Absence Epilepsy in Tottering Mutant Mice Is Associated with Calcium Channel Defects

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Mutations at the mouse tottering ( tg) locus cause a delayed-onset, recessive neurological disorder resulting in ataxia, motor seizures, and behavioral absence seizures resembling petit mal epilepsy in humans. A more severe allele, leaner ( tg la ), also shows a slow, selective degeneration of cerebellar neurons. By positional cloning, we have identified an α 1A voltage-sensitive calcium channel gene that is mutated in tg and tg la mice. The α 1A gene is widely expressed in the central nervous system with prominent, uniform expression in the cerebellum. α 1A expression does not mirror the localized pattern of cerebellar degeneration observed in tg la mice, providing evidence for regional differences in biological function of α 1A channels. These studies define the first mutations in a mammalian central nervous system–specific voltage-sensitive calcium channel and identify the first gene involved in absence epilepsy.