title: Mutations in the Cacnl1a4 calcium channel gene are associated with seizures, cerebellar degeneration, and ataxia in tottering and leaner mutant mice.
abstract: Tottering and leaner, two mutations of the mouse tottering locus, have been studied extensively as models for human epilepsy. Here we describe the isolation, mapping, and expression analysis of Cacnl1a4, a gene encoding the alpha subunit of a proposed P-type calcium channel, and also report the physical mapping and expression patterns of the orthologous human gene. DNA sequencing and gene expression data demonstrate that Cacnl1a4 mutations are the primary cause of seizures and ataxia in tottering and leaner mutant mice, and suggest that tottering locus mutations and human diseases, episodic ataxia 2 and familial hemiplegic migraine, represent mutations in mouse and human versions of the same channel-encoding gene.
authors.affiliation: Biology Division, Oak Ridge National Laboratory, Tennessee 37831-8077, USA.
authors.forename: J
authors.initials: J
authors.lastname: Doyle
authors.forename: X
authors.initials: X
authors.lastname: Ren
authors.forename: G
authors.initials: G
authors.lastname: Lennon
authors.forename: L
authors.initials: L
authors.lastname: Stubbs
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015220:Calcium Channels / Q000235:genetics*; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D002524:Cerebellar Ataxia / Q000235:genetics*; D002531:Cerebellum / Q000378:metabolism*; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D018076:DNA, Complementary; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008818:Mice, Neurologic Mutants; D008881:Migraine Disorders / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D051381:Rats; D012640:Seizures / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D013132:Spinocerebellar Degenerations / Q000235:genetics
chemical_list: D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D018076:DNA, Complementary; C105656:CACNA1A protein, human; C491367:Cacna1a protein, rat