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Abstract Background Treatment failure following androgen deprivation therapy (ADT) presents a significant challenge in the management of advanced prostate cancer. Thus, understanding the genetic factors influencing this process could facilitate the development of personalized treatments and innovative therapeutic strategies. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in controlling cell growth and tumorigenesis. We hypothesized that genetic variants within this pathway may affect the clinical outcomes of patients undergoing ADT for prostate cancer. Methods We genotyped 399 single-nucleotide polymorphisms (SNPs) across 28 core PI3K/AKT pathway genes in a cohort of 630 patients with prostate cancer undergoing ADT. We assessed the potential association of the SNPs with patient survival. Functional analyses of the implicated genes were also performed to evaluate their effects on prostate cancer. Results After multivariate Cox regression analysis and multiple testing correction, GABRB3 rs12591845 exhibited the most significant association with both overall and cancer-specific survivals (P

Background: Treatment failure following androgen deprivation therapy (ADT) presents a significant challenge in the management of advanced prostate cancer. Thus, understanding the genetic factors influencing this process could facilitate the development of personalized treatments and innovative therapeutic strategies. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in controlling cell growth and tumorigenesis. We hypothesized that genetic variants within this pathway may affect the clinical outcomes of patients undergoing ADT for prostate cancer. Methods: We genotyped 399 single-nucleotide polymorphisms (SNPs) across 28 core PI3K/AKT pathway genes in a cohort of 630 patients with prostate cancer undergoing ADT. We assessed the potential association of the SNPs with patient survival. Functional analyses of the implicated genes were also performed to evaluate their effects on prostate cancer. Results: After multivariate Cox regression analysis and multiple testing correction, GABRB3 rs12591845 exhibited the most significant association with both overall and cancer-specific survivals (P < 0.003). A comprehensive pooled analysis of 16 independent gene expression datasets revealed elevated expression of GABRB3 in prostate cancer tissues compared to that in normal tissues (P < 0.001). Furthermore, gene set enrichment analysis unveiled differential enrichment of pathways such as myogenesis, interferon γ and α responses, and the MYC proto-oncogene pathway in tumors with elevated GABRB3 expression, implying a role for GABRB3 in prostate cancer. Conclusion: Our results suggest that rs12591845 could potentially serve as a valuable prognostic indicator for patients undergoing ADT. The potential role of GABRB3 in promoting prostate tumorigenesis is also highlighted. [ABSTRACT FROM AUTHOR]

Abstract Background Neurodevelopmental 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. Results As 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. Conclusions In 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.

Background: Neurodevelopmental 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. Results: As 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. Conclusions: In 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. [ABSTRACT FROM AUTHOR]

Lennox–Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants in GABRB3 that encodes the GABAA receptor (GABAAR) β3 subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluate Gabrb3+/N328D knock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressing Gabrb3 (c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigated Gabrb3+/N328D mice for features of LGS. In 2–4-month-old male and female C57BL/J6 wild-type and Gabrb3+/N328D mice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABAAR subunit expression by Western blot. Gabrb3+/N328D mice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover, Gabrb3+/N328D mice showed reduced β3 subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude that Gabrb3+/N328D mice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs. [ABSTRACT FROM AUTHOR]

Despite several efforts to identify the causes of autism spectrum disorders (ASD), its etiology remains still unclear. Among other aspects, genes that encode neurotransmitter receptors are strong candidates for autism. Here, we wanted to study some genetic variants of gamma-aminobutyric acid (GABA) receptor subunit genes GABRB3, GABRG3, and GABRA5, located on chromosome 15q11-q13 that might contribute to the etiology of ASD in the affected children of West Bengal. rs7180158, rs2081648 (GABRB3); rs12910555 (GABRG3); rs35399885, rs35832850 (GABRA5) were analyzed in 316 children with ASD and 227 healthy controls. Phenotypic associations were evaluated by Childhood Autism Rating Scale (CARS). Gene expression levels were measured by quantitative real-time PCR. ASD probands showed a higher frequency of "A" allele for rs7180158, "G" allele for rs12901555, and "T" allele for rs35399885. The GA + AA genotypes (rs7180158) and CT + TT genotypes (rs35399885) were found to confer significant risk towards ASD. rs2081648 was found to have transmission bias in the family. Additionally, these variants were found to be associated with one or more of ASD-associated phenotypic traits. Multifactor dimensionality reduction (MDR) analyses showed mostly independent contributory effects of some of the variants. Again, the gene expression levels of GABRB3, GABRG3, and GABRA5 were downregulated in the cases than the controls. ForGABRA5 rs35399885, the CC genotypes corresponded to higher expression levels compared to the other groups. This study reveals that genetic variants of GABAA receptor subunit genes are significantly associated with ASD. No data for the mentioned variants are found in the population of West Bengal, India. [ABSTRACT FROM AUTHOR]

Objective: Infantile spasms is an epileptic encephalopathy of childhood, and its pathophysiology is largely unknown. We generated a heterozygous knock‐in mouse with the human infantile spasms‐associated de novo mutation GABRB3 (c.A328G, p.N110D) to investigate its molecular mechanisms and to establish the Gabrb3+/N110D knock‐in mouse as a model of infantile spasms syndrome. Methods: We used electroencephalography (EEG) and video monitoring to characterize seizure types, and a suite of behavioral tests to identify neurological and behavioral impairment in Gabrb3+/N110D knock‐in mice. Miniature inhibitory postsynaptic currents (mIPSCs) were recorded from layer V/VI pyramidal neurons in somatosensory cortex, and extracellular multi‐unit recordings from the ventral basal nucleus of the thalamus in a horizontal thalamocortical slice were used to assess spontaneous thalamocortical oscillations. Results: The infantile spasms–associated human de novo mutation GABRB3 (c.A328G, p.N110D) caused epileptic spasms early in development and multiple seizure types in adult Gabrb3+/N110D knock‐in mice. Signs of neurological impairment, anxiety, hyperactivity, social impairment, and deficits in spatial learning and memory were also observed. Gabrb3+/N110D mice had reduced cortical mIPSCs and increased duration of spontaneous oscillatory firing in the somatosensory thalamocortical circuit. Significance: The Gabrb3+/N110D knock‐in mouse has epileptic spasms, seizures, and other neurological impairments that are consistent with infantile spasms syndrome in patients. Multiple seizure types and abnormal behaviors indicative of neurological impairment both early and late in development suggest that Gabrb3+/N110D mice can be used to study the pathophysiology of infantile spasms. Reduced cortical inhibition and increased duration of thalamocortical oscillatory firing suggest perturbations in thalamocortical circuits. [ABSTRACT FROM AUTHOR]

