Rare variants in the GABRB3 gene have been identified with autism (e.g. Cook et al., 1998) and genetic association has been found between GABRB3 and childhood absence epilepsy (CAE) (Urak et al., 2006). As well, a number of studies have found genetic association between the GABRB3 gene and autism (including one that enriched for savant skills). Populations studied include Caucasian, African-American, Hispanic, as well as AGRE, SARC and CLSA cohorts. However, other studies found no genetic association between the GABRB3 gene and autism in IMGSAC and other cohorts.
Molecular Function
The encoded protein is a subunit of GABA-A receptor. Neurotransmission is predominantly mediated by a gated chloride channel activity intrinsic to the receptor.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers.
Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies
Cases: 118 individuals with a DSM-IV or ICD-10 diagnosis of Asperger syndrome; controls: 412 individuals with an Autism Spectrum Quotient score below 24. All individuals of Caucasian ancestry.
Cases: 118 individuals with a DSM-IV or ICD-10 diagnosis of Asperger syndrome; controls: 412 individuals with an Autism Spectrum Quotient score below 24. All individuals of Caucasian ancestry.
Cases: 118 individuals with a DSM-IV or ICD-10 diagnosis of Asperger syndrome; controls: 412 individuals with an Autism Spectrum Quotient score below 24. All individuals of Caucasian ancestry.
316 Indo-Caucasoid ASD probands (262 male, 54 female; mean age 5.96 +/- 3.31 years) from West Bengal recruited from Manovikas Kendra Rehabilitation and Research Institute of the Handicapped (MRIH), Kolkata, India, and 227 healthy controls (124 male, 103 female; mean age 8.9 +/- 6.8 years) recruited from different regions around Kolkata.
316 Indo-Caucasoid ASD probands (262 male, 54 female; mean age 5.96 +/- 3.31 years) from West Bengal and their families recruited from Manovikas Kendra Rehabilitation and Research Institute of the Handicapped (MRIH), Kolkata, India.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Homologous recombination to disrupt promoter and exons 1-3 of gabrb3 gene.
Allele Type: Targeted(Knock-Out)
Strain of Origin: Not Specified
Genetic Background: C57B1/6J x 129/SvJ
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Homologous recombination to disrupt promoter and exons 1-3 of gabrb3 gene derived maternally.
Allele Type: Targeted(Knock-Out)
Strain of Origin: Not Specified
Genetic Background: C57BL/6J X 129Sv/SvJ
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Homologous recombination to disrupt promoter and exons 1-3 of gabrb3 gene derived paternally.
Allele Type: Targeted(Knock-Out)
Strain of Origin: Not Specified
Genetic Background: C57BL/6J X 129Sv/SvJ
ES Cell Line: R3
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Targeted replacement of 2.8kb of genomic DNA containing the promoter and exons 1-3 of Gabrb3 gene derived paternally.
Allele Type: Targeted (knockout)
Strain of Origin: Not Specified
Genetic Background: C57BL/6J
ES Cell Line: Not Specified
Mutant ES Cell Line: Not specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Targeted replacement of 2.8kb of genomic DNA containing the promter and exons 1-3 of Gabrb3 gene derived paternally.
Allele Type: Targeted(Knock-Out)
Strain of Origin: Not Specified
Genetic Background: C57BL/6J
ES Cell Line: Not Specified
Mutant ES Cell Line: Not specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Gabrb3 conditional ready (floxed/floxed) homozygous mice, with a floxed exon 3, were crossed to EIIa cre mice that expressed Cre under adenovirus EIIa promoter allowing excision of the floxed exon during early embryonic development resulting in germ line deletion.
Allele Type: Targeted (knockout)
Strain of Origin: Genetic Background: 129/SvEv * C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 3 of the Gabrb3 gene using Advillin-cre, in dorsal root ganglion and trigeminal somatosensory neurons (primary somatosensory neurons). Authors report the complete absence of GABRB3 puncta associated with axonal fibers arising from DRG sensory neurons.
