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Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel
Vitko, I; Chen, YC; Arias, JM; Shen, Y; Wu, XR; Perez-Reyes, E
关键词Calcium Channels T-type Epilepsy Single Nucleotide Polymorphisms Thalamus Ion Channel Gating
刊名JOURNAL OF NEUROSCIENCE
2005-05-11
DOI10.1523/JNEUROSCI.0847-05.2005
25期:19页:4844-4855
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Neurosciences
研究领域[WOS]Neurosciences & Neurology
关键词[WOS]IDIOPATHIC GENERALIZED EPILEPSY ; CA2+ CHANNELS ; THALAMIC NEURONS ; WAVE OSCILLATIONS ; GENETIC-VARIATION ; RELAY NEURONS ; RAT ; CELLS ; EXPRESSION ; SEIZURES
英文摘要

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.

语种英语
WOS记录号WOS:000229038300018
Citation statistics
Cited Times:122[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/54353
Collection北京大学第一临床医学院_儿科
作者单位1.Natl Ctr Human Genome Res, Beijing 100176, Peoples R China
2.Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA
3.Peking Univ, Hosp 1, Dept Pediat, Beijing 100034, Peoples R China
Recommended Citation
GB/T 7714
Vitko, I,Chen, YC,Arias, JM,et al. Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel[J]. JOURNAL OF NEUROSCIENCE,2005,25(19):4844-4855.
APA Vitko, I,Chen, YC,Arias, JM,Shen, Y,Wu, XR,&Perez-Reyes, E.(2005).Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel.JOURNAL OF NEUROSCIENCE,25(19),4844-4855.
MLA Vitko, I,et al."Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel".JOURNAL OF NEUROSCIENCE 25.19(2005):4844-4855.
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