title: Absence epilepsy in apathetic, a spontaneous mutant mouse lacking the h channel subunit, HCN2.
abstract: 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.
authors.affiliation: Division of Molecular Genetics and the Naomi Berrie Diabetes Center, Columbia University Medical College, Russell Berrie Medical Science Pavilion, Room 620, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Minyoung
authors.initials: M
authors.lastname: Shin
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Jaramillo
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Leibel
authors.forename: Charles A
authors.initials: CA
authors.lastname: LeDuc
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Fischer
authors.forename: Efthia
authors.initials: E
authors.lastname: Tzilianos
authors.forename: Ayman A
authors.initials: AA
authors.lastname: Gheith
authors.forename: Alan S
authors.initials: AS
authors.lastname: Lewis
authors.forename: Dane M
authors.initials: DM
authors.lastname: Chetkovich
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics; D001483:Base Sequence; D049628:Body Size; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D003292:Convulsants / Q000008:administration & dosage; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism; D004832:Epilepsy, Absence / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D016368:Frameshift Mutation; D005684:Gait; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000235:genetics
chemical_list: D003292:Convulsants; D054815:Cyclic Nucleotide-Gated Cation Channels; C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels; D012333:RNA, Messenger