BackgroundDuplications of 15q11.2-q13.1 (Dup15q syndrome), including the paternally imprinted gene UBE3A and three nonimprinted gamma-aminobutyric acid type-A (GABAA) receptor genes, are highly penetrant for neurodevelopmental disorders such as autism spectrum disorder (ASD). To guide targeted treatments of Dup15q syndrome and other forms of ASD, biomarkers are needed that reflect molecular mechanisms of pathology. We recently described a beta EEG phenotype of Dup15q syndrome, but it remains unknown which specific genes drive this phenotype.MethodsTo test the hypothesis that UBE3A overexpression is not necessary for the beta EEG phenotype, we compared EEG from a reference cohort of children with Dup15q syndrome (n = 27) to (1) the pharmacological effects of the GABAA modulator midazolam (n = 12) on EEG from healthy adults, (2) EEG from typically developing (TD) children (n = 14), and (3) EEG from two children with duplications of paternal 15q (i.e., the UBE3A-silenced allele).ResultsPeak beta power was significantly increased in the reference cohort relative to TD controls. Midazolam administration recapitulated the beta EEG phenotype in healthy adults with a similar peak frequency in central channels (f = 23.0 Hz) as Dup15q syndrome (f = 23.1 Hz). Both paternal Dup15q syndrome cases displayed beta power comparable to the reference cohort.ConclusionsOur results suggest a critical role for GABAergic transmission in the Dup15q syndrome beta EEG phenotype, which cannot be explained by UBE3A dysfunction alone. If this mechanism is confirmed, the phenotype may be used as a marker of GABAergic pathology in clinical trials for Dup15q syndrome.

Lennox–Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants in GABRB3 that encodes the GABAA receptor (GABAAR) β3 subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluate Gabrb3+/N328D knock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressing Gabrb3 (c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigated Gabrb3+/N328D mice for features of LGS. In 2–4-month-old male and female C57BL/J6 wild-type and Gabrb3+/N328D mice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABAAR subunit expression by Western blot. Gabrb3+/N328D mice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover, Gabrb3+/N328D mice showed reduced β3 subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude that Gabrb3+/N328D mice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs.

Objective: This study aimed to comprehensively examine the genetic and phenotypic aspects of GABRB3-related epilepsy and to explore the potential prospects of personalized medicine. Methods: Genetic testing was conducted in all epilepsy patients without acquired factors for epilepsy. Through the collaboration of multicenter in China, we analyzed the genotype–phenotype correlation and antiepileptic therapy of 26 patients with GABRB3-related epilepsy. Results: Thirteen GABRB3 variants were novel, and 25 were de novo. The seizure onset age ranged from 1 to 21 months (median age 3.75 months). Seizure types predominated including focal seizures (92.3%), generalized tonic–clonic seizures (23.1%), and epileptic spasms (15.4%). Clinical features included cluster seizures (80.8%), fever sensitivity (53.8%), and developmental delay (96.2%). Neuroimaging was abnormal in 10 patients, including dysplasia of the cerebral cortex, dysplasia of the frontal and temporal cortex, delayed myelination, and corpus callosum dysplasia. Eleven patients were diagnosed with developmental and epileptic encephalopathy (DEE), four with West syndrome, three with epilepsy of infancy with migrating focal seizures (EIMFS), one with epilepsy with myoclonic-atonic seizures (EMAS), one with Dravet syndrome, and one with febrile seizures plus (FS+). Seizures were controlled in 57.7% of patients by valproate, levetiracetam, or perampanel in the majority. Conclusions: The clinical features of GABRB3-related epilepsy included seizure onset in early infancy, cluster seizures and fever sensitivity. Most patients manifest severe epilepsy phenotypes. Valproate, levetiracetam and perampanel seem to have positive effects on seizure control for patients with GABRB3 variants. [ABSTRACT FROM AUTHOR]

Guangtao Sun,1,* Xunzhong Qi,1,* Wei Wang,1,* Xintong Li,1,* Chunhua Luo,2,* Sunjie Bai,3 Shaohua Xu,2 Xiaogang Zhong,4 Chenglong Huang,5 Xiaofeng Zhu,6 Zuoyi Huang1 1Department of Neurology, The First Affiliated Hospital of Jiamusi University, Jiamusi, People’s Republic of China; 2Department of Laboratory Medicine, Yichang Central People’s Hospital, The First College of Clinical Medical Science, Three Gorges University, Hubei, People’s Republic of China; 3Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Key Laboratory of Psychoseomadsy, Stomatological Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 5Department of Laboratory Medicine, University-Town Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 6Mudanjiang Medical College, Mudanjiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zuoyi Huang Email huangzuoyi_jms@163.comIntroduction: Prefrontal cortex (PFC) and striatal neurotransmitter homeostasis is affected by alcohol dependence. In this study, the microarray dataset from the Gene Expression Omnibus (GEO) database were downloaded. The prefrontal and striatum data were cross-analyzed to reveal the co-effects of alcohol dependence on the two brain regions of mice.Methods: The GSE123114 microarray profile was downloaded from the GEO database, and differentially expressed genes (DEGs) between the two groups were acquired by GEO2R. KEGG analyses were performed to identify the pivotal pathways of these DEGs. Key differential gene expressions and their mechanism associated with alcohol exposure were investigated by an intraperitoneal alcohol model.Results: A total of 13 overlapping DEGs from the PFC and striatal datasets of the GSE123114 microarray profile were identified, and they were significantly enriched in the morphine addiction pathway. The transcript levels and protein expression of Gabrb3 were consistent with the microarray data both in the PFC and striatum. The transcript levels of HMGB1, TLR4, TNFα and IL-1β were upregulated in the PFC and striatum of mice in the alcohol group. The HMGB1 inhibitor decreased Gabrb3 transcript and protein levels as well as TNFα and IL-1β transcript levels both in the PFC and striatum in the intraperitoneal alcohol model mice.Discussion: Through the reanalysis of GSE123114 microarray profile, we found that Gabrb3 is a key gene associated with alcohol exposure. In further experiments, our findings suggest that alcohol exposure modulates Gabrb3 expression through the HMGB1/TLR4 pathway. Moreover, inflammation-associated factors, such as IL-1β and TNFα, may be related to the HMGB1/TLR4-mediated regulation of GABRB3 expression in alcohol exposure.Keywords: alcohol exposure, prefrontal cortex, striatum, Gabrb3, HMGB1/TLR4 pathway

