Alternative titles; symbols
HGNC Approved Gene Symbol: GABRB3
Cytogenetic location: 15q12 Genomic coordinates (GRCh38) : 15:26,543,552-26,773,763 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q12 | {Epilepsy, childhood absence, susceptibility to, 5} | 612269 | 3 | |
| Developmental and epileptic encephalopathy 43 | 617113 | Autosomal dominant | 3 |
Gamma-aminobutyric acid (GABA) receptors are a family of proteins involved in the GABAergic neurotransmission of the mammalian central nervous system. GABRB3 is a member of the GABA-A receptor gene family of heteromeric pentameric ligand-gated ion channels through which GABA, the major inhibitory neurotransmitter in the mammalian brain, acts. GABA-A receptors are the site of action of a number of important pharmacologic agents including barbiturates, benzodiazepines, and ethanol (summary by Whiting et al., 1999).
For additional general information about the GABA-A receptor gene family, see GABRA1 (137160).
Wagstaff et al. (1991) isolated a GABA-A receptor beta-3 subunit cDNA from a human brain cDNA library. Comparison of the human beta-3 subunit amino acid sequence with beta-3 sequences from rat, cow, and chicken demonstrated a high degree of evolutionary conservation. Most of the sequence differences between species are clustered near the C terminus, within a large intracellular domain of the protein.
The GABRB3 gene contains 10 exons, including 2 alternative first exons encoding signal peptides, and spans 250 kb (Glatt et al., 1997; Urak et al., 2006).
Miller and Aricescu (2014) described the first 3-dimensional structure of a GABA-A receptor, the human beta-3 homopentamer, at 3-angstrom resolution. This structure reveals architectural elements unique to eukaryotic cysteine-loop receptors, explains the mechanistic consequences of multiple human disease mutations, and shows an unexpected structural role for a conserved N-linked glycan. The receptor was crystallized bound to a previously unknown agonist, benzamidine, opening an avenue for the rational design of GABA-A receptor modulators. The channel region forms a closed gate at the base of the pore, representative of a desensitized state.
Wagstaff et al. (1991) showed that the GABRB3 maps to the region of 15q involved in Angelman syndrome (105830) and Prader-Willi syndrome (176270). Deletion of the gene was found in patients of both types with interstitial cytogenetic deletions. The gene was also deleted in an Angelman syndrome patient with an unbalanced 13;15 translocation but not in a PWS patient with an unbalanced 9;15 translocation. Wagstaff et al. (1991) suggested that this receptor gene may be involved in the pathogenesis of one or both of these syndromes. This is the first gene to be mapped to this region. Wagstaff et al. (1991) showed that the gene is located on mouse chromosome 7, very closely linked to 2 other genes that in the human have been mapped to the 15q11-q13 region.
Using the combined techniques of field-inversion gel electrophoresis (FIGE) and phage genomic library screening, Sinnett et al. (1993) constructed a high-resolution physical map covering nearly 1.0 Mb in the proximal region of 15q. The map showed that GABRB3 and GABRA5 (gamma-aminobutyric acid receptor alpha-5 subunit gene; 137142) are separated by less than 100 kb and are arranged in a head-to-head configuration. GABRB3 encompasses approximately 250 kb, while GABRA5 is contained within 70 kb. The difference in size is due largely to an intron of 150 kb within GABRB3. Chromosomal rearrangement breakpoints in 2 patients with Angelman syndrome were located within the large GABRB3 intron. Russek and Farb (1994) stated that the gene encoding the gamma-3 form of the GABA-A receptor (GABRG3; 600233) is located on 15q11-q13 in a cluster with GABRA5 and GABRB3.
Holopainen et al. (2001) used positron emission tomography (PET) to study brain binding of (11C)flumazenil in 4 patients with Angelman syndrome. Patients 1, 2, and 3 had a maternal deletion of 15q11-q13 leading to a loss of the GABRB3 gene, whereas patient 4 had a mutation in the ubiquitin protein ligase (UBE3A) and the GABRB3 gene was spared. (11C)Flumazenil binding potential in the frontal, parietal, hippocampal, and cerebellar regions was significantly lower in patients 1 to 3 than in patient 4. Holopainen et al. (2001) proposed that the deletion leads to a reduced number of GABRB3 receptors, which could partially explain the neurologic deficits of Angelman syndrome patients.
