Dataset Information

A novel de novo variant of GABRA1 causes increased sensitivity for GABA in vitro.

ABSTRACT: The GABRA1 gene encodes one of the most conserved and highly expressed subunits of the GABAA receptor family. Variants in this gene are causatively implicated in different forms of epilepsy and also more severe epilepsy-related neurodevelopmental syndromes. Here we study functional consequences of a novel de novo missense GABRA1 variant, p.(Ala332Val), identified through exome sequencing in an individual affected by early-onset syndromic epileptic encephalopathy. The variant is localised within the transmembrane domain helix 3 (TM3) and in silico prediction algorithms suggested this variant to be likely pathogenic. In vitro assessment revealed unchanged protein levels, regular assembly and forward trafficking to the cell surface. On the functional level a significant left shift of the apparent GABA potency in two-electrode voltage clamp electrophysiology experiments was observed, as well as changes in the extent of desensitization. Additionally, apparent diazepam potency was left shifted in radioligand displacement assays. During prenatal development mainly alpha2/3 subunits are expressed, whereas after birth a switch to alpha1 occurs. The expression of alpha1 in humans is upregulated during the first years. Thus, the molecular change of function reported here supports pathogenicity and could explain early-onset of seizures in the affected individual.

SUBMITTER: Steudle F

PROVIDER: S-EPMC7012862 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A novel de novo variant of GABRA1 causes increased sensitivity for GABA in vitro.

Steudle Friederike F Rehman Sabah S Bampali Konstantina K Simeone Xenia X Rona Zsofia Z Hauser Erwin E Schmidt Wolfgang M WM Scholze Petra P Ernst Margot M

Scientific reports 20200211 1

The GABRA1 gene encodes one of the most conserved and highly expressed subunits of the GABA<sub>A</sub> receptor family. Variants in this gene are causatively implicated in different forms of epilepsy and also more severe epilepsy-related neurodevelopmental syndromes. Here we study functional consequences of a novel de novo missense GABRA1 variant, p.(Ala332Val), identified through exome sequencing in an individual affected by early-onset syndromic epileptic encephalopathy. The variant is locali ...[more]

PMID: 32047208

Similar Datasets

Project description:BackgroundThe GABRA1 gene, encoding the GABRAR subunit α1, plays vital roles in inhibitory neurons. Previously, the GABRA1 gene has been identified to be associated with developmental and epileptic encephalopathy (DEE) and idiopathic generalized epilepsy (IGE). This study aims to explore the phenotypic spectrum of GABRA1 and molecular subregional effect analysis.MethodsTrios-based whole-exome sequencing was performed in patients with epilepsy. Previously reported GABRA1 mutations were systematically reviewed to analyze the molecular subregional effects.ResultsDe novo GABRA1 mutations were identified in six unrelated patients with heterogeneous epilepsy, including three missense mutations (p.His83Asn, p.Val207Phe, and p.Arg214Cys) and one frameshift mutation (p.Thr453Hisfs*47). The two missense mutations, p.His83Asn and p.Val207Phe, were predicted to decrease the protein stability but no hydrogen bond alteration, with which the two patients also presented with mild genetic epilepsy with febrile seizures plus and achieved seizure-free status by monotherapy. The missense variant p.Arg214Cys was predicted to decrease protein stability and destroy hydrogen bonds with surrounding residues, which was recurrently identified in three cases with severe DEE. The frameshift variant p.Thr453Hisfs*47 was located in the last fifth residue of the C-terminus and caused an extension of 47 amino acids, with which the patients presented with moderated epilepsy with generalized tonic-clonic seizures alone (GTCA) but achieved seizure-free status by four drugs. The four variants were not presented in gnomAD and were evaluated as "pathogenic/likely pathogenic" according to ACMG criteria. Analysis of all reported cases indicated that patients with mutations in the N-terminal extracellular region presented a significantly higher percentage of FS and DEE, and the patients with variants in the transmembrane region presented earlier seizure onset ages.SignificanceThis study suggested that GABRA1 variants were potentially associated with a spectrum of epilepsies, including EFS+, DEE, and GTCA. Phenotypic severity may be associated with the damaging effect of variants. The molecular subregional effects help in understanding the underlying mechanism of phenotypic variation.

Dataset Information

A novel de novo variant of GABRA1 causes increased sensitivity for GABA in vitro.

Publications

A novel de novo variant of GABRA1 causes increased sensitivity for GABA in vitro.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets