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A Cav3.2 T-Type Calcium Channel Point Mutation Has Splice-Variant-Specific Effects on Function and Segregates with Seizure Expression in a Polygenic Rat Model of Absence Epilepsy

Citation

Powell, KL and Cain, SM and Ng, C and Sirdesai, S and David, LS and Kyi, M and Garcia, E and Tyson, JR and Reid, CA and Bahlo, M and Foote, SJ and Snutch, TP and O'Brien, TJ, A Cav3.2 T-Type Calcium Channel Point Mutation Has Splice-Variant-Specific Effects on Function and Segregates with Seizure Expression in a Polygenic Rat Model of Absence Epilepsy , Journal of Neuroscience, 29, (2) pp. 371-380. ISSN 0270-6474 (2009) [Refereed Article]

DOI: doi:10.1523/JNEUROSCI.5295-08.2009

Abstract

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 Cav3.2 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.

Item Details

Item Type:Refereed Article
Keywords:idiopathic generalized epilepsy; absence seizures; T-type calcium channel; splice variant; point mutation; genetic absence epilepsy rats from Strasbourg; GAERS
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Central Nervous System
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Foote, SJ (Professor Simon Foote)
ID Code:59800
Year Published:2009
Web of Science® Times Cited:93
Deposited By:Menzies Institute for Medical Research
Deposited On:2009-12-17
Last Modified:2010-04-15
Downloads:0

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