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

Abstract

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 KCNC1 p.R317S variant. We further set out to explore the mechanistic basis for the spectrum of KCNC1 related channelopathies.Methods: Variant was identified via whole-exome sequencing and its functional impact was determined using two-electrode voltage clamp recordings in Xenopus laevis oocytes. Homolog modeling and in silico structural analysis were performed on the p.R317S variant and other KCNC1 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 Xenopus laevis 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 KCNC1 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 KCNC1 gene, expanded the spectrum of potassium channelopathy and provided mechanistic insights into KCNC1 related disorders.

Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain

“…Of note, gating charge mutations R317S and R320H are both loss-of-function variants linked to human channelopathies (Figs. 2d and S5 ) 10 , 11 , 47 . Another notable difference is that a second glutamate, E213 in the S2 segment of Kv3.1a, replaces T184 in the Kv1.2 structure (Fig.…”

Identification and Validation of Metabolism-Related Genes in Alzheimer’s Disease

“…EZR plays a key role in promoting the invasion and metastasis of malignant tumors [48]. KCNC1 encodes a subunit of the Kv3 voltage-gated potassium channels and associated with a variety of human diseases, including ataxia, epilepsy and developmental delay [49]. COLEC12 encodes a member of the C-lectin family, which is a scavenger receptor that plays a crucial role in the binding and clearance of Aβ [50].…”

Potassium channels and epilepsy

“…It has been reported that KCNC1 has a wide spectrum of related phenotypes, which can manifest not only as progressive myoclonic epilepsy (PME), but also as non‐PME, infant DEE, and developmental encephalopathy without seizures 36–39 . In China, Li et al 40 found a novel KCNC1 variant in epilepsy patients with symptoms similar to myoclonic epilepsy and ataxia due to potassium channel mutation (MEAK), but with distinct radiological features; the study confirmed it as a loss‐of‐function variant. Liu et al used peripheral blood from epilepsy patients with KCNC1 (c.959G>A) gene mutation to establish induced pluripotent stem cells (iPSCs).…”

“…34,35 It has been reported that KCNC1 has a wide spectrum of related phenotypes, which can manifest not only as progressive myoclonic epilepsy (PME), but also as non-PME, infant DEE, and developmental encephalopathy without seizures. [36][37][38][39] In China, Li et al 40 Currently, there is no targeted therapy directed at KCNC1.…”