Ducky Mouse Phenotype of Epilepsy and Ataxia Is Associated with Mutations in theCacna2d2Gene and Decreased Calcium Channel Current in Cerebellar Purkinje Cells

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Abstract
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 theCacna2d2 gene encoding the α2δ2 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 (du2J). Both mutations are predicted to result in loss of the full-length α2δ2 protein. Functional analysis shows that the α2δ2 subunit increases the maximum conductance of the α1A/β4 channel combination when coexpressedin vitro in Xenopus oocytes. The Ca2+ channel current in acutely dissociateddu/du cerebellar Purkinje cells was reduced, with no change in single-channel conductance. In contrast, no effect on Ca2+ channel current was seen in cerebellar granule cells, results consistent with the high level of expression of theCacna2d2 gene in Purkinje, but not granule, neurons. Our observations document the first mammalian α2δ mutation and complete the association of each of the major classes of voltage-dependent Ca2+ channel subunits with a phenotype of ataxia and epilepsy in the mouse.

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