Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations

Area of Science:

• Neuroscience
• Genetics
• Channelopathies

Background:

• Peripheral nerve hyperexcitability (PNH) involves muscle overactivity from spontaneous lower motor neuron discharges, often linked to antibodies against voltage-gated potassium channels.
• PNH can co-occur with episodic ataxia or epilepsy due to mutations in K(V)1.1 or K(V)7.2 channels.
• Previously, only one PNH-associated K(V)7.2 mutation (R207W) was known, found in a family with PNH and neonatal seizures.

Purpose of the Study:

• To investigate novel KCNQ2 mutations causing idiopathic peripheral nerve hyperexcitability.
• To functionally characterize the identified KCNQ2 mutants and their effect on K(V)7.2 channel function.
• To explore the therapeutic potential of retigabine in treating PNH associated with these mutations.

Main Methods:

• Peripheral nerve hyperexcitability (PNH) was assessed using video and electromyography.
• The KCNQ2 gene was sequenced to identify mutations.
• K(V)7.2 channel function was analyzed using two-microelectrode voltage-clamping in Xenopus oocytes.

Main Results:

• A new KCNQ2 mutation (R207Q) was identified in a patient with PNH, predicting the loss of a charged residue in the K(V)7.2 voltage sensor.
• Both identified mutants (R207Q and R207W) caused significant depolarizing shifts in conductance-voltage relationships and slowed activation kinetics compared to wild-type channels.
• Co-expression of mutant and wild-type K(V)7.2 channels demonstrated a dominant-negative effect, reducing current amplitude by over 70% after short depolarizations.

Conclusions:

• KCNQ2 mutations can cause isolated idiopathic peripheral nerve hyperexcitability (PNH), warranting consideration in sporadic cases.
• The identified K(V)7.2 mutants induce PNH through altered voltage-dependent activation and a dominant-negative impact on wild-type channels.
• Unlike mutations causing neonatal seizures via haploinsufficiency, these PNH-associated mutants suggest a distinct pathogenic mechanism, and retigabine may offer therapeutic benefits for PNH.