Gain-of-function HCN2 variants in genetic epilepsy

Area of Science:

• Neurogenetics
• Molecular Neuroscience

Background:

• Genetic generalized epilepsy (GGE) is a common epilepsy syndrome characterized by spike-and-wave discharges (SWDs).
• Hyperpolarization-activated cyclic nucleotide-gated channels (HCN), particularly HCN2, are implicated in SWD generation, making HCN2 a key gene candidate for GGE.

Purpose of the Study:

• To investigate the role of HCN2 missense variants in the pathogenesis of GGE.
• To functionally characterize identified HCN2 variants using electrophysiological methods.

Main Methods:

• Screening of 585 GGE patients from the Epilepsy Phenome-Genome Project (EPGP) and 238 familial GGE cases for HCN2 variants.
• Functional analysis of identified variants (p.S632W, p.V246M, p.E280K, p.A705T, p.R756C) using two-electrode voltage clamp recordings in Xenopus oocytes.

Main Results:

• The HCN2 variants p.S632W and p.V246M were identified in GGE patients and segregated within families.
• Both p.S632W and p.V246M demonstrated a gain-of-function effect, characterized by a depolarizing shift in activation voltage dependence.
• Common population variants (p.E280K, p.A705T) and a non-segregating variant (p.R756C) showed no significant biophysical changes.

Conclusions:

• HCN2 variants, specifically those causing a gain-of-function, contribute to GGE susceptibility.
• These findings highlight the critical role of HCN2 channel function in the pathophysiology of epilepsy syndromes characterized by SWDs.