Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants

Abstract

Objective:The relationship between genetic variation in the T-type calcium channel gene CACNA1H and childhood absence epilepsy is well established. The purpose of this study was to investigate the range of epilepsy syndromes for which CACNA1H variants may contribute to the genetic susceptibility architecture and determine the electrophysiological effects of these variants in relation to proposed mechanisms underlying seizures. Methods: Exons 3 to 35 of CACNA1H were screened for variants in 240 epilepsy patients (167 unrelated) and 95 control subjects by single-stranded conformation analysis followed by direct sequencing. Cascade testing of families was done by sequencing or single-stranded conformation analysis. Selected variants were introduced into the CACNA1H protein by sitedirected mutagenesis. Constructs were transiently transfected into human embryo kidney cells, and electrophysiological data were acquired.

Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype–phenotype correlation

“…5 Some of them are neuronal genes associated with epilepsy and psychiatric disorders, such as SCN2A, CACNAH1 and SLC6A3. [15][16][17][18][19][20] Interruption of gene function may interfere with those pathways, thus causing epileptic and psychiatric phenotypes.…”

The Role of Calcium Channels in Epilepsy

“…When the phenotypic spectrum was extended to include JAE, JME, and temporal lobe epilepsies, more new variants in CACNA1H were identified in affected individuals. When expressed, several of these variants altered T-type channel properties that would be predicted to augment calcium current (Khosravani et al 2005;Peloquin et al 2006;Heron et al 2007) and increase surface expression (Vitko et al 2007). More recently, when the C456S variant was expressed in neurons, it increased neuronal firing, lowered the threshold for rebound burst firing, and induced changes in gene expression (Eckle et al 2014).…”

Ca v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

“…Polymorphism or mutations of the human Ca v 3.2 gene are associated with childhood-absent epilepsy, idiopathic generalized epilepsy, and autism-spectrum disorders (25)(26)(27) −/− mice were narrow and elliptically shaped, with the long axis oriented in the anterior-posterior direction (Fig. S1A).…”