In this pilot study, we aim to identify the role of few genetic variants of GABA-receptor type A subunits GABRB3 (rs4906902, rs7171660), GABRG3 (rs208129, rs140679), GABRA5 (rs 140681) in the aetiology of autism spectrum disorders in a population of West Bengal. 192 ASD probands, their parents and 184 ethnically-matched healthy controls were recruited for the study. The rs4906902G and the rs140679T conferred significant risk towards ASD. rs7171660 and rs140679 had transmission bias in the family. Neither alleles of rs 208129 and rs 140681 showed significant over-representation in either groups. All these variants were associated with at least one deficit in ASD-associated phenotypes like 'relating to people', 'Imitation', 'emotional response', 'body use', 'taste, smell, touch response' and 'activity levels'. [ABSTRACT FROM AUTHOR]

Epiberberine (EPI) is one of the most important bioalkaloid found in the rhizome of Coptis chinensis , which has been observed to exhibit pharmaceutical effects against gastric cancer (GC). Nevertheless, the potential mechanism of EPI against GC cells still remains unclear. This study aimed to identify the core receptor on GC cells through which EPI inhibited the growth of GC cells and to explore the underlying inhibitory mechanisms. To identify hub receptor targets that respond to EPI treatment, RNA sequencing (RNA-Seq) data from a tumor-bearing mouse model were analyzed using bioinformatics method and molecular docking. The binding interaction between EPI and GABRB3 was validated through western blotting based-cellular thermal shift assay (WB-CETSA). To further verify the binding region between EPI and GABRB3 through circular dichroism (CD) chromatography, fragments of the extracellular and transmembrane domains of the GABRB3 protein were expressed and purified in vitro. Stable cell lines with the overexpression or knockdown of GABRB3 were established using the recombinant lentivirus system. MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide)) assay, colony formation assay, invasion and migration experiments, and flow cytometry were conducted to validate the inhibitory effect of EPI on the GC cells via GABRB3. Additionally, western blotting was utilized to explore the potential inhibitory mechanisms. Through the combination of multiple bioinformatics methods and molecular docking, we found that the γ-aminobutyric acid type A receptor subunit -β3 (GABRB3) might be the critical receptor target in response to EPI treatment. The results of WB-CETSA analysis indicated that EPI significantly promoted the thermostability of the GABRB3 protein. Importantly, EPI could directly bind to GABRB3 and alter the secondary structure of GABRB3 fragments similar to the natural agonist, γ-aminobutyric acid (GABA). The EPI-induced suppression of the malignant phenotype of GC cells was dependent on the presence of GABRB3. GABRB3 expression was positively correlated with TP53 in patients with GC. The binding of EPI to GABRB3 stimulated p53 accumulation in GC cells. This activated the p21/CDK1/cyclinB1 pathway, resulting in G2/M cell cycle arrest, and induced the Bcl-2/BAX/Caspase axis-dependent cell apoptosis. This study revealed the target receptor for EPI in GC cells and provided new insights into its anticancer mechanisms. [ABSTRACT FROM AUTHOR]

One of the main theories accounting for the underlying pathophysiology of schizophrenia posits alterations in GABAergic neurotransmission. While previous gene expression studies of postmortem brain samples typically report the down-regulation of GABA related genes in schizophrenia, the results are often inconsistent and not uniform across studies. We performed a systematic gene expression analysis of 22 GABA related genes in postmortem superior temporal gyrus (STG) samples of 19 elderly subjects with schizophrenia (mean age: 77) and 14 matched controls from the Icahn school of Medicine at Mount Sinai (MSSM) cohort. To test the validity and robustness of the resulting differentially expressed genes, we then conducted a meta-analysis of the MSSM and an independent dataset from the Stanley Consortium of 14 STG samples of relatively young subjects with schizophrenia (mean age: 44) and 15 matched controls. For the first time, the findings showed the down-regulation of three GABA-receptor subunits of type A, GABRA1, GABRA2 and GABRB3, in the STG samples of subjects with schizophrenia, in both the elderly and the relatively young patients. These findings, as well as previous results, lend weight to the notion of a common upstream pathology that alters GABAergic neurotransmission in schizophrenia. GABRA1, GABRA2 and GABRB3 down-regulation may contribute to the pathophysiology and clinical manifestations of schizophrenia through altered oscillation synchronization in the STG. [ABSTRACT FROM AUTHOR]

Mutations in GABAA-receptor subunit genes are associated with a heterogeneous spectrum of epilepsies. Patients with epilepsy caused by mutations in a specific GABAA-receptor (GABRA3) occasionally present with orofacial dysmorphism (e.g., cleft palates). While cleft palates have been described in Gabrb3 knockout mice and in humans with GABRB3 variants without epilepsy, the specific combination of epilepsy and cleft palate in humans with GABRB3 mutations has not yet been reported. We describe a patient with epileptic encephalopathy (EE) who presented with therapy-refractory neonatal-onset myoclonic seizures and severe developmental delay. Electroencephalogram showed burst suppression pattern at neonatal age and hypsarrhythmia at infantile age. Initial magnetic resonance imaging was unremarkable. As he additionally presented with a cleft palate, we were curious whether cleft palate and EE had the same genetic origin. Whole exome sequencing of the index patient revealed a novel pathogenic heterozygous de novo mutation in GABRB3 (c.899T > C; p.I300T). In consistency with Gabrb3 knockout mice data, this is the first report of cleft palate in a patient with GABRB3 associated EE. We suggest to add cleft palate to the phenotypic GABRB3 spectrum and to screen for mutations in GABAA-receptors in patients with EE and orofacial dysmorphism. [ABSTRACT FROM AUTHOR]

Reduced ocular pigmentation is common in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) and is long thought to be caused by OCA2 deletion. GABRB3 is located in the 15q11-13 region flanked by UBE3A, GABRA5, GABRG3, and OCA2. Mutations in GABRB3 have frequently been associated with epilepsy and autism, consistent with its role in neurodevelopment. We report here a robust phenotype in the mouse in which deletion of Gabrb3 alone causes nearly complete loss of retinal pigmentation due to atrophied melanosomes, as evidenced by electron microscopy. Using exome and RNA sequencing, we confirmed that only the Gabrb3 gene was disrupted while the Oca2 gene was intact. However, mRNA abundance of Oca2 and other genes adjacent to Gabrb3 is substantially reduced in Gabrb3−/− mice, suggesting complex transcriptional regulation in this region. These results suggest that impairment in GABRB3 downregulates OCA2 and indirectly causes ocular hypopigmentation and visual defects in AS and PWS.