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: 129/SvEv * C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of exon 3 of the Gabrb3 gene using Advillin-cre, in dorsal root ganglion and trigeminal somatosensory neurons (primary somatosensory neurons)
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: 129/SvEv * C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of exon 3 of the Gabrb3 gene using Advillin-creERT2, in dorsal root ganglion and trigeminal somatosensory neurons (primary somatosensory neurons) by treatment with tamoxifen starting at P28 and continued for 5 days (adults)
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: 129/SvEv * C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 3 of the Gabrb3 gene using Tie2-cre, in endothelial cells
Allele Type: Conditional loss-of-function
Strain of Origin: Not Specified
Genetic Background: Not Specified
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Labs
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional mutant mice with gabrb3 deleted in the sensory neurons were genrated by crossing mice that possessloxPsites on either side of exon 3 with Advillin-Cre mice; Advillin-Cre-Gabrb3^f/ ; M_GABRB3_9_CKO_HT
Allele Type: Conditional (knockout)
Strain of Origin: Genetic Background: C57BL/6J*129/SvEv*CD1
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratories; RRID:IMSR_JAX:008310; Ferguson et al., 2007.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional mutant mice with gabrb3 deleted in the sensory neurons were genrated by crossing mice that possessloxPsites on either side of exon 3 with Advillin-Cre mice; Advillin-Cre-Gabrb3^f/f; M_GABRB3_9_CKO_HT
Allele Type: Conditional (knockout)
Strain of Origin: Not specified
Genetic Background: C57BL/6J*129/SvEv*CD1
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratories; RRID:IMSR_JAX:008310; Ferguson et al., 2007.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The Gabrb3 Lbx1 conditional knockout was constructed by crossing mice with a Gabrb3-flox construct (MGI:3767248), in which exons 3 is flanked by loxP sites, to mice carrying Lbx1-Cre (MGI:3710149), where cre cDNA replaced exon 1 in the Lbx1 gene. The result is Gabrb3 deletion in 95% of all neurons in the low-threshold mechanoreceptor-recipient zone (LTMR-RZ) of the dorsal horn.
Allele Type: Conditional knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+; Not specified
Genetic Background: C57BL/6J, 129/SvEv, CD1
ES Cell Line: R1; Not specified
Mutant ES Cell Line: Model Source: Jackson Laboratory
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Homologous recombination to disrupt promoter and exons 1-3 of gabrb3 gene.
Allele Type: Targeted(Knock-Out)
Strain of Origin: Not Specified
Genetic Background: C57B1/6J x 129/SvJ
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Description: Abnormal rest-activity pattern: increased average activity period, increased total time spent in individual activity
Exp Paradigm: Motion monitoring
Description: Decreased motor coordination demonstrated by failure to improve performance on rotarod test
Exp Paradigm: Rota-rod test for motor performance and coordination
Description: Decreased surface area of cerebellar vermal lobules ii, iii, iv & v, and vi & vii
Exp Paradigm: Semi-quantitative measurement of sagittal surface area of cerebella vermal lobules
Description: Gabaa receptor density is reduced significantly in gabrb3 null neonates as determined by binding studies using radilabeled muscimol and ro15-4513
Exp Paradigm: NA
Description: Effective suppressing of clonic jerks by ethosuximide; abnormal efficacy of clonazepam, vpa, and gabab antagonist cgp 35348; abnormal efficacy leading to precipitation of seizures by carbamazepine, thip, and baclofen
Exp Paradigm: Antiepileptic drug (aed)
Description: Abnormal seizure: frequent interruptions by bursts of slowing, irregular high amplitude slow and sharp waves and small spikes coinciding with behavioral quiescence; high amplitutde interictal spikes with strong myoclonic jerks
Exp Paradigm: Electroencephalography
Description: Abnormal nest building behavior: decreased complexity of nests, abnormal location of nests away from wall or corners; decreased use of nests
Exp Paradigm: Observation of interaction with nesting material
Description: Abnormal novel inanimate object preference: decreased time spent investigating novel object, decreased number of contacts with novel object
Exp Paradigm: Interaction with novel objects in open field
Description: Abnormal spatial reference memory as demonstrated by poor retention in the learned step-through passive avoidance task
Exp Paradigm: Passive avoidance retention test
