the TC/CC combination significantly increased the risk of SCZ by 4.32 fold while the TT/GG combination conferred a protective role against SCZ. Haplotypes analysis indicated that GABRB2 polymorphisms are in weak linkage disequilibrium with each other (LD = 0.1). However, bioinformatics analyses predicted that these polymorphisms do not have significant effects on the secondary structure and the splicing of GABRB2-mRNA. Conclusions We found that intronic GABRB2 polymorphisms were associated with SCZ risk in a sample of the Iranian population. These findings provided proof of concept for the involvement of the GABAergic neurotransmission system in SCZ development. These observations should be validated across other ethnicities and clinical subtypes.

Induced pluripotent stem cell reprogramming-associated methylation at the GABRA2 promoter and chr4p12 GABAA subunit gene expression in the context of alcohol use disorder.

Twin studies indicate that there is a significant genetic contribution to the risk of developing alcohol use disorder (AUD). With the exception of coding variants in ADH1B and ALDH2, little is known about the molecular effects of AUD-associated loci. We previously reported that the AUD-associated synonymous polymorphism rs279858 within the GABAA α2 receptor subunit gene, GABRA2, was associated with gene expression of the chr4p12 GABAA subunit gene cluster in induced pluripotent stem cell (iPSC)-derived neural cultures. Based on this and other studies that showed changes in GABRA2 DNA methylation associated with schizophrenia and aging, we examined methylation in GABRA2. Specifically, using 69 iPSC lines and neural cultures derived from 47 of them, we examined whether GABRA2 rs279858 genotype predicted methylation levels and whether methylation was related to GABAA receptor subunit gene expression. We found that the GABRA2 CpG island undergoes random stochastic methylation during reprogramming and that methylation is associated with decreased GABRA2 gene expression, an effect that extends to the GABRB1 gene over 600 kb distal to GABRA2. Further, we identified additive effects of GABRA2 CpG methylation and GABRA2 rs279858 genotype on expression of the GABRB1 subunit gene in iPSC-derived neural cultures.

Analysis of GABRB3 gene mRNA expression and motor coordination after administration of valerian extracts (Valeriana officinalis) in BALB/c mice

Background: Valeriana officinalis has often been used to treat sleep disorders as a traditional medicine for 2000 years. The sedative effect of valerian extract is facilitated by the GABAA receptor β3 subunit. The aim of this study is to determine the effect of valerian extract on GABRB3 gene mRNA expression and sedative effect in BALB/c mice. Methods: This is an experimental preclinical study using a posttest-only control group design. A total of 20 BALB/c mice were randomly allocated into four groups consisting of five mice each. Group I was given 5 ml of Aqua Dest (distilled water), group II was given 0.025 mg/10 g of diazepam, group III was given 2.5 mg/10 g of valerian extract, and group IV was given 5 mg/10 g of valerian extract. The drugs were administrated for seven days through a gastric gavage. The rotarod test was performed on the seventh day. A blood sample was taken on the first day before drug administration and after the rotarod test on the seventh day to be analyzed using quantitative real-time PCR. Results: GABRB3 gene mRNA expression showed a significant increase in groups II, III, and IV (p &lt;0.0001). There was significant difference between group III and IV. The examination of motor coordination (rotarod test) showed a significant difference (p &lt;0.05) between group I and group II, between group I and group III, and between group I and group IV. There was no significant difference between group II and both groups III and IV. Conclusions: GABRB3 gene mRNA expression was significantly increased after the administration of valerian extract. Based on the rotarod test, valerian extract and diazepam had a clinically similar sedation effect. A higher dose of valerian extract does not yield a higher level of GABRB3 gene mRNA expression nor sedative effects.

Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies.

