title: Augmented currents of an HCN2 variant in patients with febrile seizure syndromes.
abstract: The genetic architecture of common epilepsies is largely unknown. HCNs are excellent epilepsy candidate genes because of their fundamental neurophysiological roles. Screening in subjects with febrile seizures and genetic epilepsy with febrile seizures plus revealed that 2.4% carried a common triple proline deletion (delPPP) in HCN2 that was seen in only 0.2% of blood bank controls. Currents generated by mutant HCN2 channels were approximately 35% larger than those of controls; an effect revealed using automated electrophysiology and an appropriately powered sample size. This is the first association of HCN2 and familial epilepsy, demonstrating gain of function of HCN2 current as a potential contributor to polygenic epilepsy.
authors.affiliation: SA Pathology at the Women's and Children's Hospital, North Adelaide, South Australia, Australia.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reid
authors.forename: Bree
authors.initials: B
authors.lastname: Hodgson
authors.forename: Evan A
authors.initials: EA
authors.lastname: Thomas
authors.forename: Alison M
authors.initials: AM
authors.lastname: Phillips
authors.forename: Elena
authors.initials: E
authors.lastname: Gazina
authors.forename: Brett A
authors.initials: BA
authors.lastname: Cromer
authors.forename: Alison L
authors.initials: AL
authors.lastname: Clarke
authors.forename: Tallie Z
authors.initials: TZ
authors.lastname: Baram
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
mesh_terms: D000818:Animals; D001703:Biophysics / Q000379:methods; D000242:Cyclic AMP / Q000494:pharmacology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D004558:Electric Stimulation / Q000379:methods; D005787:Gene Frequency; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000235:genetics*; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D015221:Potassium Channels / Q000235:genetics; D011392:Proline / Q000235:genetics; D003294:Seizures, Febrile / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D014162:Transfection / Q000379:methods; D014981:Xenopus
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C578710:HCN2 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels; D011392:Proline; D000242:Cyclic AMP