Augmented currents of an HCN2 variant in patients with febrile seizure syndromes

• Published in: Annals of neurology 2010-04, Vol.67 (4), p.542-546
• Main Authors: Dibbens, Leanne M., Reid, Christopher A., Hodgson, Bree, Thomas, Evan A., Phillips, Alison M., Gazina, Elena, Cromer, Brett A., Clarke, Alison L., Baram, Tallie Z., Scheffer, Ingrid E., Berkovic, Samuel F., Petrou, Steven
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biophysics - methods; Cyclic AMP - pharmacology; Cyclic Nucleotide-Gated Cation Channels - genetics; DNA Mutational Analysis - methods; Electric Stimulation - methods; Gene Frequency; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ion Channels - genetics; Medical sciences; Membrane Potentials - drug effects; Membrane Potentials - genetics; Nervous system (semeiology, syndromes); Neurology; Oocytes; Patch-Clamp Techniques - methods; Potassium Channels - genetics; Proline - genetics; Seizures, Febrile - genetics; Sequence Deletion - genetics; Transfection - methods; Xenopus
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.21909

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 ∼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. ANN NEUROL 2010;67:542–546