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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

journal contribution
posted on 2023-05-17, 00:58 authored by Powell, KL, Cain, SM, Ng, C, Sirdesai, S, David, LS, Kyi, M, Garcia, E, Tyson, JR, Reid, CA, Bahlo, M, Simon James FooteSimon James Foote, Snutch, TP, O'Brien, TJ
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.

History

Publication title

Journal of Neuroscience

Volume

29

Pagination

371-380

ISSN

0270-6474

Department/School

Menzies Institute for Medical Research

Publisher

Soc Neuroscience

Place of publication

11 Dupont Circle, Nw, Ste 500, Washington, USA, Dc

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified