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.
Highlights
Febrile seizures (FS) and idiopathic generalized epilepsy (IGE), including genetic epilepsy with febrile seizures plus (GEFS+), are common epilepsy syndromes that show complex inheritance, where a combination of susceptibility variants is proposed to underlie the etiology in most cases.[1,2,3] A small number of susceptibility genes for IGE have been identified and predominantly include ion channel genes.[4]
Analysis of HCN2 revealed a number of synonymous single nucleotide polymorphisms (SNPs) (Table 1) and a variant, c. 2156-2164delCGCCGCCGC, p.719-721PPP, predicted to lead to the deletion of 3 consecutive proline residues in the HCN2 protein. delPPP was found to be heterozygous in 3/65 unrelated patients with GEFS+ (OMIM #604233), 3/61 unrelated patients with FS, 3/772 blood bank controls, and 0/72 patients with classical IGE
Because the delPPP variant is close to the cyclic nucleotide-binding domain, we investigated whether Cyclic adenosine monophosphate (cAMP) gating was altered by comparing channel sensitivity to forskolin, an activator of adenylate cyclase
Summary
Febrile seizures (FS) and idiopathic generalized epilepsy (IGE), including genetic epilepsy with febrile seizures plus (GEFS+), are common epilepsy syndromes that show complex inheritance, where a combination of susceptibility variants is proposed to underlie the etiology in most cases.[1,2,3] A small number of susceptibility genes for IGE have been identified and predominantly include ion channel genes.[4]. There is growing evidence for a role of HCN in both idiopathic[5,6] and acquired epilepsy.[7,8,9,10,11] HCN1 and HCN2 variants have been identified, but functional analyses have failed to determine a statistical difference in channel properties.[12] The functional changes associated with gene variants that contribute to polygenic disease are, by definition, subtle Both biological and experimental variability contribute to the variance seen in functional analyses, with the probability of failing to detect a real difference in 2 populations rising dramatically as variation increases. Currents generated by mutant HCN2 channels were ~35% larger than controls, an increase that could enhance neuronal excitability.[8,9]
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