Absence epilepsy in tottering mutant mice is associated with calcium channel defects

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 alpha(1A) voltage-sensitive calcium channel gene that is mutated in tg and tg(la) mice. The alpha(1A) gene is widely expressed in the central nervous system with prominent, uniform expression in the cerebellum. alpha(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 alpha(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.