Cued or contextual fear conditioning: memory of context1
Abnormal
Description: Abnormal contextual fear conditioning: decreased freezing behavior
Exp Paradigm: Pavlovian fear conditioning followed by measurement of freezing response in absence of foot shock
Electroencephalogram (eeg): signature of seizure/epilepsy1
Increased
Description: Increased rhythmic and oscillatory short waves; increased theta-frequency events; no change in eeg power
Exp Paradigm: Electroencephalography; eeg power analysis in 1-hz frequency bins across the 2-15 hz interval of female mice
Electroencephalogram (eeg): signature of seizure/epilepsy1
Abnormal
Description: Small effect on frequency distribution of eeg
Exp Paradigm: Analysis of eeg recording after carbamazepine, 20 mg/kg administration using fast fourier transformation (fft) in male mice
Electroencephalogram (eeg): signature of seizure/epilepsy1
Increased
Description: Increased rhythmic and oscillatory short waves; increased theta-frequency events abolished by administration of ethosuximide; increased eeg power at 5-10 hz
Exp Paradigm: Electroencephalography simultaneous to pharmacological manipulation; eeg power analysis in 1-hz frequency bins across the 2-15 hz interval of male mice
Electroencephalogram (eeg): signature of seizure/epilepsy1
Abnormal
Description: Small effect on frequency distribution of eeg
Exp Paradigm: Analysis of eeg recording after carbamazepine, 20 mg/kg administration using fast fourier transformation (fft) in female mice
Cued or contextual fear conditioning: memory of context1
Increased
Description: Increased contextual learning demonstrated by decrease in locomotor activity between trials
Exp Paradigm: Comparison of activity of female mice in open field test between two trials
Electroencephalogram (eeg): signature of seizure/epilepsy1
Decreased
Description: Decreased oscillatory and rhythmic activity, with fewer theta bursts; frequent isolated sharp waves of 2-3 times baseline amplitude; increased sigma - frequency activity and decreased delta - frequency activity
Exp Paradigm: Electroencephalography; eeg power analysis in 1-hz frequency bins across the 2-15 hz interval of male mice
Electroencephalogram (eeg): signature of seizure/epilepsy1
Decreased
Description: Decreased oscillatory and rhythmic activity, with fewer theta bursts; frequent isolated sharp waves of 2-3 times baseline amplitude; decreased sigma - frequency activity and increased delta - frequency activity
Exp Paradigm: Electroencephalography; eeg power analysis in 1-hz frequency bins across the 2-15 hz interval of female mice
Electroencephalogram (eeg): signature of seizure/epilepsy1
Abnormal
Description: Large deviations in frequency distribution in eeg power distribution
Exp Paradigm: Analysis of eeg recording after carbamazepine, 20 mg/kg administration using fast fourier transformation (fft) in male mice
Electroencephalogram (eeg): signature of seizure/epilepsy1
Abnormal
Description: Large deviations in frequency distribution in eeg power distribution
Exp Paradigm: Analysis of eeg recording after carbamazepine, 20 mg/kg administration using fast fourier transformation (fft) in female mice
Cued or contextual fear conditioning: memory of context1
Increased
Description: Increased contextual learning demonstrated by decrease in locomotor activity between trials
Exp Paradigm: Comparison of activity of female mice in open field test between two trials
Description: Decreased muscle coordination demonstrated by saturation of performance on rotarod
Exp Paradigm: Male mice: rota-rod test for motor performance and coordination
Description: Increased sensitivity to pentylenetetrazol (ptz) induced seizures
Exp Paradigm: Male mice: seizure measurements using schwaller et. al method after administration of 35 mg/kg ptz i.p.
Description: Decreased acoustic startle reflex at acoustic intensities between 100 and 120 db
Exp Paradigm: Male mice: acoustic startle reflex at varying acoustic intensities
Description: Decreased acoustic startle reflex at acoustic intensities between 100 and 120 db
Exp Paradigm: Female mice: acoustic startle reflex at varying acoustic intensities
Description: Decreased muscle coordination demonstrated by saturation of performance on rotarod
Exp Paradigm: Male mice: rota-rod test for motor performance and coordination
Description: Decreased muscle coordination demonstrated by saturation of performance on rotarod
Exp Paradigm: Female mice: rota-rod test for motor performance and coordination
Description: Increased sensitivity to pentylenetetrazol (ptz) induced seizures
Exp Paradigm: Male mice: seizure measurements using schwaller et. al method after administration of 35 mg/kg ptz i.p.
