Key result
Kv7.2 p.V175L mutation drives gain-of-function via faster activation and hyperpolarizing shift versus wild-type channels.
Why the study?
Mutations in KCNQ2 causing EOEE have mostly been shown to induce loss of function or affect channel distribution, but the functional consequences of the p.V175L mutation were unclear.
Does the p.V175L mutation of Kv7.2 cause a gain or loss of function in Kv7/M channels?
Does the p.V175L mutation of Kv7.2 cause a gain or loss of function in Kv7/M channels?
The p.V175L mutation in Kv7.2 is a gain-of-function mutation, suggesting that Kv7 channel openers could have adverse effects in patients with this specific variant of early onset epileptic encephalopathy.
Mutations in the KCNQ2 gene encoding the voltage-gated potassium channel subunit Kv7.2 cause early onset epileptic encephalopathy (EOEE). Most mutations have been shown to induce a loss of function or to affect the subcellular distribution of Kv7 channels in neurons. Herein, we investigated functional consequences and subcellular distribution of the p.V175L mutation of Kv7.2 (Kv7.2(V175L) ) found in a patient presenting EOEE. We observed that the mutation produced a 25-40 mV hyperpolarizing shift of the conductance-voltage relationship of both the homomeric Kv7.2(V175L) and heteromeric Kv7.2(V175L) /Kv7.3 channels compared to wild-type channels and a 10 mV hyperpolarizing shift of Kv7.2(V175L) /Kv7.2/Kv7.3 channels in a 1:1:2 ratio mimicking the patient situation. Mutant channels also displayed faster activation kinetics and an increased current density that was prevented by 1 μm linopirdine. The p.V175L mutation did not affect the protein expression of Kv7 channels and its localization at the axon initial segment. We conclude that p.V175L is a gain of function mutation. This confirms previous observations showing that mutations having opposite consequences on M channels can produce EOEE. These findings alert us that drugs aiming to increase Kv7 channel activity might have adverse effects in EOEE in the case of gain-of-function variants.
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Devaux et al. (2016) studied Early onset epileptic encephalopathy (EOEE). p.V175L mutation of Kv7.2 vs. Wild-type channels was evaluated on Conductance-voltage relationship and activation kinetics. The p.V175L mutation of Kv7.2 produced a 25-40 mV hyperpolarizing shift and faster activation kinetics compared to wild-type channels, indicating it is a gain-of-function mutation.
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