A KCNC1‐related neurological disorder due to gain of Kv3.1 function

Abstract

Objective To further clarify genotype:phenotype correlations associated with variants in KCNC1 encoding the voltage‐gated potassium (K+) channel subunit Kv3.1 and which are an emerging cause of a spectrum of neurological disease including intellectual disability, isolated myoclonus, progressive myoclonus epilepsy, and developmental and epileptic encephalopathy. Methods We describe the clinical and genetic characteristics of a series of three patients with de novo heterozygous missense variants in KCNC1 associated with nonspecific developmental delay/intellectual disability and central hypotonia without epilepsy or ataxia. All three variants lead to amino acids alterations with mild predicted differences in physicochemical properties yet are localized to the S6 pore region of the Kv3.1 protein between the selectivity filter and PXP motif important for K+ channel gating. We performed whole‐cell voltage clamp electrophysiological recording of wild‐type versus variants in a heterologous mammalian expression system. Results We demonstrate a prominent leftward (hyperpolarized) shift in the voltage dependence of activation and slowed deactivation of all variants in the clinically defined series. Interpretation Electrophysiological recordings are consistent with a gain of K+ channel function that is predicted to exert a loss of function on the excitability of Kv3‐expressing high frequency‐ firing neurons based on the unique electrophysiological properties of Kv3 channels. These results define a clinical‐genetic syndrome within the spectrum of KCNC1 ‐related neurological disorders.

A novel KCNC1 gain‐of‐function variant causing developmental and epileptic encephalopathy: “Precision medicine” approach with fluoxetine

“…6 More recently, three de novo heterozygous KCNC1 GoF variants (M430I, V432M, and V434L) were described in three patients with developmental delay and hypotonia, without epilepsy or myoclonus. 9 In the present study, we report a patient with DEE carrying a previously unreported de novo missense KCNC1 variant (V425M) characterized by an in vitro mixed functional pattern with prevalent GoF effects, and we show that fluoxetine counteracted the mutation-induced functional defects in vitro, resulting in a significant and longlasting clinical improvement when administered to the proband.…”

“…16 Kv3.1 channels are mainly expressed in fast-spiking inhibitory neurons, where they contribute to action potential repolarization without affecting the threshold for action potential generation, thereby allowing high-frequency firing. 1,17 Thus, we may speculate that the Kv3.1 V425M GoF variant, similarly to other GoF pore variants, 9 may hyperpolarize the resting membrane potential and hamper fast-spiking activity of these neurons in vivo, thus increasing the excitation/inhibition balance that triggers epileptic activity.…”

“…Two additional nonsense LoF variants have been identified, one (R339X) in a proband with intellectual disability without epilepsy, 8 the other (Q492X) in three patients (including two familiar cases) with developmental encephalopathy 6 . More recently, three de novo heterozygous KCNC1 GoF variants (M430I, V432M, and V434L) were described in three patients with developmental delay and hypotonia, without epilepsy or myoclonus 9 …”

Unusual Voltage-Gated Sodium and Potassium Channelopathies Related to Epilepsy

“…The phenotypes include epilepsy in infancy with migrating focal seizures, progressive myoclonic epilepsy, epileptic encephalopathy, ataxia, and intellectual disability. 56 57 58 …”

A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction

“…Parvalbumin-positive fast-spiking GABAergic interneurons (PV-INs) specifically express Kv3.1 and Kv3.2 which determines the fast-spiking phenotype of these cells ( 6 – 9 ); recent work using cell type–specific proteomics in mice confirmed that Kcnc2 is among the most highly differentially expressed proteins in neocortical PV-INs ( 10 ). Variants in the Kv3 subfamily member gene KCNC1 cause a spectrum of neurologic disorders including developmental delay/intellectual disability, progressive myoclonus epilepsy, and early-onset developmental and epileptic encephalopathy (DEE) ( 11 – 15 ). Mice lacking Kv3.2 exhibit abnormal EEG patterns and increased susceptibility to PTZ-induced seizures, supporting the role of KCNC2 in human disease ( 7 ).…”