GABAA receptors are ligand-gated anion channels that are important regulators of neuronal inhibition. Mutations in several genes encoding receptor subunits have been identified in patients with various types of epilepsy, ranging from mild febrile seizures to severe epileptic encephalopathy. Using whole-genome sequencing, we identified a novel de novo missense variant in GABRA5 (c.880G > C, p.V294L) in a patient with severe early-onset epilepsy and developmental delay. Targeted resequencing of 279 additional epilepsy patients identified 19 rare variants from nine GABAA receptor genes, including a novel de novo missense variant in GABRA2 (c.875C > A, p.T292K) and a recurrent missense variant in GABRB3 (c.902C > T, p.P301L). Patients with the GABRA2 and GABRB3 variants also presented with severe epilepsy and developmental delay. We evaluated the effects of the GABRA5, GABRA2 and GABRB3 missense variants on receptor function using whole-cell patch-clamp recordings from human embryonic kidney 293T cells expressing appropriate α, β and γ subunits. The GABRA5 p.V294L variant produced receptors that were 10-times more sensitive to GABA but had reduced maximal GABA-evoked current due to increased receptor desensitization. The GABRA2 p.T292K variant reduced channel expression and produced mutant channels that were tonically open, even in the absence of GABA. Receptors containing the GABRB3 p.P301L variant were less sensitive to GABA and produced less GABA-evoked current. These results provide the first functional evidence that de novo variants in the GABRA5 and GABRA2 genes contribute to early-onset epilepsy and developmental delay, and demonstrate that epilepsy can result from reduced neuronal inhibition via a wide range of alterations in GABAA receptor function. [ABSTRACT FROM AUTHOR]

Several lines of evidence have suggested that the GABA receptor subunit β3 (GABRB3) gene is a genetic contributor in the autism spectrum disorder (ASD). The aberrant expression of GABRB3 is reported in ASD patients which may be a consequence of the presence of certain genetic variants in the promoter region of the gene. The associations between single-nucleotide polymorphisms (SNPs) within this gene and ASD have been analyzed in previous studies. However, the results are conflicting. In the present study, we performed a meta-analysis on association between two SNPs located in the promoter region of GABRB3 gene (rs4906902 and rs20317) and ASD. The literature search was performed based on criteria provided by the meta-analysis of observational studies in epidemiology (MOOSE). The association between mentioned SNPs and ASD was calculated using pooled odd ratios (ORs) and 95% confidence intervals. The result of the present meta-analysis indicates that neither rs4906902 nor rs20317 are significantly associated with the risk of ASD. The underlying mechanism of the aberrant expression of GABRB3 gene in ASD patients should be investigated in other biological levels. [ABSTRACT FROM AUTHOR]

Background Recently, a study providing insight into GABRB3 mutational spectrum was published (Møller et al 2017). The authors report considerable pleiotropy even for single mutations and were not able to identify any genotype-phenotype correlations. Methods The proband (twin B) was referred for massively parallel sequencing of epilepsy-related gene panel because of hypotonia and neonatal seizures. The revealed variant was confirmed with Sanger sequencing in the proband and the twin A, and both parents were tested for the presence of the variant. Results We report a case of epilepsy of infancy with migrating focal seizures (EIMFS) of neonatal onset inmonozygotic twinswith a de novo novel GABRB3 variant p.Thr281Ala. The variant has a uniform presentation on an identical genomic background. In addition, early seizure-onset epilepsy associated with GABRB3 mutation has been until now described only for the p.Leu256Gln variant in the GABRB3 (Møller et al 2017, Myers et al 2016) located in the transmembrane domain just as the p.Thr281Ala variant described here. Conclusion De novo GABRB3 mutations may cause neonatal-onset EIMFS with earlyonset hypotonia, respiratory distress, and severe developmental delay. [ABSTRACT FROM AUTHOR]

Objective Several previous linkage and association studies and an expression analysis have suggested the gamma-aminobutyric acid type A receptor beta3 subunit ( GABRB3 ) gene as an important candidate gene for autism. In addition, polymorphisms in the promoter region of GABRB3 might modulate the expression of this gene. In order to investigate the underlying mechanism of the role of GABRB3 in autism susceptibility, we designed a case-control study to analyze the association of the rs4906902 single nucleotide polymorphism (SNP) in the promoter region of the GABRB3 gene with autism spectrum disorder (ASD) in Iranian patients. Materials & methods The rs4906902 polymorphism was genotyped using the polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) technique. The frequency of the risk allele and its association with disease was examined in 518 patients and 472 control individuals. Result The results demonstrated that the genotype frequencies were in Hardy-Weinberg equilibrium in both the case and the control groups. The results shown that neither allelic frequencies nor genotypic distribution of the rs4906902 was significantly different between autism patients and healthy controls. In conclusion It seems that the GABRB3 gene may influence the Autism susceptibility via a different SNPs in this gene. Also, another independent mechanisms like epigenetic effects should not be ignored when we want to explore the link between GABRB3 and ASD. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore whether schizophrenia occurrence is associated with polymorphisms in the 5′ regulatory region of GABRB3 (gamma-aminobutyric acid type A receptor beta 3, subunit gene). The study included 324 patients with schizophrenia and 327 unaffected participants; all individuals were northern Han Chinese. Genotype and haplotype frequency distributions were compared for the 2 groups by means of PCR amplification and direct sequencing of the promoter region of GABRB3. The genotype distribution among control participants was in accordance with the Hardy-Weinberg equilibrium. Five common single-nucleotide polymorphism (SNP) sites were detected in the 5′ promoter region of GABRB3: rs4243768, rs7171660, rs4363842, rs4906902, and rs8179184. Only rs8179184 and rs4906902 differed significantly in frequency between controls and cases ( P < 0.05); this difference remained significant when only women in each group were compared. The 2 SNP sites showed linkage disequilibrium, resulting in 2 haplotypes: T-G and C-A. The frequency of C-A was significantly higher among patients with schizophrenia than among controls. Our findings suggest that rs4906902 and rs8179184 in the 5′ promoter region of GABRB3 are associated with schizophrenia. The C-A haplotype may entail an increased risk of schizophrenia, and the onset of schizophrenia may be gender-specific. [ABSTRACT FROM AUTHOR]