Variants in the GABRB3 gene encoding the β3-subunit of the γ-aminobutyric acid type A ( receptor are associated with various developmental and epileptic encephalopathies. Typically, these variants cause a loss-of-function molecular phenotype whereby γ-aminobutyric acid has reduced inhibitory effectiveness leading to seizures. Drugs that potentiate inhibitory GABAergic activity, such as nitrazepam, phenobarbital or vigabatrin, are expected to compensate for this and thereby reduce seizure frequency. However, vigabatrin, a drug that inhibits γ-aminobutyric acid transaminase to increase tonic γ-aminobutyric acid currents, has mixed success in treating seizures in patients with GABRB3 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A GABRB3 variant that responds well to vigabatrin involves a truncation variant (p.Arg194*) resulting in a clear loss-of-function. We hypothesized that patients with a hypersensitive response to vigabatrin may exhibit a different γ-aminobutyric acid A receptor phenotype. To test this hypothesis, we evaluated the phenotype of de novo variants in GABRB3 (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the GABRB3 p.Glu77Lys and p.Thr287Ile variants into a concatenated synaptic and extrasynaptic γ-aminobutyric acid A receptor construct, to resemble the γ-aminobutyric acid A receptor expression by a patient heterozygous for the GABRB3 variant. The mRNA of these constructs was injected into Xenopus oocytes and activation properties of each receptor measured by two-electrode voltage clamp electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the GABRB3 p.Glu77Lys and p.Thr287Ile variants characterized by increased potency of γ-aminobutyric acid A without change to the estimated maximum open channel probability, deactivation kinetics or absolute currents. Modelling of the activation properties of the receptors indicated that either variant caused increased chloride flux in response to low concentrations of γ-aminobutyric acid that mediate tonic currents. We therefore propose that the hypersensitivity reaction to vigabatrin is a result of GABRB3 variants that exacerbate GABAergic tonic currents and caution is required when prescribing vigabatrin. In contrast, drug strategies increasing tonic currents in loss-of-function variants are likely to be a safe and effective therapy. This study demonstrates that functional genomics can explain beneficial and adverse anti-epileptic drug effects, and propose that vigabatrin should be considered in patients with clear loss-of-function GABRB3 variants.

Association analysis of single nucleotide polymorphisms in the promoter region of GAD1 and GABRB3 with schizophrenia in Chinese Han population

Association analysis of single nucleotide polymorphisms in the promoter region of GAD1 and GABRB3 with schizophrenia in Chinese Han population

Clinical features of epilepsies associated with GABRB2 variants

Objective: To analyze the clinical phenotypes of epilepsies in children with GABRB2 variants. Methods: Data of 8 epileptic patients with heterozygous GABRB2 variants were retrospectively collected at the Department of Pediatrics, Peking University First Hospital from April 2016 to December 2018. The clinical, electroencephalographic, neuroimaging characteristics, therapeutic and follow-up were analyzed. Results: Eight patients (4 boys, 4 girls) with heterozygous GABRB2 gene pathogenic variants were enrolled. Eight patients had different GABRB2 variants, among whom 2 patients inherited the variants from either parent, and the other 6 patients had de novo variants. Seven variants were novel. Ages at seizure onset ranged from 1 day to 22 months after birth, and the median age was 6 months. The seizure was first observed within one month of age in 2 patients, 1-6 months in 2 patients, 7-12 months in 2 patients, and beyond 1 year of age in 2 patients. Multiple seizure types were observed, including focal seizures in 6 patients, generalized tonic clonic seizures (GTCS) in 4 patients, myoclonic seizures in 3 patients, and epileptic spasm in 2 patients. Developmental delay was present in 6 patients. In 8 patients, Dravet syndrome was diagnosed in 3 patients, febrile seizures plus and West syndrome in 2 patients, respectively, Ohtahara syndrome in 1 patient. Six patients had epilepsy with fever sensitivity, and status epilepticus developed in all these patients. The ages at the last follow-up ranged from 8 months to 11 years, and the follow-up data showed that 5 patients were seizure-free, and 2 patients still had seizures, and 1 patient died of recurrent status epilepticus complicated with fungal infection. Conclusions: Epilepsies associated with GABRB2 variants were characterized by an onset in infancy, and the clinical features were heterogenous in seizure types and severities. Most patients had multiple seizures with fever sensitivity, and status epilepticus was common. Their seizures were easily induced by fever or infection. Additionally, the majority of the patients had varying degrees of developmental delay.