Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations

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Neurology. 2007 Nov 27;69(22):2045-53.

Comment in: Neurology. 2007 Nov 27;69(22):2036-7.

Peripheral nerve hyperexcitability due to dominant-negative KCNQ2

mutations.

Wuttke TV, Jurkat-Rott K, us W, Garncarek M, Lehmann-Horn F,

Lerche H.

Institut für Angewandte Physiologie, Universität Ulm, Germany.

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 K(V)1.1 or K

(V)7.2 channels. Only one PNH-associated mutation has been described

so far in K(V)7.2 (R207W), in a family with both PNH and neonatal

seizures.

METHODS: PNH was characterized by video and electromyography. The

KCNQ2 gene was sequenced and K(V)7.2 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 K(V)7.2 (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 K(V)7 channels,

reversed the depolarizing shift.

CONCLUSIONS: Mutations in KCNQ2 can cause idiopathic PNH alone and

should be considered in sporadic cases. Both K(V)7.2 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 K(V)7.3 mutations which cause neonatal

seizures by haploinsufficiency. Retigabine may be beneficial in

treating PNH.