Alternative titles; symbols
HGNC Approved Gene Symbol: GABRB1
Cytogenetic location: 4p12 Genomic coordinates (GRCh38): 4:46,993,647-47,426,447 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p12 | Developmental and epileptic encephalopathy 45 | 617153 | Autosomal dominant | 3 |
Gamma-aminobutyric acid (GABA) receptors are a family of proteins involved in the GABAergic neurotransmission of the mammalian central nervous system. GABRB1 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).
GABRB1, like GABRA2 (137140), has been shown by in situ hybridization to be located on 4p13-p12 (Buckle et al., 1989). Kirkness et al. (1991) likewise localized the GABRB1 gene to 4p13-p12. Dean et al. (1991) confirmed the assignment to chromosome 4 by genetic linkage using a tetranucleotide repeat polymorphism. They placed the gene between D4S104, which is on 4p, and albumin (103600), which is at 4q11-q13. Thus, the location is consistent with the earlier assignment to 4p13-p12.
Danciger et al. (1993) found that the murine homologs of GABRA2 and GABRB1 are tightly linked on mouse chromosome 5 between the markers Pgm-1 and Kit. The 2 genes map near the mouse 'circling mutation' pi (pirouette).
Studying the spectral power of beta oscillations in the electroencephalogram (EEG; see 130190), Porjesz et al. (2002) found significant linkage between the beta frequencies and a GABRB1 microsatellite marker. Their results suggested the location of a quantitative trait locus influencing the EEG beta frequencies in or near the GABRB1 gene on chromosome 4p.
In a boy with developmental and epileptic encephalopathy-45 (DEE45; 617153), the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified a de novo heterozygous missense mutation in the GABRB1 gene (F246S; 137190.0001). The patient was part of a cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. Functional studies of the variant were not performed.
In a boy with DEE45, Lien et al. (2016) identified a de novo heterozygous missense mutation in the GABRB1 gene (T287I; 137190.0002). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed.
In a 2-year-old girl (patient 63), born of unrelated parents of Italian and Moroccan origin, with DEE45, Burgess et al. (2019) identified a de novo heterozygous missense mutation in the GABRB1 gene (I247T; 137190.0003). The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
Anstee et al. (2013) identified 2 dominant mutations in the mouse Gabrb1 gene that induced a phenotypic switch from alcohol aversion to a sustained, strongly heritable alcohol preference. The leu285-to-arg (L285R) mutation was generated through an N-ethyl-N-nitrosourea mutagenesis screen, and the pro228-to-his (P228H) mutation was spontaneous. Both Gabrb1 +/L285R and Gabrb1 +/P228H mutant mice were smaller than wildtype, particularly the Gabrb1 +/L285R mutants. Both mutant lines exhibited complete female infertility characterized by underdeveloped corpora lutea and significant hypothalamic-pituitary axis dysfunction. Increased alcohol preference in mutant animals was accompanied by greater sensitivity to the sedative and ataxic effects of ethanol and increased tonic currents in the nucleus accumbens. When expressed in HEK293 cells, both mutations increased receptor sensitivity to GABA and caused spontaneous GABA ion channel opening.
In a 4.5-year-old boy with developmental and epileptic encephalopathy-45 (DEE45; 617153), the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified a de novo heterozygous mutation in the GABRB1 gene, resulting in a phe246-to-ser (F246S) substitution. Functional studies of the variant were not performed. The patient had onset of seizures at age 12 months and showed developmental regression at age 35 months. EEG showed hypsarrhythmia. He had global developmental delay, hypotonia, ataxia, cortical visual impairment, and thin corpus callosum.
Janve et al. (2016) noted that the F246S mutation occurs at a highly conserved residue in transmembrane domain 1. In vitro functional studies in HEK293 cells showed that the mutation altered the kinetic properties of the channel, resulting in the net loss of GABAergic inhibition.
In a 32-month-old boy with developmental and epileptic encephalopathy-45 (DEE45; 617153), Lien et al. (2016) identified a de novo heterozygous c.860C-T transition (c.860C-T, NM_000812.3) in the GABRB1 gene, resulting in a thr287-to-ile (T287I) substitution at a highly conserved residue in the second helix of the transmembrane domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed. The patient developed refractory epilepsy at age 3 months and showed severe developmental delay and hypotonia. Brain imaging was normal.
