Barclay J, Balaguero N, Mione M, Ackerman S L, Letts V A, Brodbeck J, Canti C, Meir A, Page K M, Kusumi K, Perez-Reyes E, Lander E S, Frankel W N, Gardiner R M, Dolphin A C, Rees M
Department of Paediatrics and Child Health, Royal Free and University College Medical School, The Rayne Institute, London, WC1E 6JJ, United Kingdom.
J Neurosci. 2001 Aug 15;21(16):6095-104. doi: 10.1523/JNEUROSCI.21-16-06095.2001.
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 alpha2delta2 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 alpha2delta2 protein. Functional analysis shows that the alpha2delta2 subunit increases the maximum conductance of the alpha1A/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 alpha2delta 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.
小鼠突变体ducky是失神癫痫的一种模型，其特征为棘波发作和共济失调。ducky基因先前被定位到小鼠9号染色体远端。高分辨率遗传和物理图谱分析已鉴定出编码α2δ2电压依赖性钙通道亚基的Cacna2d2基因。在原始ducky（du）品系和新鉴定的品系（du(2J)）中，发现Cacna2d2突变是ducky表型的基础。预计这两种突变都会导致全长α2δ2蛋白的缺失。功能分析表明，当在非洲爪蟾卵母细胞中进行体外共表达时，α2δ2亚基可增加α1A/β4通道组合的最大电导率。急性分离的du/du小脑浦肯野细胞中的Ca(2+)通道电流降低，单通道电导率无变化。相比之下，在小脑颗粒细胞中未观察到对Ca(2+)通道电流的影响，这一结果与Cacna2d2基因在浦肯野神经元而非颗粒神经元中的高表达水平一致。我们的观察记录了首例哺乳动物α2δ突变，并完成了每种主要类型的电压依赖性Ca(2+)通道亚基与小鼠共济失调和癫痫表型的关联。