• GABRG3 gene rs140679 polymorphism is important risk factor in the pathophysiology of ASD. • There is role of the HTR2A gene rs6313 variant C allele in the pathophysiology of ASD. • GABRG3 gene rs140679 polymorphism was researched for the first time in a Turkish population. Autism spectrum disorder (ASD) is a neurodevelopmental and neurobehavioral disorder characterized by impaired social communication, repetitive and restricted patterns of behavior, activity, or interest, and altered emotional processing. Reported prevalence is 4 times higher in men and it has increased in recent years. Immunological, environmental, epigenetic, and genetic factors play a role in the pathophysiology of autism. Many neurochemical pathways and neuroanatomical events are effective in determining the disease. It is still unclear how the main symptoms of autism occur because of this complex and heterogeneous situation. In this study, we focused on gamma amino butyric acid (GABA) and serotonin, which are thought to contribute to the etiology of autism; it is aimed to elucidate the mechanism of the disease by investigating variant changes in the GABA receptor subunit genes GABRB3, GABRG3 and the HTR2A gene, which encodes one of the serotonin receptors. 200 patients with ASD between the ages of 3–9 and 100 healthy volunteers were included in the study. Genomic DNA isolation was performed from peripheral blood samples taken from volunteers. Genotyping was performed using the RFLP method with PCR specific for specific variants. Data were analyzed with SPSS v25.0 program. According to the data obtained in our study; In terms of HTR2A (rs6313 T102C) genotypes, the homozygous C genotype carrying frequency in the patient group and the homozygous T genotype carrying frequency in the GABRG3 (rs140679 C/T) genotypes were found to be significantly higher in the patient group compared to the control group (*p: 0.0001, p: 0.0001). It was determined that the frequency of individuals with homozygous genotype was significantly higher in the patient group compared to the control group and having homozygous genotypes increased the disease risk approximately 1.8 times. In terms of GABRB3 (rs2081648 T/C) genotypes, it was determined that there was no statistically significant difference in the frequency of carrying homozygous C genotype in the patient group compared to the control group (p: 0.36). According to the results of our study, we think that the HTR2A (rs6313 T102C) polymorphism is effective in modulating the empathic and autistic characteristics of individuals, and that the HTR2A (rs6313 T102C) polymorphism is more distributed in the post-synaptic membranes in individuals with a higher number of C alleles. We believe that this situation can be attributed to the spontaneous stimulatory distribution of the HTR2A gene in the postsynaptic membranes because of T102C transformation. In genetically based autism cases, carrying the point mutation in the rs6313 variant of the HTR2A gene and the C allele and the point mutation in the rs140679 variant of the GABRG3 gene and accordingly carrying the T allele provide a predisposition to the disease. [ABSTRACT FROM AUTHOR]

Dravet syndrome is a rare and severe type of epilepsy in infants. Approximately, 70-80% of patients with Dravet syndrome have mutations in SCN1A, the gene encoding the alpha-1 subunit of the sodium channel, while some simplex patients have variants in one of several other genes, including but not limited to GABRA1, SCN2A, STXBP1, GABRG2, and SCN1B. In this study, we performed exome sequencing in six patients with SCN1A-negative Dravet syndrome to identify other genes related to this disorder. In one affected individual, we detected a novel de novo heterozygous missense variant, c.695G>A, p.(Arg232Gln), in GABRB3, the gene encoding the β3-subunit of the gamma-aminobutyric acid type A (GABAA) receptor, which mediates inhibitory signaling within the central nervous system. In summary, the data in this study identify GABRB3 as a candidate gene for Dravet syndrome. [ABSTRACT FROM AUTHOR]

Dysfunction of gamma-aminobutyric acid (GABA)ergic circuits is strongly associated with neurodevelopmental disorders. However, it is unclear how genetic predispositions impact circuit assembly. Using in vivo two-photon and widefield calcium imaging in developing mice, we show that Gabrb3 , a gene strongly associated with autism spectrum disorder (ASD) and Angelman syndrome (AS), is enriched in contralaterally projecting pyramidal neurons and is required for inhibitory function. We report that Gabrb3 ablation leads to a developmental decrease in GABAergic synapses, increased local network synchrony, and long-lasting enhancement in functional connectivity of contralateral—but not ipsilateral—pyramidal neuron subtypes. In addition, Gabrb3 deletion leads to increased cortical response to tactile stimulation at neonatal stages. Using human transcriptomics and neuroimaging datasets from ASD subjects, we show that the spatial distribution of GABRB3 expression correlates with atypical connectivity in these subjects. Our studies reveal a requirement for Gabrb3 during the emergence of interhemispheric circuits for sensory processing. [Display omitted] • Gabrb3 is necessary for cortical network desynchronization in murine S1 • GABAergic disruption results in enhanced contralateral, but not ipsilateral, connectivity • Gabrb3 ablation leads to increased whisker-dependent responses during mouse development • Spatial pattern of human GABRB3 expression correlates with atypical connectivity in ASD Babij, Ferrer, et al. use mouse genetics and in vivo imaging to show that Gabrb3 is required for the developmental decorrelation of cortical networks. Gabrb3 removal leads to enhanced contralateral connectivity and hypersensitivity to tactile stimuli. In addition, GABRB3 expression is spatially correlated with atypical connectivity in ASD human subjects. [ABSTRACT FROM AUTHOR]

