De novo GABRG2 mutations associated with epileptic encephalopathies.
Brain
; 140(1): 49-67, 2017 01.
Article
en En
| MEDLINE
| ID: mdl-27864268
ABSTRACT
Epileptic encephalopathies are a devastating group of severe childhood onset epilepsies with medication-resistant seizures and poor developmental outcomes. Many epileptic encephalopathies have a genetic aetiology and are often associated with de novo mutations in genes mediating synaptic transmission, including GABAA receptor subunit genes. Recently, we performed next generation sequencing on patients with a spectrum of epileptic encephalopathy phenotypes, and we identified five novel (A106T, I107T, P282S, R323W and F343L) and one known (R323Q) de novo GABRG2 pathogenic variants (mutations) in eight patients. To gain insight into the molecular basis for how these mutations contribute to epileptic encephalopathies, we compared the effects of the mutations on the properties of recombinant α1ß2γ2L GABAA receptors transiently expressed in HEK293T cells. Using a combination of patch clamp recording, immunoblotting, confocal imaging and structural modelling, we characterized the effects of these GABRG2 mutations on GABAA receptor biogenesis and channel function. Compared with wild-type α1ß2γ2L receptors, GABAA receptors containing a mutant γ2 subunit had reduced cell surface expression with altered subunit stoichiometry or decreased GABA-evoked whole-cell current amplitudes, but with different levels of reduction. While a causal role of these mutations cannot be established directly from these results, the functional analysis together with the genetic information suggests that these GABRG2 variants may be major contributors to the epileptic encephalopathy phenotypes. Our study further expands the GABRG2 phenotypic spectrum and supports growing evidence that defects in GABAergic neurotransmission participate in the pathogenesis of genetic epilepsies including epileptic encephalopathies.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Receptores de GABA-A
/
Epilepsia
/
Epilepsia Refractaria
Tipo de estudio:
Clinical_trials
/
Risk_factors_studies
Límite:
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Brain
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos