期刊
JOURNAL OF NEUROSCIENCE
卷 29, 期 2, 页码 371-380出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5295-08.2009
关键词
idiopathic generalized epilepsy; absence seizures; T-type calcium channel; splice variant; point mutation; genetic absence epilepsy rats from Strasbourg; GAERS
资金
- National Health and Medical Research Council [406640, 454655]
- Molly McDonnell Foundation Scholarship
- Canadian Institutes of Health Research Grant [10677]
Low-voltage-activated, or T-type, calcium (Ca2+) channels are believed to play an essential role in the generation of absence seizures in the idiopathic generalized epilepsies (IGEs). We describe a homozygous, missense, single nucleotide (G to C) mutation in the Ca(v)3.2 T-type Ca2+ channel gene (Cacna1h) in the genetic absence epilepsy rats from Strasbourg (GAERS) model of IGE. The GAERS Cav3.2 mutation (gcm) produces an arginine to proline (R1584P) substitution in exon 24 of Cacna1h, encoding a portion of the III-IV linker region in Cav3.2. gcm segregates codominantly with the number of seizures and time in seizure activity in progeny of an F1 intercross. We have further identified two major thalamic Cacna1h splice variants, either with or without exon 25. gcm introduced into the splice variants acts epistatically, requiring the presence of exon 25 to produce significantly faster recovery from channel inactivation and greater charge transference during high-frequency bursts. This gain-of-function mutation, the first reported in the GAERS polygenic animal model, has a novel mechanism of action, being dependent on exonic splicing for its functional consequences to be expressed.
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