title: A targeted mutation in Cacng4 exacerbates spike-wave seizures in stargazer (Cacng2) mice.
abstract: The voltage-dependent calcium channel gamma4 subunit protein, CACNG4, is closely related to the gamma2 subunit, CACNG2. Both are expressed primarily in the brain and share 53% amino acid identity. The Cacng2 gene is disrupted in the stargazer mouse, with its distinctive phenotype including ataxia, frequent absence seizure episodes, and head elevation. A disruption within Cacng4 was engineered to assess its particular function. The homozygous Cacng4-targeted mutant mouse appeared normal with no ataxic gait or absence seizures, suggesting that other members of the gamma subunit family might functionally compensate for the absence of CACNG4. To test this hypothesis, the targeted Cacng4 mutation was combined with alleles of Cacng2. Absence seizures were observed in combination with the stargazer 3J mutation, which itself does not have seizures, and increased seizure activity was observed in combination with the waggler allele. Furthermore, within the corticothalamic loop, where absence seizures arise, CACNG4 expression is restricted to the thalamus. Our studies show that the CACNG4 protein has seizure suppressing activity, but this effect is revealed only when CACNG2 expression is also compromised, suggesting that CACNG subunits have in vivo overlapping functions.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA. val@jax.org
authors.forename: Verity A
authors.initials: VA
authors.lastname: Letts
authors.forename: Connie L
authors.initials: CL
authors.lastname: Mahaffey
authors.forename: Barbara
authors.initials: B
authors.lastname: Beyer
authors.forename: Wayne N
authors.initials: WN
authors.lastname: Frankel
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D004567:Electrodes, Implanted; D004569:Electroencephalography; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005838:Genotype; D008297:Male; D018782:Maze Learning; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010641:Phenotype; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D045442:Rotarod Performance Test; D012640:Seizures / Q000235:genetics
chemical_list: C113940:Cacng2 protein, mouse; C499759:Cacng4 protein, mouse; D015220:Calcium Channels; D021122:Protein Subunits