Zinc ions regulate GABA-A receptors by inhibiting receptor function via an allosteric mechanism that is critically dependent on the receptor subunit composition. Hosie et al. (2003) used molecular modeling to identify 3 discrete sites that mediate zinc inhibition: one is located within the ion channel and comprises subunit beta-3 his267 and glu270, and the other 2 are on the external N-terminal face of the receptor and require the coordination of subunit alpha-1 (137160) glu137 and his141 and beta-3 glu 182. The characteristically low zinc sensitivity of GABA-A receptors containing the gamma-2 subunit (137164) results from disruption of 2 of the 3 sites after subunit assembly.
Epigenetics
Using coding SNPs within the GABA receptor gene cluster on chromosome 15q11-q13, Hogart et al. (2007) demonstrated that the GABRG3, GABRB3, and GABRA5 genes are biallelically expressed in the cerebral cortex of 21 postmortem human brain samples, and thus not normally subject to imprinting. Previously, Nicholls et al. (1993) showed that the mouse Gabrb3 transcript was expressed equally well from the maternal or paternal mouse chromosome 7, and they concluded that its expression was not imprinted in mouse brain. However, there was conflicting evidence on the imprinting status of human GABA-A receptor genes from Meguro et al. (1997), who had found exclusive paternal expression in mouse A9 hybrids containing a single normal human chromosome 15.
Hogart et al. (2007) found that 4 of 8 postmortem brain samples from patients with autism and 1 of 5 postmortem brain samples from patients with Rett syndrome (312750) had monoallelic or highly skewed allelic expression of 1 or more of the GABRB3, GABRA5, or GABRG3 genes, which correlated with decreased expression of GABRB3. These findings suggested that epigenetic dysregulation of these genes is common to both disorders. Chromatin immunoprecipitation assays in human neuroblastoma cells and normal human brain showed that MECP2 (300005) bound to methylated CpG sites at an intronic site within GABRB3, but there was no difference in methylation between autism samples and controls.
Knoll et al. (1994) studied DNA replication within chromosome 15q11-q13, a region subject to genomic imprinting, by fluorescence in situ hybridization. Asynchronous replication between homologs was observed in cells from normal persons and in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients with chromosome 15 deletions but not in PWS patients with maternal uniparental disomy. Opposite patterns of allele-specific replication timing between homologous loci were observed: paternal early/maternal late at the GABRB3 gene; maternal early/paternal late at the more distal GABRA5 locus.
Susceptibility to Childhood Absence Epilepsy 5
Childhood absence epilepsy (ECA) shows a complex nonmendelian pattern of inheritance. Urak et al. (2006) screened 45 ECA patients for sequence variations in GABRB3. The authors defined 4 haplotypes between the promoter region and intron 3. A transmission disequilibrium test demonstrated significant association of this region and ECA (p = 0.007). The locus was termed ECA5 (612269). Reporter gene assays indicated that the disease-associated haplotype 2 promoter caused significantly lower transcriptional activity than the haplotype 1 promoter, which was overrepresented in the controls. In silico analysis suggested that an exchange from T to C within haplotype 2 may impair binding of the neuron-specific transcriptional activator N-Oct-3 (POU5F1; 164177). Electrophoretic mobility shift assays demonstrated that the respective polymorphism reduced the binding of N-Oct-3. The authors proposed that reduced expression of GABRB3 could be one potential cause for the development of ECA.
Tanaka et al. (2008) identified 3 different heterozygous GABRB3 mutations (137192.0002-137192.0004) in affected members of 4 (8%) of 48 families with childhood absence epilepsy. Some patients had generalized tonic-clonic seizures; absences and accompanying seizures disappeared after 12 years of age in all four probands. Several mutation carriers were unaffected, indicating incomplete penetrance. The authors noted that patients with Angelman syndrome and deletion of GABRB3 also show absence seizures.
