The ducky mutation in Cacna2d2 results in altered Purkinje cell morphology and is associated with the expression of a truncated α2δ-2 protein with abnormal function

Abstract

The mouse mutant ducky, a model for absence epilepsy, is characterized by spike-wave seizures and cerebellar ataxia. A mutation in Cacna2d2, the gene encoding the α2δ-2 voltage-dependent calcium channel accessory subunit, has been found to underlie the ducky phenotype. The α2δ-2 mRNA is strongly expressed in cerebellar Purkinje cells. We show that du/du mice have abnormalities in their Purkinje cell dendritic tree. The mutation in α2δ-2 results in the introduction of a premature stop codon and predicts the expression of a truncated protein encoded by the first three exons of Cacna2d2, followed by 8 novel amino acids. We show that both mRNA and protein corresponding to this predicted transcript are expressed in duldu cerebellum and present in Purkinje cells. Whereas the α2δ-2 subunit increased the peak current density of the Cav2.1/β4 channel combination when co-expressed in vitro, co-expression with the truncated mutant α2δ-2 protein reduced current density, indicating that it may contribute to the du phenotype.