The de novo missense mutation F224S in GABRB2, identified in epileptic encephalopathy and developmental delay,...

Genetic variants in genes encoding subunits of the γ-aminobutyric acid-A receptor (GABA_AR) have been found to cause neurodevelopmental disorders and epileptic encephalopathy. In a patient with epilepsy and developmental delay, a de novo heterozygous missense mutation c.671 T > C (p.F224S) was discovered in the GABRB2 gene, which encodes the β2 subunit of GABA_AR. Based on previous studies on GABRB2 variants, this new GABRB2 variant (F224S) would be pathogenic. To confirm and investigate the effects of this GABRB2 mutation on GABA_AR channel function, we conducted transient expression experiments using GABA_AR subunits in HEK293T cells. The GABA_ARs containing mutant β2 (F224S) subunit showed poor trafficking to the cell membrane, while the expression and distribution of the normal α1 and γ2 subunits were unaffected. Furthermore, the peak current amplitude of the GABA_AR containing the β2 (F224S) subunit was significantly smaller compared to the wild type GABA_AR. We propose that GABRB2 variant F224S is pathogenic and GABA_ARs containing this β2 mutant reduce response to GABA under physiological conditions, which could potentially disrupt the excitation/inhibition balance in the brain, leading to epilepsy.