Developmental and Epileptic Encephalopathy 43
In 4 unrelated patients with developmental and epileptic encephalopathy-43 (DEE43; 617113), the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified different de novo heterozygous mutations in the GABRB3 gene. The patients were part of a larger cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. A statistical likelihood analysis indicated that the probability of this finding occurring by chance was p = 4.1 x 10(-10). Functional studies of the mutations were not performed. The Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) concluded that their results implicated the GABRB3 gene in epileptic encephalopathy.
In 7 previously unreported patients with DEE43, the Epi4K Consortium (2016) identified heterozygous mutations in the GABRB3 gene (see, e.g., 137192.0005-137192.0008). The mutations were found by targeted sequencing of 27 candidate genes in 531 patients with a similar disorder. Functional studies of the variants and studies of patient cells were not performed. Five of the mutations were confirmed de novo, 1 could not be confirmed de novo, and 1 segregated with a GEFS+ phenotype in a family (proband EG0258). GABRB3 mutations accounted for 1.3% of the cohort.
Janve et al. (2016) noted that 4 de novo heterozygous missense mutations in the GABRB3 gene (D120N, 137192.0005; E180G; Y302C; and N110D) identified in patients with DEE43 by the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) occurred at highly conserved residues that are part of major structural domains. In vitro functional studies in HEK293 cells showed that the mutations either reduced GABA-evoked peak current amplitudes or altered the kinetic properties of the channel, resulting in the net loss of GABAergic inhibition.
In a male patient with DEE43, Papandreou et al. (2016) identified a de novo heterozygous missense mutation in the GABRB3 gene (T287I; 137192.0009). The mutation was identified by sequencing of a panel of 48 genes associated with early infantile epileptic encephalopathy and confirmed by Sanger sequencing.
In a mother and child (cases 1 and 2) with DEE43, Absalom et al. (2020) identified a heterozygous nonsense mutation in the GABRB3 gene (R194X; 137192.0010). The mutation was identified by sequencing of a panel of genes associated with epilepsy and confirmed by Sanger sequencing. Absalom et al. (2020) evaluated the molecular effects of de novo heterozygous mutations (E77K; T287I, 137192.0009) in the GABRB3 gene that were identified in 2 patients with DEE43 and hypersensitivity to vigabatrin. The functional effects of each of the mutations in GABRB3 was tested in Xenopus oocytes injected with constructs containing all 5 GABA-A receptor subunits. Each of these mutations resulted in gain of function of the GABA-A receptor, with increased sensitivity to GABA. This was thought to be due to abnormally increased chloride flux at lower GABA concentrations, which exacerbated GABAergic tonic currents. These effects on the GABA-A receptor were in contrast to those resulting from the R194X nonsense mutation in GABRB3 in their vigabatrin-responsive child with DEE43, which was predicted via modeling to result in reduced chloride flux at all GABA concentrations. Absalom et al. (2020) concluded that hypersensitivity to vigabatrin therapy in patients with DEE43 results from specific mutations in GABRB3 that increase GABAergic tonic currents.
Associations Pending Confirmation
Insomnia
Buhr et al. (2002) screened 124 individuals for SNPs of the alpha-1 (GABRA1; 137160), beta-3, and gamma-2 (GABRG2; 137164) genes of the GABA(A) receptor in the regions corresponding to the ligand-binding domains on the protein level. In 1 patient with chronic insomnia, an arg192-to-his mutation (137192.0001) was found in the GABRB3 gene in heterozygous state. Functional studies suggested the possibility of decreased GABAergic inhibition contributing to insomnia, from which some members of the patient's family suffered.
