De novo KCNA6 variants with attenuated K_V1.6 channel deactivation in patients with epilepsy

Abstract

Objective: Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies.

Selective block of human Kv1.1 channels and an epilepsy‐associated gain‐of‐function mutation by AETX‐K peptide

“…In addition, gain‐of‐function mutations of Kv1.1 have been reported, including the drug‐resistant Kv1.1‐L 296 F mutation in the VSD we consider here as well as a Kv1.1‐A 261 T mutation in the S3 transmembrane segment that causes mild, drug‐responsive, focal epilepsy in patients 8 . Recently, gain‐of‐function mutations of Kv1.6 were found to be associated with neurodevelopmental disorders and seizures in patients 40 . Because Kv1.6 and Kv1.1 share high similarity in the pore region (Figure S3) and form heterotetrametric channels in the human brain, AETX‐K is anticipated to suppress excess current passed by these gain‐of‐function channels as well.…”

“…8 Recently, gain-of-function mutations of Kv1.6 were found to be associated with neurodevelopmental disorders and seizures in patients. 40 Because Kv1.6 and Kv1.1 share high similarity in the pore region (Figure S3) and form heterotetrametric channels in the human brain, AETX-K is anticipated to suppress excess current passed by these gain-of-function channels as well. The increased K + currents likely lead to excess repolarization, and action potential shortening, disrupting the firing frequency and dampening neuronal excitability.…”

Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome

“…Raw data were processed and filtered with established pipelines at diagnostic or research laboratories as described previously. 9 , 10 , 11 , 12 Variant (single nucleotide and indel) calling and filtering was performed using the Genome Analysis Tool Kit (GATK). Variants that did not adhere to the following criteria were excluded from further analysis: allele balance of >0.70, QUAL of >20, and coverage of >20×.…”

Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia

“…The Kv1.6 channel is encoded by the gene KCNA6 . A recent study identified de novo gain-of-function mutations in KCNA6 in patients with epilepsy [ 57 ]. Mutant Kv1.6 channels display slowed channel closing time and a negative shift in deactivation voltage.…”