The de novo missense mutation F224S in GABRB2, identified in epileptic encephalopathy and developmental delay, impairs GABAAR function.
Neuroscience
; 553: 172-184, 2024 Aug 16.
Article
en En
| MEDLINE
| ID: mdl-38964454
ABSTRACT
Genetic variants in genes encoding subunits of the γ-aminobutyric acid-A receptor (GABAAR) 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 ß2 subunit of GABAAR. 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 GABAAR channel function, we conducted transient expression experiments using GABAAR subunits in HEK293T cells. The GABAARs containing mutant ß2 (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 GABAAR containing the ß2 (F224S) subunit was significantly smaller compared to the wild type GABAAR. We propose that GABRB2 variant F224S is pathogenic and GABAARs containing this ß2 mutant reduce response to GABA under physiological conditions, which could potentially disrupt the excitation/inhibition balance in the brain, leading to epilepsy.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Discapacidades del Desarrollo
/
Receptores de GABA-A
/
Mutación Missense
/
Epilepsia
Límite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
Neuroscience
Año:
2024
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Estados Unidos