Cleft Lip with or without Cleft Palate
Scapoli et al. (2002) found significant linkage disequilibrium between GABRB3 and nonsyndromic cleft lip with or without cleft palate (CL/P; 119530). They noted that knockout of the Gabrb3 gene in mice causes clefting of the secondary palate only (Homanics et al., 1997). Tanabe et al. (2000) found no evidence that the GABRB3 gene is involved in clefting in Japanese cases.
Autism
Buxbaum et al. (2002) noted that cytogenetic abnormalities in the Prader-Willi/Angelman syndrome critical region have been described in individuals with autism. They performed an association analysis for a marker of GABRB3 called 155CA-2, using the transmission disequilibrium test (TDT) in a set of 80 autism families (59 multiplex and 21 trios). Four additional markers (69CA, 155CA-1, 85CA, and A55CA-1) located within 150 kb of 155CA-2 were also assayed. Both the multiallelic TDT (P less than 0.002) and the TDT (P less than 0.004) demonstrated association between autistic disorder and 155CA-2 in these families. Buxbaum et al. (2002) suggested that genetic variants within the GABA receptor gene complex in 15q11-q13 may play a role in autistic disorder (see AUTS4; 608636).
Rett syndrome (312750), an X-linked dominant disorder caused by MECP2 (300005) mutations, and Angelman syndrome (105830), an imprinted disorder caused by maternal 15q11-q13 or UBE3A (601623) deficiency, have phenotypic and genetic overlap with autism. Samaco et al. (2005) tested the hypothesis that MECP2 deficiency may affect the level of expression of UBE3A and neighboring autism candidate gene GABRB3 without necessarily affecting imprinted expression. Multiple quantitative methods revealed significant defects in UBE3A expression in 2 different Mecp2-deficient mouse strains, as well as in Rett, Angelman, and autism brain samples compared to control samples. Although no difference was observed in the allelic expression of several imprinted transcripts in Mecp2-null mouse brain, Ube3a sense expression was significantly reduced, consistent with the decrease in protein. GABRB3 also showed significantly reduced expression in multiple Rett, Angelman, and autism brain samples, as well as Mecp2-deficient mice. Samaco et al. (2005) proposed an overlapping pathway of gene dysregulation within chromosome 15q11-q13 in Rett syndrome, Angelman syndrome, and autism, and implicated MECP2 in the regulation of UBE3A and GABRB3 expression in the postnatal mammalian brain.
Among 166 unrelated Japanese patients with autism and 412 controls, Tochigi et al. (2007) found evidence for association with SNP (rs3212337), located 2.4 kb telomeric to microsatellite 155CA-2 in the GABRB3 gene (p = 0.029 after Bonferroni correction).
Saitoh et al. (1992) studied a highly informative family in which 3 sibs had Angelman syndrome and a deletion of one GABRB3 gene. The mother had the same deletion which she had inherited from her father. The finding supported the possibility that GABRB3 is the Angelman gene and indicated that the genes for AS and PWS are different since transmission of the deletion from the grandfather to the mother of the affected children did not result in PWS.
DeLorey et al. (2008) observed that Gabrb3-null mice showed significant deficits in activities related to social behavior, including sociability, social novelty, and nesting, compared to wildtype controls. Gabrb3-null mice also showed decreased exploratory behavior, increased stereotypic hyperactive circling behavior, and reductions in the frequency and duration of rearing episodes compared to controls. Brain tissue analysis showed that Gabrb3-null mice had hypoplasia of the cerebellar vermis compared to wildtype controls. DeLorey et al. (2008) concluded that the Gabrb3-null mouse provides a mouse model of autism spectrum disorder.
This variant, formerly titled INSOMNIA, has been reclassified because its association with the disorder has not been confirmed.
In a patient with insomnia who also had relatives who suffered from the condition, Buhr et al. (2002) found a G-to-A transition in exon 6 of the GABRB3 gene, which resulted in an arg192-to-his (R192H) change in the mature beta-3 subunit. Buhr et al. (2002) pointed out that the beta-3 subunit had been implicated in sleep processes independently, by the observation that mice lacking beta-3 lose the hypnotic response to oleamide (Laposky et al., 2001). Segregation of the variant with the disorder in the family was not shown.
