Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells
Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells
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DOI：
10.1523/jneurosci.21-16-06095.2001
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发表时间：
2001-08-15
影响因子：
5.3
通讯作者：
Rees, M
中科院分区：
文献类型：
--
作者：
Barclay, J;Balaguero, N;Rees, M
小鼠突变体ducky是失神癫痫的模型，其特征在于棘波癫痫发作和共济失调。ducky基因先前被定位于小鼠9号染色体远端。高分辨率的遗传和物理作图已导致Cacna 2d 2基因编码的α 2 δ 2电压依赖性钙通道亚基的鉴定。发现Cacna 2d 2中的突变是原始ducky（du）菌株和新鉴定的菌株（du（2 J））中的ducky表型的基础。预计这两种突变都会导致全长α 2 δ 2蛋白的丢失。功能分析表明，在非洲爪蟾卵母细胞体外共表达时，α 2 δ 2亚基增加了α 1A/β 4通道组合的最大电导。急性分离的du/du小脑浦肯野细胞的Ca（2+）通道电流降低，而单通道电导无变化。相反，在小脑颗粒细胞中未观察到对Ca（2+）通道电流的影响，结果与Cacna 2d 2基因在浦肯野神经元而非颗粒神经元中的高水平表达一致。我们的观察记录了第一个哺乳动物α 2 δ突变，并完成了每一个主要类别的电压依赖性Ca（2+）通道亚基与共济失调和癫痫的小鼠表型的关联。
The mouse mutant ducky, a model for absence epilepsy, is characterized by spike-wave seizures and ataxia. The ducky gene was mapped previously to distal mouse chromosome 9. High-resolution genetic and physical mapping has resulted in the identification of the Cacna2d2 gene encoding the alpha2 delta2 voltage-dependent calcium channel subunit. Mutations in Cacna2d2 were found to underlie the ducky phenotype in the original ducky (du) strain and in a newly identified strain (du(2J)). Both mutations are predicted to result in loss of the full-length alpha2 delta2 protein. Functional analysis shows that the alpha2 delta2 subunit increases the maximum conductance of the alpha 1A/beta4 channel combination when coexpressed in vitro in Xenopus oocytes. The Ca(2+) channel current in acutely dissociated du/du cerebellar Purkinje cells was reduced, with no change in single-channel conductance. In contrast, no effect on Ca(2+) channel current was seen in cerebellar granule cells, results consistent with the high level of expression of the Cacna2d2 gene in Purkinje, but not granule, neurons. Our observations document the first mammalian alpha2 delta mutation and complete the association of each of the major classes of voltage-dependent Ca(2+) channel subunits with a phenotype of ataxia and epilepsy in the mouse.