Kv3.1 channelopathy: a novel loss-of-function variant and the mechanistic basis of its clinical phenotypes.

BACKGROUND

KCNC1 encodes Kv3.1, a subunit of the Kv3 voltage-gated potassium channels. It is predominantly expressed in inhibitory GABAergic interneurons and cerebellar neurons. Kv3.1 channelopathy has been linked to a variety of human diseases including epilepsy, developmental delay, and ataxia. Characterization of structural and functional disturbances of this channel, and its relationship to a heterogenous group of clinical phenotypes, is a current topic of research. We herein characterize the clinical phenotype as well as the functional and structural consequences of the novel p.R317S variant. We further set out to explore the mechanistic basis for the spectrum of related channelopathies.

METHODS

Variant was identified via whole-exome sequencing and its functional impact was determined using two-electrode voltage clamp recordings in oocytes. Homolog modeling and structural analysis were performed on the p.R317S variant and other related variants.

RESULTS

We identified a novel loss-of-function KCNC1 variant c.949C>A (p.R317S) presenting with symptoms similar to myoclonic epilepsy and ataxia due to potassium channel (MEAK), but with distinct radiological features. Functional analysis in the oocyte's expression system revealed that the current amplitudes were significantly decreased in the p.R317S variant compared to the wild type, indicating a dominant-negative effect. Atomic structural analysis of the related variants provided a possible mechanistic explanation for the heterogeneity in the clinical spectrum.

CONCLUSIONS

We have identified the p.R317S loss-of-function variant in the gene, expanded the spectrum of potassium channelopathy and provided mechanistic insights into related disorders.