In affected members of 2 unrelated Mexican families with childhood absence epilepsy-5 (ECA5; 612269), Tanaka et al. (2008) identified a heterozygous 31C-T transition in exon 1a of the GABRB3 gene, resulting in a pro11-to-ser (P11S) substitution in the alternative signal peptide. A total of 3 unaffected family members from both families carried the mutation, indicating incomplete penetrance. In vitro cellular functional expression studies showed that the mutant protein was hyperglycosylated and had reduced mean current densities compared to wildtype. Tanaka et al. (2008) did not identify the P11S mutation in 630 controls, but noted that it is listed as rs25409 in the SNP database.
In a patient from Honduras with childhood absence epilepsy-5 (ECA5; 612269), Tanaka et al. (2008) identified a heterozygous 44C-T transition in exon 1a the GABRB3 gene, resulting in a ser15-to-phe (S15F) substitution in the alternative signal peptide. He had onset of absence seizures at age 7 years and a grand mal seizure at age 12. Absence seizures ceased at age 12. The mutation was also present in his unaffected mother and half-brother, indicating incomplete penetrance. The mutation was not identified in 630 controls. In vitro cellular functional expression studies showed that the mutant protein was hyperglycosylated and had reduced mean current densities compared to wildtype.
In 2 affected members of a family from Honduras with ECA5 (612269), Tanaka et al. (2008) identified a heterozygous 962G-A transition in exon 2 of the GABRB3 gene, resulting in a gly32-to-arg (G32R) substitution. Two additional family members with the mutation showed EEG abnormalities without absence seizures, and 1 had a febrile seizure. The mutation was not identified in 630 controls. In vitro cellular functional expression studies showed that the mutant protein was hyperglycosylated and had reduced mean current densities compared to wildtype.
In a 12-year-old boy (EG0254) with developmental and epileptic encephalopathy-43 (DEE43; 617113), the Epi4K Consortium (2016) identified a de novo heterozygous c.358G-A transition (c.358G-A, NM_000814.4) in the GABRB3 gene, resulting in an asp120-to-asn (D120N) substitution. The patient had onset of myoclonic-astatic epilepsy at 1 year of age after normal early development.
In a girl (T22598) with developmental and epileptic encephalopathy-43 (DEE43; 617113), the Epi4K Consortium (2016) identified a de novo heterozygous c.545A-T transversion (c.545A-T, NM_000814.4) in the GABRB3 gene, resulting in a tyr182-to-phe (Y182F) substitution. The patient had onset of grimacing at 6 months of age and died of epileptic encephalopathy at 3 years of age.
In a 19-year-old woman (T25111) with developmental and epileptic encephalopathy-43 (DEE43; 617113), the Epi4K Consortium (2016) identified a de novo heterozygous c.745C-A transversion (c.745C-A, NM_000814.4) in the GABRB3 gene, resulting in a gln249-to-lys (Q249K) substitution. The patient had onset of tonic-clonic seizures at 12 years of age, but had delayed development since 6 months of age.
In a 14-year-old boy (T25708) with developmental and epileptic encephalopathy-43 (DEE43; 617113), the Epi4K Consortium (2016) identified a de novo heterozygous c.913G-A transition (c.913G-A, NM_000814.4) in the GABRB3 gene, resulting in an ala305-to-thr (A305T) substitution. The patient had onset of seizure-like episodes at 5 months of age.
In a male patient with developmental and epileptic encephalopathy-43 (DEE43; 617113), Papandreou et al. (2016) identified a c.860C-T transition (c.860C-T, NM_021912.4) in the GABRB3 gene, resulting in a thr287-to-ile (T287I) substitution. The mutation was identified by sequencing of a panel of 48 genes associated with early infantile epileptic encephalopathy. Sanger sequencing in the patient and his parents confirmed that the mutation was de novo. The mutation was not present in the ExAC, 1000 Genomes Project, and Exome Variant Server databases. Clinical features in the patient included seizures and severe global developmental delay. He had severe hypotonia, sedation, and respiratory difficulties in response to antiepileptic treatment with vigabatrin, a GABA transaminase inhibitor. Vigabatrin was weaned and multiple other therapies were tried, but seizures continued. At 3 years and 2 months of age, he had microcephaly, hypotonia, and absence of speech.
