Aliases: DEE78, EIEE78
Chromosome No: 4
Chromosome Band: 4p12
Genetic Category: Rare single gene variant-Functional-Rare single gene variant/Functional
ASD Reports: 7
Recent Reports: 0
Annotated variants: 13
Associated CNVs: 5
Evidence score: 3
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Relevance to Autism
Heterozygous variants in GABRA2 are responsible for developmental and epileptic encephalopathy 78 (DDE78; OMIM 618557). Adamo-Croux et al., 2025 reported six new patients with GABRA2 variants identified through a French national collaboration; all six individuals presented with epilepsy and developmental delay, and four were reported to present with autism spectrum disorder. Maljevic et al., 2019 had previously identified a DDE78 patient with ASD and a de novo GABRA2 missense variant, as well as two siblings with an attenuated form of DEE78 caused by a mosaic paternally-inherited missense variant (the proband was diagnosed with ASD, while his sister did not have autistic features); functional analysis in Xenopus oocytes demonstrated that both of these ASD-associated missense variants resulted in a loss-of-function effect. Several de novo missense variants in this gene have been identified in ASD probands, including a missense variant that was absent in ExAC and gnomAD and predicted to be damaging by CADD, REVEL, and MPC in a SPARK proband (Takata et al., 2018; Zhou et al., 2022; Fu et al., 2022). Gabra2 interacts with collybistin, the protein encoded by the ARHGEF9 gene (Hines et al., 2018). Hines et al., 2022 found that mutating the collybistin-binding motif within the large intracellular loop of Gabra2 and replacing it with the binding motif for gephyrin from Gabra1 (Gabra2-1) resulted in strongly downregulated collybistin expression in addition to deficits in working and recognition memory, hyperactivity, anxiety, and reduced social preference, recapitulating the frequently reported features of patients with ARHGEF9 mutations.
Molecular Function
Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain. GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interfaces. When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient. Chloride influx into the postsynaptic neuron following GABAAR opening decreases the neuron ability to generate a new action potential, thereby reducing nerve transmission.
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