Description: Decreased acoustic startle reflex at acoustic intensities between 100 and 120 db
Exp Paradigm: Female mice: acoustic startle reflex at varying acoustic intensities
Description: Increased sensorimotor gating demonstrated by increase in pre-pulse inhibition
Exp Paradigm: Male mice: prepulse inhibition of the acoustic startle response around 70 to 80 db as a measure of sensorimotor gating.
Description: Decreased acoustic startle reflex at acoustic intensities between 100 and 120 db
Exp Paradigm: Male mice: acoustic startle reflex at varying acoustic intensities
Description: Gabrb3 heterozygous pups show greater displacement magnitude, measured by optical flow point, in response to air puff stimuli.
Exp Paradigm: optical flow point tracking to measure reactivity to single presentations of 0.10-, 0.25-, 0.50- and 0.75-psi air puff stimuli
Description: Gabrb3 heterozygous mice exhibit enhanced sensitivity to back hairy skin stimulation, as measured by tactile prepulse inhibition (PPI) of an acoustic startle response.
Exp Paradigm: 0.9-psi air puff preceded 120 dB acoustic startle pulse,delivered at variable interstimulus intervals
Description: Gabrb3 heterozygous perinatal pups show greater displacement magnitude, in response to optogenetically stimulated
Exp Paradigm: optogenetic activation of Ret+ fast-conducting low-threshold mechanoreceptor (LTMR) terminals in the skin and assessment of behavioral reactivity
Description: Gabrb3 het mice have reduced tactile discrimination (glabrous skin) and memory for objects differing in texture (rough or smooth) and do not preferentially interact with a novel textured-object over a familiar one
Exp Paradigm: NA
Description: Gabrb3 het mice have reduced dominant or aggressive behavior as in the tube test of dominance they have significantly fewer wins compared to controls
Exp Paradigm: NA
Description: Gabrb3 het mice have reduced time spent in the center of of and reduced preference for the open arms in the elevated plus maze test indicating increased anxiety
Exp Paradigm: Open field test
Description: Gabrb3 heterozygous pups show greater displacement magnitude, measured by optical flow point, in response to repeated air puff stimuli. A smaller number of pups show habituation to repeated stimuli.
Exp Paradigm: optical flow point tracking to measure reactivity to ten presentations of a 1.0-psi stimulus at 20- to 30-s intervals
Description: Gabrb3 het mice have reduced time spent in the center of of and reduced preference for the open arms in the elevated plus maze test indicating increased anxiety
Exp Paradigm: Elevated plus maze test
Description: Avil-Cre Gabrb3 conditional knockout mice exhibit enhanced sensitivity to back hairy skin stimulation, as measured by tactile prepulse inhibition (PPI) of an acoustic startle response.
Description: Avil-Cre Gabrb3 conditional knockout pups show greater displacement magnitude, measured by optical flow point, in response to air puff stimuli.
Exp Paradigm: optical flow point tracking to measure reactivity to single presentations of 0.10-, 0.25-, 0.50- and 0.75-psi air puff stimuli
Description: Avl-cre gabrb3 homozygotes fail to in habituate to aversive startle from controls (unliked acl-cre gabrb3 homozygous mice)
Exp Paradigm: NA
Description: Avil-Cre Gabrb3 conditional knockout pups show greater displacement magnitude, measured by optical flow point, in response to repeated air puff stimuli. A smaller number of pups show habituation to repeated stimuli.