In a 2-year-old girl (patient 63), born of unrelated parents of Italian and Moroccan origin, with developmental and epileptic encephalopathy-45 (DEE45; 617153), Burgess et al. (2019) identified a de novo heterozygous c.740T-C transition in the GABRB1 gene, resulting in an ile247-to-thr (I247T) substitution. The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of focal and tonic seizures at 4 months of age with cessation of seizures at about 2 years of age. She had profoundly impaired intellectual development with hypotonia, dysmorphic features, and progressive cerebral and white matter atrophy on brain imaging. The patient was part of a large cohort of individuals with epilepsy of infancy with migrating focal seizures (EIMFS) who underwent genetic studies.
Anstee, Q. M., Knapp, S., Maguire, E. P., Hosie, A. M., Thomas, P., Mortensen, M., Bhome, R., Martinez, A., Walker, S. E., Dixon, C. I., Ruparelia, K., Montagnese, S. and 16 others. Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition. Nature Commun. 4: 2816, 2013. Note: Electronic Article. [PubMed: 24281383] [Full Text: https://doi.org/10.1038/ncomms3816]
Buckle, V. J., Fujita, N., Bateson, A. N., Darlison, M. G., Barnard, E. A. Localization of human GABA-A receptor subunit genes to chromosomes 4 and 5. (Abstract) Cytogenet. Cell Genet. 51: 972 only, 1989.
Burgess, R., Wang, S., McTague, A., Boysen, K. E., Yang, X., Zeng, Q., Myers, K. A., Rochtus, A., Trivisano, M., Gill, D., EIMFS Consortium, Sadleir, L. G., Specchio, N., Guerrini, R., Marini, C., Zhang, Y.-H., Mefford, H. C., Kurian, M. A., Poduri, A. H., Scheffer, I. E. The genetic landscape of epilepsy of infancy with migrating focal seizures. Ann. Neurol. 86: 821-831, 2019. Note: Erratum: Ann. Neurol. 87: 658 only, 2020. [PubMed: 31618474] [Full Text: https://doi.org/10.1002/ana.25619]
Danciger, M., Farber, D. B., Kozak, C. A. Genetic mapping of three GABA-A receptor-subunit genes in the mouse. Genomics 16: 361-365, 1993. [PubMed: 8390964] [Full Text: https://doi.org/10.1006/geno.1993.1198]
Dean, M., Lucas-Derse, S., Bolos, A., O'Brien, S. J., Kirkness, E. F., Fraser, C. M., Goldman, D. Genetic mapping of the beta-1 GABA receptor gene to human chromosome 4, using a tetranucleotide repeat polymorphism. Am. J. Hum. Genet. 49: 621-626, 1991. [PubMed: 1652891]
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]
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]
Kirkness, E. F., Kusiak, J. W., Fleming, J. T., Menninger, J., Gocayne, J. D., Ward, D. C., Venter, J. C. Isolation, characterization, and localization of human genomic DNA encoding the beta-1 subunit of the GABA-A receptor (GABRB1). Genomics 10: 985-995, 1991. [PubMed: 1655634] [Full Text: https://doi.org/10.1016/0888-7543(91)90189-l]
Lien, E., Vatevik, A. K., Ostern, R., Haukanes, B. I., Houge, G. A second patient with a de novo GABRB1 mutation and epileptic encephalopathy. (Letter) Ann. Neurol. 80: 311-312, 2016. [PubMed: 27273810] [Full Text: https://doi.org/10.1002/ana.24699]
Porjesz, B., Almasy, L., Edenberg, H. J., Wang, K., Chorlian, D. B., Foroud, T., Goate, A., Rice, J. P., O'Connor, S. J., Rohrbaugh, J., Kuperman, S., Bauer, L. O., Crowe, R. R., Schuckit, M. A., Hesselbrock, V., Conneally, P. M., Tischfield, J. A., Li, T.-K., Reich, T., Begleiter, H. Linkage disequilibrium between the beta frequency of the human EEG and a GABA-A receptor gene locus. Proc. Nat. Acad. Sci. 99: 3729-3733, 2002. [PubMed: 11891318] [Full Text: https://doi.org/10.1073/pnas.052716399]
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]