De novo variants in KCNA3 cause developmental and epileptic encephalopathy

Abstract

ObjectiveVariants in several potassium channel genes, including KCNA1 and KCNA2, cause Developmental and Epileptic Encephalopathies (DEEs). We investigated whether variants in KCNA3, another mammalian homologue of the Drosophila shaker family and encoding for Kv1.3 subunits, can cause DEE.MethodsGenetic analysis of study individuals was performed by routine exome or genome sequencing, usually of parent‐offspring trios. Phenotyping was performed via a standard clinical questionnaire. Currents from wild‐type and/or mutant Kv1.3 subunits were investigated by whole‐cell patch‐clamp upon their heterologous expression.ResultsFourteen individuals, each carrying a de novo heterozygous missense variant in KCNA3, were identified. Most (12/14; 86%) had DEE with marked speech delay with or without motor delay, intellectual disability, epilepsy, and autism spectrum disorder. Functional analysis of Kv1.3 channels carrying each variant revealed heterogeneous functional changes, ranging from “pure” loss‐of‐function (LoF) effects due to faster inactivation kinetics, depolarized voltage‐dependence of activation, slower activation kinetics, increased current inactivation, reduced or absent currents with or without dominant‐negative effects, to “mixed” loss‐ and gain‐of‐function (GoF) effects. Compared to controls, Kv1.3 currents in lymphoblasts from one of the proband displayed functional changes similar to those observed upon heterologous expression of channels carrying the same variant. The antidepressant drug fluoxetine inhibited with similar potency the currents from wild‐type and one of the Kv1.3 GoF variant.InterpretationWe describe a novel association of de novo missense variants in KCNA3 with a human DEE, and provide evidence that fluoxetine might represent a potential targeted treatment for individuals carrying variants with significant GoF effects.This article is protected by copyright. All rights reserved.

Newly Identified KCNA3 Gene Variants Put the “Excite”-ment Back in Kv1.3 Channelopathy

“…Their recent work reveals the first link between genetic variants in KCNA3 and developmental and epileptic encephalopathy (DEE). 4 Developmental and epileptic encephalopathy is a neurodevelopmental disorder marked by early-onset epileptic seizures coupled with developmental impairment. 5 About 100 genes are implicated in DEE, with approximately one-third encoding ion channels or transporters, including KCNA1 and KCNA2 , which are closely related to KCNA3 .…”