Three de novo missense variants in the GABRB2 gene, including one that was predicted to be damaging (defined as MPC 2), were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (Iossifov et al., 2014; Satterstrom et al., 2020), while two protein-truncating variants in this gene were observed in case samples from the Danish iPSYCH study (Satterstrom et al., 2020). TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified GABRB2 as a candidate gene with a false discovery rate (FDR) between 0.05 and 0.1 (0.05 < FDR 0.1).
Molecular Function
The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 2 subunit. Heterozygous mutations in this gene are responsible for infantile or early childhood epileptic encephalopathy-2 (IECEE2; OMIM 617829), a neurodevelopmental disorder characterized in most patients by onset of seizures in infancy or childhood and associated with global developmental delay and variable intellectual disability.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
The GABRB2 KO mice, and HT mice to a lesser extent, display prepulse inhibition (PPI) deficit, locomotor hyperactivity, stereotypy, sociability impairments, spatial-working and spatial-reference memory deficits, reduced depression and anxiety, accelerated pentylenetetrazol (PTZ)-induced seizure, increased susceptibility to audiogenic epilepsy, GABAergic parvalbumin (PV)-positive interneuron dystrophy, astrocyte dystrophy, inreased microglia activation in the frontotemporal corticolimbic regions, decreased newborn neurons in the hippocampus, increased brain levels of oxidative stress and the pro-inflammatory cytokines TNFa and IL6. Risperidone and diazepam ameliorated some phenotypes in GABRB2 KO mice.
References
Type
Title
Author, Year
Primary
Gabrb2-knockout Mice Displayed Schizophrenia-Like and Comorbid Phenotypes With Interneuron-Astrocyte-Microglia Dysregulation
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice with genomic deletion of exon7 of Gabrb2 were generated by crossing mice where a genomic fragment containing exon 7 was replaced with a loxP flanked neomycin selection cassette and CMV-Cre mice that expresses Cre recombinase transgene under the control of a human cytomegalovirus (CMV) promoter, active in most cells and tissues.
Allele Type: Knockout
Strain of Origin: 129S7/SvEvBrd-Hprt^b-m2
Genetic Background: C57BL/6*129*SvEvhybrid
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Taconic Farms, Inc., New York; Sur C et al, J Neurosci, 2001
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice with genomic deletion of exon7 of Gabrb2 were generated by crossing mice where a genomic fragment containing exon 7 was replaced with a loxP flanked neomycin selection cassette and CMV-Cre mice that expresses Cre recombinase transgene under the control of a human cytomegalovirus (CMV) promoter, active in most cells and tissues.
Allele Type: Knockout
Strain of Origin: 129S7/SvEvBrd-Hprt^b-m2
Genetic Background: C57BL/6*129*SvEvhybrid
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Taconic Farms, Inc., New York; Sur C et al, J Neurosci, 2001
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice with genomic deletion of exon7 of Gabrb2 were generated by crossing mice where a genomic fragment containing exon 7 was replaced with a loxP flanked neomycin selection cassette and CMV-Cre mice that expresses Cre recombinase transgene under the control of a human cytomegalovirus (CMV) promoter, active in most cells and tissues. To examine effects of parent-of-origin, paternal het (HT-P) mice were generated by mating WT male with KO female such that a normal copy of Gabrb2 was acquired from the father in HT-P mice.
Allele Type: Knockout
Strain of Origin: 129S7/SvEvBrd-Hprt^b-m2
Genetic Background: C57BL/6*129*SvEvhybrid
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Taconic Farms, Inc., New York; Sur C et al, J Neurosci, 2001
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice with genomic deletion of exon7 of Gabrb2 were generated by crossing mice where a genomic fragment containing exon 7 was replaced with a loxP flanked neomycin selection cassette and CMV-Cre mice that expresses Cre recombinase transgene under the control of a human cytomegalovirus (CMV) promoter, active in most cells and tissues. To examine effects of parent-of-origin, maternal het (HT-M) mice were generated by mating KO male with WT female, such that a normal copy of Gabrb2 was acquired from the mother in HT-M mice.
Allele Type: Knockout
Strain of Origin: 129S7/SvEvBrd-Hprt^b-m2
Genetic Background: C57BL/6*129*SvEvhybrid
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Taconic Farms, Inc., New York; Sur C et al, J Neurosci, 2001
Description: Mutants show decrease in the number of parvalbumin positive interneurons in the anterior cingulate and piriform cortices but no change in the number of parvalbumin positive neurons in the dentate gyrus or the hippocampus or the central amygdaloid nucleus.
Exp Paradigm: Pv
Description: Mutants show decrease in the number of gfap positive astrocytes in the ca1 hippocampus and the dentate gyrus but not in the acc.
Exp Paradigm: Gfap
Description: Mutants show upregulation of gabrb1, gabrg1, and gabrg2 and down-regulation of downregulations for gabra1, gabra2, and gabra5 in the ko cerebrum.
Exp Paradigm: Gaba-a
Description: Mutants show increased levels of malondialdehyde in the brain but no elevation of oxidative markers in the blood or liver.
Exp Paradigm: NA
Description: Mutants show increased susceptibility and decreased latency for ptz induced seizures compared with controls. the average latency to seizure was shorter for female than for male.
Exp Paradigm: NA
Description: Mutants show increased audiogenic seizures characterized by wild running followed by tonic seizure compared with controls. the average latency to seizure was shorter for female ko than for male ko at both week-3 and week-10.
Exp Paradigm: NA
Description: Mutants show decreased ppi compared with controls at 77110, 77120, and 83110 db prepulse-pulse combinations but not at 83120 db combinations.
Exp Paradigm: NA
Description: Mutants show decrease in time spent and number of contacts with an unfamiliar mouse over a familiar mouse compared with controls.
Exp Paradigm: NA
Description: Mutants show decrease in time spent and number of contacts with an unfamiliar mouse over an empty cup compared with controls.
Exp Paradigm: NA
Description: Mutants show small litter sizes when both parents were nave ko mutants compared to litter sizes when nave male ko mice were mated with nave female ht or wt or when wt pairs were mated.
Exp Paradigm: NA
Description: Mutants show increased levels of malondialdehyde in the brain but no elevation of oxidative markers in the blood or liver.
Exp Paradigm: NA
Description: Mutants show increased susceptibility and decreased latency for ptz induced seizures compared with controls. the average latency to seizure was shorter for female than for male.
Exp Paradigm: NA
Description: Mutants show decrease in time spent and number of contacts with an unfamiliar mouse over a familiar mouse compared with controls.
Exp Paradigm: NA
Description: Mutants show decrease in time spent and number of contacts with an unfamiliar mouse over an empty cup compared with controls.
Exp Paradigm: NA
