Differential behaviour of Kv7.2 (KCNQ2) potassium channel mutants in neonatal epilepsy and peripheral nerve hyperexcitability

Background: Benign familial neonatal convulsions (BFNC) is caused by mutations in the voltage-gated potassium channels Kv7.2 and Kv7.3, being expressed in CNS and PNS. BFNC is characterized by frequent unprovoked seizures, typically beginning within the first days of life and spontaneously disappearing after several weeks to months. Peripheral nerve hyperexcitability (PNH, neuromyotonia, myokymia) is characterized by muscle overactivity due to spontaneous discharges of lower motor neurons. Antibodies against or mutations within different types of voltage-gated potassium channels can cause PNH. PNH could only be linked to one single Kv7.2 mutation (R207W) so far, in a family with PNH and BFNC. Here we describe novel mutations within the Kv7.2 channel, leading either to BFNC (E119G) or to PNH alone (R207Q). Our results have an important impact on the differential molecular mechanisms of both diseases.

Methods: Genomic DNA from patients was amplified and sequenced. WT and mutant Kv7.2 channels were heterologously expressed in Xenopus oocytes and functionally characterized using two-electrode voltage-clamping.

Results: Electrophysiological studies of E119G demonstrated a slight depolarizing shift of the voltage dependence of steady-state activation (<10 mV) resulting in a significant reduction of the relative current amplitude, which is restricted to the subthreshold range of an action potential. In contrast, functional characterization of R207Q and R207W revealed large depolarizing shifts of the conductance-voltage relationships (up to +40 mV) and a marked slowing of the activation time course. Co-expression of R207 mutant channels with wild type channels revealed a dominant negative effect reducing the relative current amplitudes by 70–90%. The novel anticonvulsant Retigabin was able to reverse the effects of the mutations.

Conclusions: Most of the known BFNC mutations result in a more or less complete loss of function and haploinsufficiency. Our results indicate that subtle changes in channel gating are sufficient to cause neonatal seizures, and show in a human disease model that the physiologically relevant range of this channel is restricted to subthreshold voltages at which it regulates the neuronal firing rate. In contrast, only a drastic reduction of channel function by a dominant-negative effect of R207Q/W mutations is able to affect peripheral motoneurons in a clinically relevant way. Retigabin should be considered as a new treatment option in PNH.