In a mother and child (cases 1 and 2) with developmental and epileptic encephalopathy-43 (DEE43; 617113), Absalom et al. (2020) identified a heterozygous c.580C-T transition in the GABRB3 gene, resulting in an arg194-to-ter (R194X) substitution. The mutation was identified by sequencing of a panel of genes associated with epilepsy and confirmed by Sanger sequencing. The mutation was predicted to result in absent protein product due to loss of the transmembrane and pore regions.
Absalom, N. L., Liao, V. W. Y., Kothur, K., Indurthi, D. C., Bennetts, B., Troedson, C., Mohammad, S. S., Gupta, S., McGregor, I. S., Bowen, M. T., Lederer, D., Mary, S., and 9 others. Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies. Brain Commun. 2: fcaa162, 2020. [PubMed: 33585817] [Full Text: https://doi.org/10.1093/braincomms/fcaa162]
Buhr, A., Bianchi, M. T., Baur, R., Courtet, P., Pignay, V., Boulenger, J. P., Gallati, S., Hinkle, D. J., Macdonald, R. L., Sigel, E. Functional characterization of the new human GABA(A) receptor mutation beta-3(R192H). Hum. Genet. 111: 154-160, 2002. [PubMed: 12189488] [Full Text: https://doi.org/10.1007/s00439-002-0766-7]
Buxbaum, J. D., Silverman, J. M., Smith, C. J., Greenberg, D. A., Kilifarski, M., Reichert, J., Cook, E. H., Jr., Fang, Y., Song, C.-Y., Vitale, R. Association between a GABRB3 polymorphism and autism. Molec. Psychiat. 7: 311-316, 2002. [PubMed: 11920158] [Full Text: https://doi.org/10.1038/sj.mp.4001011]
DeLorey, T. M., Sahbaie, P., Hashemi, E., Homanics, G. E., Clark, J. D. Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder. Behav. Brain Res. 187: 207-220, 2008. [PubMed: 17983671] [Full Text: https://doi.org/10.1016/j.bbr.2007.09.009]
Epi4K Consortium and Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 501: 217-221, 2013. [PubMed: 23934111] [Full Text: https://doi.org/10.1038/nature12439]
Epi4K Consortium. De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am. J. Hum. Genet. 99: 287-298, 2016. [PubMed: 27476654] [Full Text: https://doi.org/10.1016/j.ajhg.2016.06.003]
Glatt, K., Glatt, H., Lalande, M. Structure and organization of GABRB3 and GABRA5. Genomics 41: 63-69, 1997. Note: Erratum: Genomics 44: 155 only, 1997. [PubMed: 9126483] [Full Text: https://doi.org/10.1006/geno.1997.4639]
Hogart, A., Nagarajan, R. P., Patzel, K. A., Yasui, D. H., Lasalle, J. M. 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Hum. Molec. Genet. 16: 691-703, 2007. [PubMed: 17339270] [Full Text: https://doi.org/10.1093/hmg/ddm014]
Holopainen, I. E., Metsahonkala, E.-L., Kokkonen, H., Parkkola, R. K., Manner, T. E., Nagren, K., Korpi, E. R. Decreased binding of [11C]flumazenil in Angelman syndrome patients with GABA-A receptor beta-3 subunit deletions. Ann. Neurol. 49: 110-113, 2001. [PubMed: 11198279] [Full Text: https://doi.org/10.1002/1531-8249(200101)49:1<110::aid-ana17>3.0.co;2-t]
Homanics, G. E., DeLorey, T. M., Firestone, L. L., Quinlan, J. J., Handforth, A., Harrison, N. L., Krasowski, M. D., Rick, C. E. M., Korpi, E. R., Makela, R., Brilliant, M. H., Hagiwara, N., Ferguson, C., Snyder, K., Olsen, R. W. Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc. Nat. Acad. Sci. 94: 4143-4148, 1997. [PubMed: 9108119] [Full Text: https://doi.org/10.1073/pnas.94.8.4143]
