Progressive myoclonus epilepsy KCNC1 variant causes a developmental dendritopathy

Abstract

Objective

Mutations in KCNC1 can cause severe neurological dysfunction, including intellectual disability, epilepsy, and ataxia. The Arg320His variant, which occurs in the voltage‐sensing domain of the channel, causes a highly penetrant and specific form of progressive myoclonus epilepsy with severe ataxia, designated myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK). KCNC1 encodes the voltage‐gated potassium channel KV3.1, a channel that is important for enabling high‐frequency firing in interneurons, raising the possibility that MEAK is associated with reduced interneuronal function.

Methods

To determine how this variant triggers MEAK, we expressed KV3.1bR320H in cortical interneurons in vitro and investigated the effects on neuronal function and morphology. We also performed electrophysiological recordings of oocytes expressing KV3.1b to determine whether the mutation introduces gating pore currents.

Results

Expression of the KV3.1bR320H variant profoundly reduced excitability of mature cortical interneurons, and cells expressing these channels were unable to support high‐frequency firing. The mutant channel also had an unexpected effect on morphology, severely impairing neurite development and interneuron viability, an effect that could not be rescued by blocking KV3 channels. Oocyte recordings confirmed that in the adult KV3.1b isoform, R320H confers a dominant negative loss‐of‐function effect by slowing channel activation, but does not introduce potentially toxic gating pore currents.

Significance

Overall, our data suggest that, in addition to the regulation of high‐frequency firing, KV3.1 channels play a hitherto unrecognized role in neuronal development. MEAK may be described as a developmental dendritopathy.

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