title: Absence epilepsy in tottering mutant mice is associated with calcium channel defects.
abstract: 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 alpha1A voltage-sensitive calcium channel gene that is mutated in tg and tg(la) mice. The alpha1A gene is widely expressed in the central nervous system with prominent, uniform expression in the cerebellum. alpha1A expression does not mirror the localized pattern of cerebellar degeneration observed in tg(la) mice, providing evidence for regional differences in biological function of alpha1A 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.
authors.affiliation: Mammalian Genetics Laboratory, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA.
authors.forename: C F
authors.initials: CF
authors.lastname: Fletcher
authors.forename: C M
authors.initials: CM
authors.lastname: Lutz
authors.forename: T N
authors.initials: TN
authors.lastname: O'Sullivan
authors.forename: J D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: R
authors.initials: R
authors.lastname: Hawkes
authors.forename: W N
authors.initials: WN
authors.lastname: Frankel
authors.forename: N G
authors.initials: NG
authors.lastname: Copeland
authors.forename: N A
authors.initials: NA
authors.lastname: Jenkins
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015220:Calcium Channels / Q000145:classification / Q000235:genetics*; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D002531:Cerebellum / Q000473:pathology; D002874:Chromosome Mapping; D018244:Chromosomes, Artificial, Yeast; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D004832:Epilepsy, Absence / Q000209:etiology / Q000235:genetics*; D017403:In Situ Hybridization; D015640:Ion Channel Gating / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000145:classification / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D017422:Sequence Analysis, DNA
chemical_list: D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D009419:Nerve Tissue Proteins