Hosie, A. M., Dunne, E. L., Harvey, R. J., Smart, T. G. Zinc-mediated inhibition of GABA-A receptors: discrete binding sites underlie subtype specificity. Nature Neurosci. 6: 362-369, 2003. [PubMed: 12640458] [Full Text: https://doi.org/10.1038/nn1030]
Janve, V. S., Hernandez, C. C., Verdier, K. M., Hu, N., Macdonald, R. L. Epileptic encephalopathy de novo GABRB mutations impair gamma-aminobutyric acid type A receptor function. Ann. Neurol. 79: 806-825, 2016. [PubMed: 26950270] [Full Text: https://doi.org/10.1002/ana.24631]
Knoll, J. H. M., Cheng, S.-D., Lalande, M. Allele specificity of DNA replication timing in the Angelman/Prader-Willi syndrome imprinted chromosomal region. Nature Genet. 6: 41-46, 1994. [PubMed: 8136833] [Full Text: https://doi.org/10.1038/ng0194-41]
Laposky, A. D., Homanics, G. E., Baile, A., Mendelson, W. B. Deletion of the GABA(A) receptor beta 3 subunit eliminates the hypnotic actions of oleamide in mice. Neuroreport 12: 4143-4147, 2001. [PubMed: 11742254] [Full Text: https://doi.org/10.1097/00001756-200112210-00056]
Meguro, M., Mitsuya, K., Sui, H., Shigenami, K., Kugoh, H., Nakao, M., Oshimura, M. Evidence for uniparental, paternal expression of the human GABA-A receptor subunit genes, using microcell-mediated chromosome transfer. Hum. Molec. Genet. 6: 2127-2133, 1997. [PubMed: 9328477] [Full Text: https://doi.org/10.1093/hmg/6.12.2127]
Miller, P. S., Aricescu, A. R. Crystal structure of a human GABA-A receptor. Nature 512: 270-275, 2014. [PubMed: 24909990] [Full Text: https://doi.org/10.1038/nature13293]
Nicholls, R. D., Gottlieb, W., Russell, L. B., Davda, M., Horsthemke, B., Rinchik, E. M. Evaluation of potential models for imprinted and nonimprinted components of human chromosome 15q11-q13 syndromes by fine-structure homology mapping in the mouse. Proc. Nat. Acad. Sci. 90: 2050-2054, 1993. [PubMed: 8095339] [Full Text: https://doi.org/10.1073/pnas.90.5.2050]
Papandreou, A., McTague, A., Trump, N., Ambegaonkar, G., Ngoh, A., Meyer, E., Scott, R. H., Kurian, M. A. GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy. Dev. Med. Child Neurol. 58: 416-420, 2016. [PubMed: 26645412] [Full Text: https://doi.org/10.1111/dmcn.12976]
Russek, S. J., Farb, D. H. Mapping of the beta-2 subunit gene (GABRB2) to microdissected human chromosome 5q34-q35 defines a gene cluster for the most abundant GABA-A receptor isoform. Genomics 23: 528-533, 1994. [PubMed: 7851879] [Full Text: https://doi.org/10.1006/geno.1994.1539]
Saitoh, S., Kubota, T., Ohta, T., Jinno, Y., Niikawa, N., Sugimoto, T., Wagstaff, J., Lalande, M. Familial Angelman syndrome caused by imprinted submicroscopic deletion encompassing GABA(A) receptor beta(3)-subunit gene. (Letter) Lancet 339: 366-367, 1992. [PubMed: 1346439] [Full Text: https://doi.org/10.1016/0140-6736(92)91686-3]
Samaco, R. C., Hogart, A., LaSalle, J. M. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum. Molec. Genet. 14: 483-492, 2005. [PubMed: 15615769] [Full Text: https://doi.org/10.1093/hmg/ddi045]