Exp Paradigm: optical flow point tracking to measure reactivity to ten presentations of a 1.0-psi stimulus at 20- to 30-s intervals
Quantal post synaptic current frequency: excitatory1
Increased
Description: Psdcs have increased frequency of evoked qepscs in avl-cre gabrb3 mice indicating changes in presynaptic release probability
Exp Paradigm: NA
Description: Avl-cre gabrb3 het mice have decreased dorsal root potential indicating decrease in activity dependent presynaptic inhibition (psi) in the dorsal root, authors indicate that loss of gabrb3 from primary somatosensory neurons causes deficiency of gabaa receptors mediated psi (drp, indicative of psi is decreased in these mice) this in turn causes increase in sensitivity to light touch
Exp Paradigm: NA
Description: Avl-cre gabrb3 het mice have impaired sensorimotor gating as they exhibit enhanced response to tactile prepulse (air puff)
Exp Paradigm: NA
Description: Avl-cre gabrb3 het mice have impaired sensorimotor gating as they exhibit enhanced response to tactile prepulse (air puff)
Exp Paradigm: NA
Description: Avl-cre gabrb3 mice with heterozygous loss of gabrb3 from somatosensory neurons in adults have impaired sensorimotor gating as they exhibit enhanced response to tactile prepulse (air puff)
Exp Paradigm: NA
Description: Avl-cre gabrb3 mice with heterozygous loss of gabrb3 from somatosensory neurons in adults have impaired sensorimotor gating as they exhibit enhanced response to tactile prepulse (air puff)
Exp Paradigm: NA
Description: Avl-cre gabrb3 mice with heterozygous loss of gabrb3 from somatosensory neurons as adults have increased number of wins compared to controls in tube test of dominance
Exp Paradigm: NA
Description: Avl-cre gabrb3 mice with heterozygous loss of gabrb3 from somatosensory neurons as adults have decreased preference for social novelty and social memory as they do not prefer novel mouse over stranger mouse
Exp Paradigm: NA
Description: Mutants show decrease in gaba interneurons in the hippocampus, cingulate cortex, motor cortex, and somatosensory cortex, compared to controls.
Exp Paradigm: Gaba
Description: Mutants show a decrease in the tangential stream of neurons that migrate from the basal to the dorsal telencephalon, compared to controls.
Exp Paradigm: NA
Description: Mutants show disruptions in the the anatomical landmarks of the telencephalon, the corpus callosum, the hippocampal layer stratum oriens, the triangular septal nucleus, and ventral hippocampal commissure compared to controls.
Exp Paradigm: NA
Description: Mutants show poor nest building behavior in normal and enriched conditions compared to controls.
Exp Paradigm: Wood chip bedding pressed cotton nestlets or shredded paper strips
Description: Mutants show reduction in blood vessel density and pattern formation compared to controls. mutants show disruption in the rhombic vascular patterns in the ganglionic eminence that ensheath deep gabaergic neuronal populations, compared to controls. mutants show decreased cortical vascular densities at e18 compared to controls. mutants show abnormally stretched vessels in the telencephalon compared to controls, by igg staining, but no igg leakage. mutants show slight reduction in the expression of claudin5, a tight junction protein, compared to controls. mutants continue to show decrease in isolecithin b4 vessels in the piriform cortex, cingulate cortex, motor cortex, and somatosensory cortex, into adulthood, compared to controls, indicating vascular defects.
Exp Paradigm: NA
Description: Mutants show an increase in the average lectin positive area per perfused blood vessel compared to controls, upon retro-orbital lectin perfusion and cd31 immunohistocheistry.
Exp Paradigm: Retro-orbitallectin perfusion and cd31 immunohistochemistry (ihc)
Description: Mutants show increase in percent prepulse inhibition of the startle response to a 125 db noise, when the startle noise is preceded by a light air puff.
Exp Paradigm: In vivo drg multielectrode recordings in left l4 ganglia; 1h after subcutaneous injection of isoguvacine (2 mg/kg), tactile stimulus-evoked (brush or air puff stimulus) ltmr responsivity was recorded.
Description: Homozygous deletion of gabrb3 in peripheral sensory neurons exhibited increased percent prepulse inhibition of the startle response to a 125 db noise, when the startle noise is preceded by a light air puff.
Exp Paradigm: NA
Description: Abnormal seizure: frequent interruptions by bursts of slowing, irregular high amplitude slow and sharp waves and small spikes coinciding with behavioral quiescence; high amplitutde interictal spikes with strong myoclonic jerks
Exp Paradigm: Electroencephalography
Description: Effective suppressing of clonic jerks by ethosuximide; abnormal efficacy of clonazepam, vpa, and gabab antagonist cgp 35348; abnormal efficacy leading to precipitation of seizures by carbamazepine, thip, and baclofen
Exp Paradigm: Antiepileptic drug (aed)