Objective: Infantile spasms is an epileptic encephalopathy of childhood, and its pathophysiology is largely unknown. We generated a heterozygous knock-in mouse with the human infantile spasms-associated de novo mutation GABRB3 (c.A328G, p.N110D) to investigate its molecular mechanisms and to establish the Gabrb3 +/N110D knock-in mouse as a model of infantile spasms syndrome., Methods: We used electroencephalography (EEG) and video monitoring to characterize seizure types, and a suite of behavioral tests to identify neurological and behavioral impairment in Gabrb3 +/N110D knock-in mice. Miniature inhibitory postsynaptic currents (mIPSCs) were recorded from layer V/VI pyramidal neurons in somatosensory cortex, and extracellular multi-unit recordings from the ventral basal nucleus of the thalamus in a horizontal thalamocortical slice were used to assess spontaneous thalamocortical oscillations., Results: The infantile spasms-associated human de novo mutation GABRB3 (c.A328G, p.N110D) caused epileptic spasms early in development and multiple seizure types in adult Gabrb3 +/N110D knock-in mice. Signs of neurological impairment, anxiety, hyperactivity, social impairment, and deficits in spatial learning and memory were also observed. Gabrb3 +/N110D mice had reduced cortical mIPSCs and increased duration of spontaneous oscillatory firing in the somatosensory thalamocortical circuit., Significance: The Gabrb3 +/N110D knock-in mouse has epileptic spasms, seizures, and other neurological impairments that are consistent with infantile spasms syndrome in patients. Multiple seizure types and abnormal behaviors indicative of neurological impairment both early and late in development suggest that Gabrb3 +/N110D mice can be used to study the pathophysiology of infantile spasms. Reduced cortical inhibition and increased duration of thalamocortical oscillatory firing suggest perturbations in thalamocortical circuits., (© 2022 International League Against Epilepsy.)

Summary Reduced ocular pigmentation is common in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) and is long thought to be caused by OCA2 deletion. GABRB3 is located in the 15q11-13 region flanked by UBE3A , GABRA5 , GABRG3 , and OCA2 . Mutations in GABRB3 have frequently been associated with epilepsy and autism, consistent with its role in neurodevelopment. We report here a robust phenotype in the mouse in which deletion of Gabrb3 alone causes nearly complete loss of retinal pigmentation due to atrophied melanosomes, as evidenced by electron microscopy. Using exome and RNA sequencing, we confirmed that only the Gabrb3 gene was disrupted while the Oca2 gene was intact. However, mRNA abundance of Oca2 and other genes adjacent to Gabrb3 is substantially reduced in Gabrb3 −/− mice, suggesting complex transcriptional regulation in this region. These results suggest that impairment in GABRB3 downregulates OCA2 and indirectly causes ocular hypopigmentation and visual defects in AS and PWS. [ABSTRACT FROM AUTHOR]

Copy number variations encompassing the chromosome 15q11-q13 region have been implicated in the pathogenesis of several neurodevelopmental disorders including schizophrenia. The study aimed to investigate whether the GABRB3 gene mapped to 15q12 was associated with schizophrenia.We resequenced the promoter and all the exonic regions of the GABRB3 gene in 349 patients with schizophrenia and 386 control participants from Taiwan using the Sanger sequencing method. We also used a reporter gene assay to assess the functional impact of variants identified from the promoter region.We identified a total of six common single nucleotide polymorphisms and eight rare variants in this sample. No genetic association of these common single nucleotide polymorphisms with schizophrenia was detected. A missense mutation Y402H at exon 9 was detected in two patients and two controls. Polyphen-2 predicted that the impact of this variant was benign. In addition, we identified two patient-specific variants at the promoter of GABRB3 that showed significantly increased promoter activity in a reporter gene assay.The identification of two private patient-only variants at the promoter region with enhanced promoter activity supports the rare allele hypothesis of schizophrenia and suggests that increased GABRB3 expression may confer an increased risk of schizophrenia. [ABSTRACT FROM AUTHOR]

Background GABRB3 is a position candidate gene at chromosome 15q12 that has been implicated in the neurobiology of autism spectrum disorders (ASD). The aim of this study was to examine the genetic association of GABRB3 with ASD. Methods The sample consisted of 356 patients with clinical diagnosis of ASD according to the DSMIV diagnostic criteria and confirmed by the Autism Diagnostic Interview-Revised and 386 unrelated controls. We searched for mutations at all the exonic regions and 1.6 Kb of the 5' region of GABRB3 in the genomic DNA of all the participants using the Sanger sequencing. We implemented a case-control association analysis of variants detected in this sample, and conducted a reporter gene assay to assess the functional impact of variants at the 5' regulatory region. Results We detected six known common SNPs; however, they were not associated with ASD. Besides, a total of 22 rare variants (12 at 5' regulatory, 4 at intronic, and 6 at exonic regions) were detected in 18 patients and 6 controls. The frequency of rare variants was significantly higher in the patient group than in the control group (18/356 versus 6/386, odds ratio = 3.37, P = 0.007). All the 12 rare variants at the 5' regulatory region were only detected in 7 patients, but not in any of the controls (7/356 versus 0/386, Fisher's exact test, P = 0.006). Two patients carried multiple rare variants. Family studies showed that most of these rare variants were transmitted from their parents. Reporter gene assays revealed that four rare variants at the 5' regulatory region and 1 at exon 1a untranslated region had elevated reporter gene activities compared to two wild type alleles. Conclusions Our data suggest rare variants of GABRB3 might be associated with ASD, and increased GABRB3 expression may contribute to the pathogenesis of ASD in some patients. Trial registration Clinical trial registration: Identifier: NCT00494754 [ABSTRACT FROM AUTHOR]

Abstract: Recently, microsatellite polymorphisms have been reported to be associated with four genes, GABRB3, MAOB, PAH, and SLC6A4, and their relationships have been tested to five symptom factors: hallucinations, delusions, negative symptoms, mania, and depression. These factors were frequently present in schizophrenia spectrum disorders in the Irish Study of High Density Schizophrenia Families (ISHDSF) with a proband with the diagnosis of schizophrenia (Bergen et al., 2009). Of these, GABRB3 and PAH were reported to be significantly associated with hallucinations and delusions in a 90-family subset of the ISHDSF, respectively. In this study, we tested the association of genetic markers from these four gene regions with the approximate five clinical symptoms, based upon 256 schizophrenia patients, with genotypic data obtained by higher resolution single nucleotide polymorphism (SNP) genotyping. We found one GABRB3 SNP (rs1426891, 70.8kb downstream of this gene) and haplotype constructed by three SNPs (rs1426891, rs2912602, and rs2912600) were significantly associated with hallucinations in Caucasians after Bonferroni correction for multiple testing (Bonferroni corrected P: 0.032 and 0.016, respectively). Additionally, we found one haplotype constructed by two SNPs, rs5905587–rs37615860, in MAOB/NDP gene region was significantly associated with delusions in all samples tested (Bonferroni corrected P: 0.048). These results provide additional evidence that GABRB3 and MAOB/NDP gene regions might constitute risk factors for hallucinations and delusions in schizophrenia. [Copyright &y& Elsevier]

