Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations

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Abstract
Background: Peripheral nerve hyperexcitability (PNH) is characterized by muscle overactivity due to spontaneous discharges of lower motor neurons usually associated with antibodies against voltage-gated potassium channels. PNH may also occur in combination with episodic ataxia or epilepsy caused by mutations in KV1.1 or KV7.2 channels. Only one PNH-associated mutation has been described so far in KV7.2 (R207W), in a family with both PNH and neonatal seizures. Methods: PNH was characterized by video and electromyography. The KCNQ2 gene was sequenced and KV7.2 channels were functionally characterized using two-microelectrode voltage-clamping in Xenopus oocytes. Results: In a patient with PNH without other neurologic symptoms, we identified a novel KCNQ2 mutation predicting loss of a charged residue within the voltage sensor of KV7.2 (R207Q). Functional analysis of both PNH-associated mutants revealed large depolarizing shifts of the conductance-voltage relationships and marked slowing of the activation time course compared to wild type (WT) channels, less pronounced for R207Q than R207W. Co-expression of both mutant with WT channels revealed a dominant negative effect reducing the relative current amplitudes after short depolarizations by >70%. The anticonvulsant retigabine, an activator of neuronal KV7 channels, reversed the depolarizing shift. Conclusions: Mutations in KCNQ2 can cause idiopathic PNH alone and should be considered in sporadic cases. Both KV7.2 mutants produce PNH by changing voltage-dependent activation with a dominant negative effect on the WT channel. This distinguishes them from all hitherto examined Kv7.2 or KV7.3 mutations which cause neonatal seizures by haploinsufficiency. Retigabine may be beneficial in treating PNH.