Dataset Information

Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy.

ABSTRACT:

Objective

Genetic generalized epilepsy (GGE) encompasses seizure disorders characterized by spike-and-wave discharges (SWD) originating within thalamo-cortical circuits. Hyperpolarization-activated (HCN) and T-type Ca²⁺ channels are key modulators of rhythmic activity in these brain regions. Here, we screened HCN4 and CACNA1H genes for potentially contributory variants and provide their functional analysis.

Methods

Targeted gene sequencing was performed in 20 unrelated familial cases with different subtypes of GGE, and the results confirmed in 230 ethnically matching controls. Selected variants in CACNA1H and HCN4 were functionally assessed in tsA201 cells and Xenopus laevis oocytes, respectively.

Results

We discovered a novel CACNA1H (p.G1158S) variant in two affected members of a single family. One of them also carried an HCN4 (p.P1117L) variant inherited from the unaffected mother. In a separate family, an HCN4 variant (p.E153G) was identified in one of several affected members. Voltage-clamp analysis of CACNA1H (p.G1158S) revealed a small but significant gain-of-function, including increased current density and a depolarizing shift of steady-state inactivation. HCN4 p.P1117L and p.G153E both caused a hyperpolarizing shift in activation and reduced current amplitudes, resulting in a loss-of-function.

Significance

Our results are consistent with a model suggesting cumulative contributions of subtle functional variations in ion channels to seizure susceptibility and GGE.

SUBMITTER: Becker F

PROVIDER: S-EPMC5862120 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Functional variants in <i>HCN4</i> and <i>CACNA1H</i> may contribute to genetic generalized epilepsy.

Becker Felicitas F Reid Christopher A CA Hallmann Kerstin K Tae Han-Shen HS Phillips A Marie AM Teodorescu Georgeta G Weber Yvonne G YG Kleefuss-Lie Ailing A Elger Christian C Perez-Reyes Edward E Petrou Steven S Kunz Wolfram S WS Lerche Holger H Maljevic Snezana S

Epilepsia open 20170805 3

<h4>Objective</h4>Genetic generalized epilepsy (GGE) encompasses seizure disorders characterized by spike-and-wave discharges (SWD) originating within thalamo-cortical circuits. Hyperpolarization-activated (HCN) and T-type Ca<sup>2+</sup> channels are key modulators of rhythmic activity in these brain regions. Here, we screened <i>HCN4</i> and <i>CACNA1H</i> genes for potentially contributory variants and provide their functional analysis.<h4>Methods</h4>Targeted gene sequencing was performed in ...[more]

PMID: 29588962

Similar Datasets

Project description:ObjectiveWe aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE.MethodsWe performed a case-control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18 834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding γ-aminobutyric acid type A [GABAA ] receptors, 113 genes representing the GABAergic pathway).ResultsGABRG2 was associated with GGE (p = 1.8 × 10-5 ), approaching study-wide significance in familial GGE (p = 3.0 × 10-6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 1.9-7.8, false discovery rate [FDR]-adjusted p = .0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3-6.7, FDR-adjusted p = .022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3-2.5, FDR-adjusted p = .0024) but not with sporadic GGE (OR = 1.3, 95% CI = .9-1.9, FDR-adjusted p = .19).SignificanceURVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.