Augmented currents of an HCN2 variant in patients with febrile seizure syndromes.
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.
Dibbens
Leanne M
LM
SA Pathology at the Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Reid
Christopher A
CA
Hodgson
Bree
B
Thomas
Evan A
EA
Phillips
Alison M
AM
Gazina
Elena
E
Cromer
Brett A
BA
Clarke
Alison L
AL
Baram
Tallie Z
TZ
Scheffer
Ingrid E
IE
Berkovic
Samuel F
SF
Petrou
Steven
S
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
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