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Absence epilepsy in apathetic, a spontaneous mutant mouse lacking the h channel subunit, HCN2.

Chung WK, Shin M, Jaramillo TC, Leibel RL, LeDuc CA, Fischer SG, Tzilianos E, Gheith AA, Lewis AS, Chetkovich DM
Neurobiol Dis. 2009 33 (3): 499-508

PMID: 19150498 · PMCID: PMC2643333 · DOI:10.1016/j.nbd.2008.12.004

Analysis of naturally occurring mutations that cause seizures in rodents has advanced understanding of the molecular mechanisms underlying epilepsy. Abnormalities of I(h) and h channel expression have been found in many animal models of absence epilepsy. We characterized a novel spontaneous mutant mouse, apathetic (ap/ap), and identified the ap mutation as a 4 base pair insertion within the coding region of Hcn2, the gene encoding the h channel subunit 2 (HCN2). We demonstrated that Hcn2(ap) mRNA is reduced by 90% compared to wild type, and the predicted truncated HCN2(ap) protein is absent from the brain tissue of mice carrying the ap allele. ap/ap mice exhibited ataxia, generalized spike-wave absence seizures, and rare generalized tonic-clonic seizures. ap/+ mice had a normal gait, occasional absence seizures and an increased severity of chemoconvulsant-induced seizures. These findings help elucidate basic mechanisms of absence epilepsy and suggest HCN2 may be a target for therapeutic intervention.

MeSH Terms (24)

Amino Acid Sequence Animals Ataxia Base Sequence Body Size Brain Chlorocebus aethiops Convulsants COS Cells Cyclic Nucleotide-Gated Cation Channels Epilepsy, Absence Female Frameshift Mutation Gait Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Ion Channels Male Mice Mice, Mutant Strains Molecular Sequence Data Phenotype Potassium Channels RNA, Messenger Seizures

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