Abstract: Autism spectrum disorder (ASD) is diagnosed based on three core features: impaired social interactions, deficits in communication and repetitive or restricted behavioral patterns. Against this backdrop, abnormal sensory processing receives little attention despite its prevalence and the impact it exerts on the core diagnostic features. Understanding the source of these sensory abnormalities is paramount to developing intervention strategies aimed at maximizing the coping ability of those with ASD. Consequently, we chose to examine whether sensory abnormalities were present in mice heterozygous for the Gabrb3 gene, a gene strongly associated with ASD. Mice were assessed for tactile and heat sensitivity, sensorimotor competence (accelerating rotarod task) and sensorimotor gating by prepulse inhibition of the acoustic startle reflex (PPI). All heterozygotes exhibited an increase in seizure susceptibility and similar reductions in Gabrb3 expression in the dorsal root ganglia, spinal cord, whole brain and amygdala. Interestingly, significant differences were noted between heterozygous variants in regards to tactile sensitivity, heat sensitivity, sensorimotor competence and PPI along with differences in Gabrb3 expression in the reticular thalamic nucleus and the bed nucleus of stria terminalis. These differences were influenced by the heterozygotes’ gender and whether the Gabrb3 gene was of paternal or maternal origin. These results are not adequately explained by simple haploinsufficiency of Gabrb3, therefore, additional mechanisms are likely to be involved. In addition, this is the first report of the occurrence of tactile and heat hypersensitivity in an ASD mouse model, two features often associated with ASD. [Copyright &y& Elsevier]

Maternal 15q11-q13 duplication is the most common copy number variant in autism, accounting for ∼1-3% of cases. The 15q11-q13 region is subject to epigenetic regulation, and genomic copy number losses and gains cause genomic disorders in a parent-of-origin-specific manner. One 15q11-q13 locus encodes the GABAA receptor β3 subunit gene (GABRB3), which has been implicated by several studies in both autism and absence epilepsy, and the co-morbidity of epilepsy in autism is well established. We report that maternal transmission of a GABRB3 signal peptide variant (P11S), previously implicated in childhood absence epilepsy, is associated with autism. An analysis of wild-type and mutant β3 subunit-containing α1β3γ2 or α3β3γ2 GABAA receptors shows reduced whole-cell current and decreased β3 subunit protein on the cell surface due to impaired intracellular β3 subunit processing. We thus provide the first evidence of an association between a specific GABAA receptor defect and autism, direct evidence that this defect causes synaptic dysfunction that is autism relevant and the first maternal risk effect in the 15q11-q13 autism duplication region that is linked to a coding variant. [ABSTRACT FROM AUTHOR]

Mutations in the GABRB3 have been recently associated with childhood absence epilepsy (CAE) in families from Honduras and Mexico. In this study, we aimed to determine the frequency of mutation in this gene in our cohort of families with CAE and other related idiopathic generalized epilepsy (IGE) syndromes. We screened the open reading frame of GABRB3 in 183 French-Canadian individuals with IGE, including 88 with CAE. A total of nine single nucleotide polymorphisms (SNPs) have been identified, five of which are novel. The previously described P11S missense mutation was found in three affected and one unaffected individuals from a French-Canadian family. However, the P11S variant was also found in one of our 190 control individuals of French-Canadian origin, suggesting that this variant is rather a rare polymorphism in this population. Further screening of other IGE cohorts from various ethnic origins would help to confirm the association between this rare functional variant and epilepsy. [ABSTRACT FROM AUTHOR]

Abstract: We tested four genes [phenylalanine hydroxylase (PAH), the serotonin transporter (SLC6A4), monoamine oxidase B (MAOB), and the gamma-aminobutyric acid A receptor β-3 subunit (GABRB3)] for their impact on five schizophrenia symptom factors: delusions, hallucinations, mania, depression, and negative symptoms. In a 90 family subset of the Irish Study of High Density Schizophrenia Families, the PAH 232 bp microsatellite allele demonstrated significant association with the delusions factor using both QTDT (F=8.0, p=.031) and QPDTPHASE (chi-square=12.54, p=.028). Also, a significant association between the GABRB3 191 bp allele and the hallucinations factor was detected using QPDTPHASE (chi-square=15.51, p=.030), but not QTDT (chi-square=2.07, p=.560). [Copyright &y& Elsevier]

Abstract: Prenatal exposure to diazepam, a prototype sedative drug that belongs to Benzodiazepines, can lead to orofacial clefting in human newborns. By using real-time PCR, in the present study we investigated whether diazepam elicits gene expression alterations in extracellular matrix (ECM) components, growth factors and gamma-aminobutyric acid receptor (GABRB3), implicated in the coordinate regulation of palate development. Palate fibroblasts were treated with diazepam (Dz-N fibroblasts) and compared to cleft lip-palate (CLP) fibroblasts obtained from patients with no known exposure to diazepam or other teratogens. Untreated fibroblasts from non-CLP patients were used as control. The results showed significant convergences in gene expression pattern of collagens, fibromodulin, vitronectin, tenascin C, integrins and metalloprotease MMP13 between Dz-N and CLP fibroblasts. Among the growth factors, constitutive Fibroblast Growth Factor 2 (FGF2) was greatly enhanced in Dz-N and CLP fibroblasts and associated with a higher reduction of FGF receptor. Transforming Growth Factor beta 3 (TGFβ3) resulted up-regulated in CLP fibroblasts and decreased in Dz-N fibroblasts. We found phenotypic differences exhibited by Dz-N and CLP fibroblasts in GABRB3 gene regulation, so further studies are necessary to determine whether GABAergic system could be involved in the development of diazepam mediated CLP phenotype. Taken together the results elucidate the molecular mechanisms underlying possible toxicology effects induced by diazepam. Counselling of women on the safety of diazepam exposure is clinically important, also for the forensic consequences. [Copyright &y& Elsevier]

