Abstract
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. 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 site-directed mutagenesis. Constructs were transiently transfected into human embryo kidney cells, and electrophysiological data were acquired. More than 100 variants were detected, including 19 novel variants leading to amino acid changes in subjects with phenotypes including childhood absence, juvenile absence, juvenile myoclonic and myoclonic astatic epilepsies, as well as febrile seizures and temporal lobe epilepsy. Electrophysiological analysis of 11 variants showed that 9 altered channel properties, generally in ways that would be predicted to increase calcium current. Variants in CACNA1H that alter channel properties are present in patients with various generalized epilepsy syndromes. We propose that these variants contribute to an individual's susceptibility to epilepsy but are not sufficient to cause epilepsy on their own. The genetic architecture is dominated by rare functional variants; therefore, CACNA1H would not be easily identified as a susceptibility gene by a genome-wide case-control study seeking a statistical association.
Highlights
Two-hundred and forty patients (167 unrelated) were screened in total. Their clinical phenotypes included 37 childhood absence epilepsy (CAE), 14 juvenile absence epilepsy (JAE), 31 juvenile myoclonic epilepsy, 5 juvenile myoclonic epilepsy evolved from CAE, 20 other idiopathic generalized epilepsies (IGEs), 55 myoclonic-astatic epilepsy (MAE), 17 (FS), 28 generalized epilepsy with febrile seizures plus (GEFSϩ), 5 other generalized epilepsies, 11 temporal lobe epilepsy (TLE), 3 other focal epilepsies, 10 miscellaneous epilepsy patients, and 4 unaffected family members of epilepsy patients
The T-type calcium channels are involved in the thalamocortical network,[15] and variants in the gene coding for one of these channels, CACNA1H, have been related to CAE and rare cases with IGE.[16]
Nine of the variants altered channel kinetics consistent with epileptogenesis. These variants were observed in patients with a range of epilepsy syndromes including classic IGEs (CAE, JAE, juvenile myoclonic epilepsy, IGE with generalized tonic-clonic seizures), GEFSϩ (MAE, FS), and TLE
Summary
The relationship between genetic variation in the T-type calcium channel gene CACNA1H and childhood absence epilepsy is well established. The GABA receptor subunit gene GABRD has been shown to contain variants likely to increase seizure susceptibility.[4] A polymorphism in the promoter of the GABA receptor subunit gene GABRB3 is associated with childhood absence epilepsy (CAE) in some cohorts and has been shown to affect transcription efficiency.[5,6] A truncation mutation of the potassium channel subunit gene KCND2 has been identified in a patient with temporal lobe epilepsy (TLE), as well as some unaffected family members, suggesting that it is a probable susceptibility allele rather than a dominant mutation of large effect.[7] Variants in the T-type calcium channel gene CACNA1H have been associated with CAE in Chinese patients,[8,9] and these variants alter channel function in ways consistent with epileptogenesis.[10,11,12] Two CACNA1H variants in patients with febrile seizures (FS) and myoclonic-astatic epilepsy (MAE) alter channel function,[13,14] suggesting that variation in this gene plays a more general role in epilepsy susceptibility. Electrophysiological studies of 11 of the variants identified showed that 9 exhibit biophysical alterations that may contribute to epilepsy susceptibility
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