What is the clinical evidence from this study?

Study design: Other. Population: Childhood absence epilepsy. Intervention: CACNA1H variants (SNPs) vs. Wild-type CACNA1H. Primary outcome: Channel gating properties and predicted neuronal firing.

May 11, 2005Journal of Neuroscience181 citationsOpen Access

Functional Characterization and Neuronal Modeling of the Effects of Childhood Absence Epilepsy Variants ofCACNA1H, a T-Type Calcium Channel

IVIuliia VitkoUniversity of Virginia YCYucai ChenShanghai Children's Hospital JAJuan Manuel AriasUniversidad Autónoma de la Ciudad de México

Key Result

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.

PICO

Population

In vitro and in silico study characterizing the functional effects of 12 childhood absence epilepsy-associated SNPs in the CACNA1H gene using transfected HEK-293 cells and neuronal modeling.

Exposure / Comparator

CACNA1H variants (SNPs) vs Wild-type CACNA1H

Primary Outcome

Channel gating properties and predicted neuronal firing

Limitations

In vitro expression in HEK-293 cells may not fully replicate the native neuronal environment
Computer models are simplifications of complex thalamocortical circuits
Species differences between human and rat channels may affect interpretation of previous studies

Abstract

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.

Ask AI

Helpful

Bookmark

View Full Paper