Eleven of twelve childhood absence epilepsy-associated SNPs in the CACNA1H gene altered channel gating, with computer simulations predicting that seven SNPs would increase neuronal firing.
CAE-specific SNPs in the CACNA1H gene alter T-type calcium channel gating, which computer models predict would enhance neuronal burst firing, supporting its role as a susceptibility gene for childhood absence epilepsy.
Sequencing of the T-type Ca2+ channel gene CACNA1H revealed 12 nonsynonymous single nucleotide polymorphisms (SNPs) that were found only in childhood absence epilepsy (CAE) patients. One SNP, G773D, was found in two patients. The present study reports the finding of a third patient with this SNP, as well as analysis of their parents. Because of the role of T-channels in determining the intrinsic firing patterns of neurons involved in absence seizures, it was suggested that these SNPs might alter channel function. The goal of the present study was to test this hypothesis by introducing these polymorphisms into a human Ca(v)3.2a cDNA and then study alterations in channel behavior using whole-cell patch-clamp recording. Eleven SNPs altered some aspect of channel gating. Computer simulations predict that seven of the SNPs would increase firing of neurons, with three of them inducing oscillations at similar frequencies, as observed during absence seizures. Three SNPs were predicted to decrease firing. Some CAE-specific SNPs (e.g., G773D) coexist with SNPs also found in controls (R788C); therefore, the effect of these polymorphisms were studied. The R788C SNP altered activity in a manner that would also lead to enhanced burst firing of neurons. The G773D-R788C combination displayed different behavior than either single SNP. Therefore, common polymorphisms can alter the effect of CAE-specific SNPs, highlighting the importance of sequence background. These results suggest that CACNA1H is a susceptibility gene that contributes to the development of polygenic disorders characterized by thalamocortical dysrhythmia, such as CAE.
Vitko et al. (2005) studied Childhood absence epilepsy. CACNA1H variants (SNPs) vs. Wild-type CACNA1H was evaluated on Channel gating properties and predicted neuronal firing. Eleven of twelve childhood absence epilepsy-associated SNPs in the CACNA1H gene altered channel gating, with computer simulations predicting that seven SNPs would increase neuronal firing.