Scapoli, L., Martinelli, M., Pezzetti, F., Carinci, F., Bodo, M., Tognon, M., Carinci, P. Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate. Hum. Genet. 110: 15-20, 2002. [PubMed: 11810291] [Full Text: https://doi.org/10.1007/s00439-001-0639-5]
Sinnett, D., Wagstaff, J., Glatt, K., Woolf, E., Kirkness, E. J., Lalande, M. High-resolution mapping of the gamma-aminobutyric acid receptor subunit beta-3 and alpha-5 gene cluster on chromosome 15q11-q13, and localization of breakpoints in two Angelman syndrome patients. Am. J. Hum. Genet. 52: 1216-1229, 1993. [PubMed: 8389098]
Tanabe, A., Taketani, S., Endo-Ichikawa, Y., Tokunaga, R., Ogawa, Y., Hiramoto, M. Analysis of the candidate genes responsible for non-syndromic cleft lip and palate in Japanese people. Clin. Sci. (Lond.) 99: 105-111, 2000. [PubMed: 10918043]
Tanaka, M., Olsen, R. W., Medina, M. T., Schwartz, E., Alonso, M. E., Duron, R. M., Castro-Ortega, R., Martinez-Juarez, I. E., Pascual-Castroviejo, I., Machado-Salas, J., Silva, R., Bailey, J. N., Bai, D., Ochoa, A., Jara-Prado, A., Pineda, G., Macdonald, R. L., Delgado-Escueta, A. V. Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. Am. J. Hum. Genet. 82: 1249-1261, 2008. [PubMed: 18514161] [Full Text: https://doi.org/10.1016/j.ajhg.2008.04.020]
Tochigi, M., Kato, C., Koishi, S., Kawakubo, Y., Yamamoto, K., Matsumoto, H., Hashimoto, O., Kim, S.-Y., Watanabe, K., Kano, Y., Nanba, E., Kato, N., Sasaki, T. No evidence for significant association between GABA receptor genes in chromosome 15q11-q13 and autism in a Japanese population. J. Hum. Genet. 52: 985-989, 2007. [PubMed: 17957331] [Full Text: https://doi.org/10.1007/s10038-007-0207-5]
Urak, L., Feucht, M., Fathi, N., Hornik, K., Fuchs, K. A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity. Hum. Molec. Genet. 15: 2533-2541, 2006. Note: Erratum: Hum. Molec. Genet. 15: 3272 only, 2006. [PubMed: 16835263] [Full Text: https://doi.org/10.1093/hmg/ddl174]
Wagstaff, J., Chaillet, J. R., Lalande, M. The GABA(A) receptor beta-3 subunit gene: characterization of a human cDNA from chromosome 15q11q13 and mapping to a region of conserved synteny on mouse chromosome 7. Genomics 11: 1071-1078, 1991. [PubMed: 1664410] [Full Text: https://doi.org/10.1016/0888-7543(91)90034-c]
Wagstaff, J., Knoll, J. H. M., Fleming, J., Kirkness, E. F., Martin-Gallardo, A., Greenberg, F., Graham, J. M., Jr., Menninger, J., Ward, D., Venter, J. C., Lalande, M. Localization of the gene encoding the GABA(A) receptor beta-3 subunit to the Angelman/Prader-Willi region of human chromosome 15. Am. J. Hum. Genet. 49: 330-337, 1991. [PubMed: 1714232]
Whiting, P. J., Bonnert, T. P., McKernan, R. M., Farrar, S., le Bourdelles, B., Heavens, R. P., Smith, D. W., Hewson, L., Rigby, M. R., Sirinathsinghji, D. J. S., Thompson, S. A., Wafford, K. A. Molecular and functional diversity of the expanding GABA-A receptor gene family. Ann. N.Y. Acad. Sci. 868: 645-653, 1999. [PubMed: 10414349] [Full Text: https://doi.org/10.1111/j.1749-6632.1999.tb11341.x]