Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells

The mouse mutant ducky, a model for absence epilepsy, is characterized by s pike-wave seizures and ataxia. The ducky gene was mapped previously to dist al mouse chromosome 9. High-resolution genetic and physical mapping has res ulted in the identification of the Cacna2d2 gene encoding the alpha2 delta2 voltage-dependent calcium channel subunit. Mutations in Cacna2d2 were foun d 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 al pha 1A/beta4 channel combination when coexpressed in vitro in Xenopus oocyt es. The Ca2+ channel current in acutely dissociated du/du cerebellar Purkin je cells was reduced, with no change in single-channel conductance. In cont rast, no effect on Ca2+ channel current was seen in cerebellar granule cell s, results consistent with the high level of expression of the Cacna2d2 gen e in Purkinje, but not granule, neurons. Our observations document the firs t mammalian alpha2 delta mutation and complete the association of each of t he major classes of voltage-dependent Ca2+ channel subunits with a phenotyp e of ataxia and epilepsy in the mouse.