Relevance to Autism

Multiple de novo variants in the GABRG2 gene, including a de novo loss-of-function variant and several de novo missense variants that are predicted to be deleterious, have been identified in ASD probands (De Rubeis et al., 2014; Zhou et al., 2022; Miyake et al., 2023); two of the ASD-associated missense variants in this gene had previously been identified in individuals with developmental and epileptic encephalpathy in Shen et al., 2016 and experimentally shown to result in reduced surface expression and decreased GABA-evoked whole-cell current amplitudes. Additional loss-of-function and missense variants with CADD scores > 30 were reported in individuals with a primary diagnosis of ASD in Wang et al., 2020. Hand stereotypies were reported in 1 of 8 individuals with de novo GABRG2 missense variants resulting in developmental and epileptic encephalopathy in Shen et al., 2016, and autism spectrum disorder was diagnosed in a patient with a p.Pro83Ser missense variant that had previously been identified in a family with idiopathic generalized epilepsy in Komulainen-Ebrahim et al., 2019. A polymorphism in the GABRG2 gene had previously been shown to be overrepresented in ASD cases by haplotype analysis (Sesarini et al., 2015).

Molecular Function

This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammlian brain, where it acts at GABA-A receptors, which are ligand-gated chloride channels. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene are responsible for developmental and epileptic encephalopathy-74 (DEE74; OMIM 618396) and familial febrile seizures-8 (FEB8; OMIM 607681).

External Links

References