Gamma-aminobutyric acid A (GABAA) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation. We investigated the expression of four GABAA receptor subunits and observed significant reductions in GABRA1, GABRA2, GABRA3, and GABRB3 in parietal cortex (Brodmann’s Area 40 (BA40)), while GABRA1 and GABRB3 were significantly altered in cerebellum, and GABRA1 was significantly altered in superior frontal cortex (BA9). The presence of seizure disorder did not have a significant impact on GABAA receptor subunit expression in the three brain areas. Our results demonstrate that GABAA receptors are reduced in three brain regions that have previously been implicated in the pathogenesis of autism, suggesting widespread GABAergic dysfunction in the brains of subjects with autism. [ABSTRACT FROM AUTHOR]

Abstract: The studies on the genetic risk factors of the children of alcoholics (COAs) are still in an early stage. The A1 allele of the dopamine receptor 2 gene (DRD2) may be associated with positive alcohol expectancy of the COAs. In addition, several researchers reported that the COAs might be associated with the GABAA receptor β3 subunit gene (GABRB3) and serotonin transporter gene (5-HTTLPR). In this study, we investigated the association of the polymorphism of the DRD2, Dopamine D4 receptor gene (DRD4), GABRB3, 5-HTTLPR with the COAs. Twenty-two COAs and 23 age and sex-matched control children were included for the genetic study (children of nonAlcoholics; nonCOAs). All COAs aged 6–18 were recruited and selected from family of alcoholic patients in Alcohol Clinic of the University hospital. The genotyping of the DRD2, DRD4, GABRB3, 5-HTTLPR was carried out. We used the Chi-square method for evaluating the association of genetic polymorphic allelic status with the COAs. The frequency of the A1+ allele at DRD2 in the COAs was significantly higher than nonCOAs. Significant association between the genotype at DRD4 and the COAs was found. The G1− alleles of the GABRB3 in COAs were significantly higher than nonCOAs. However, no association of the polymorphic alleles of the 5-HTTLPR with the COAs was found. We found that the children of alcoholics had a significantly increased number of risk alleles of candidate genes of alcohol drinking expectancy. Despite of several limitations, this study provides some preliminary information on the risk and protective factors associated with the COAs, which can be used as a foundation for prevention and intervention of future psychopathology. [Copyright &y& Elsevier]

The γ-aminobutyric acid (GABA) receptor genes GABRB3, GABRA5, and GABRG3 located on chromosome 15q11–q13 have been major candidates for susceptibility genes for autism, a neurodevelopmental disorder with a complex genetic etiology. In this study, we first investigated the association between the GABA receptor genes and autism in a Japanese population by analyzing 11 single nucleotide polymorphisms (SNPs). Intron 3 of GABRB3 was densely mapped because the previous studies observed the association of the microsatellite 155CA-2 located in the region. We observed no significant difference in allelic frequencies or genotypic distributions of the 11 SNPs between patients and controls. A permutation test showed no significant global differences in estimated haplotype frequencies between patients and controls. Analysis after confining the subjects to males showed similar results. Thus, this study provides no positive evidence of an association between the GABA receptor genes and autism in a Japanese population. However, in a SNP (rs3212337) located near the microsatellite 155CA-2, a significant deviation from the Hardy–Weinberg equilibrium was observed in patients ( p = 0.029, corrected for multiple testing). This finding may suggest further studies around the markers for more definitive conclusions. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Mutation screening and linkage disequilibrium mapping of the gene encoding the GABAA β3 subunit (GABRB3) identified a common genetic variant in the exon 1a promoter region (C-allele of rs4906902) which displayed a reduced transcriptional activity and showed a strong allelic association with childhood absence epilepsy (CAE). The present population-based association study tested whether the C-allele of rs4906902 confers susceptibility to CAE or other common syndromes of idiopathic generalized epilepsy (IGE) in a German sample. Methods: Seven hundred and eighty unrelated German IGE patients (250 CAE, 123 juvenile absence epilepsy, 303 juvenile myoclonic epilepsy (JME), 104 epilepsy with generalized tonic-clonic seizures on awakening) and 559 healthy population controls were genotyped for the single nucleotide polymorphism (SNP) rs4906902. Results: The frequency of the risk-conferring C-allele did not differ significantly between CAE patients (f(C)=0.190) and controls (f(C)=0.183; P =0.376, one-tailed). Similarly, no evidence for an allelic association was found for 373 patients with idiopathic absence epilepsy, 303 JME patients, and the entire IGE sample (P >0.77, two-tailed). Conclusion: Our study failed to replicate an association of the common GABRB3 exon 1a promoter SNP rs4906902 with CAE. Moreover, the present results do not provide evidence that the common functional C-variant confers a substantial epileptogenic effect to a broad spectrum of IGE syndromes in the German population. [Copyright &y& Elsevier]

Molecular genetic research has identified promising markers of alcohol dependence, including alleles of the D2 dopamine receptor (DRD2) and the GABAA receptor β3 subunit (GABRB3) genes. Whether such genetic risk manifests itself in stronger alcohol-related outcome expectancies, or in difficulty resisting alcohol, is unknown. In the present study, A1+ (A1A1 and A1A2 genotypes) and A1- (A2A2 genotype) alleles of the DRD2 and G1+ (G1G1 and G1 non-G1 genotypes) and G1- (non-G1 non-G1 genotype) alleles of the GABRB3 gene were determined in a group of 56 medically ill patients diagnosed with alcohol dependence. Mood-related alcohol expectancy (AE) and drinking refusal self-efficacy (DRSE) were assessed using the Drinking Expectancy Profile (Manual for the Drinking Expectancy Profile, Behaviour Research and Therapy Centre, Brisbane, 1996). Patients with the DRD2 A1+ allele, compared with those with the DRD2 A1- allele, reported significantly lower DRSE in situations of social pressure. Similarly, lower DRSE was reported under social pressure by patients with the GABRB3 G1+ allele when compared to those with the GABRB3 G1- alleles. Patients with the GABRB3 G1+ allele also revealed reduced DRSE in situations characterized by negative affect than those with the GABRB3 G1- alleles. Patients carrying the GABRB3 G1+ allele showed stronger AE relating to negative affective change (for example, increased depression) than their GABRB3 G1- counterparts. Biological influence in the development of some classes of cognitions is hypothesized. The clinical implications, particularly with regard to patient-treatment matching and the development of an integrated psychological and pharmacogenetic approach, are discussed. [Copyright &y& Elsevier]

Purpose: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations., Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated., Results: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain., Conclusion: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences., Competing Interests: Conflicts of Interest The authors of declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)