The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function

Abstract

Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel NaV1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the NaV1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of NaV1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.

Cold and warmth intensify pain-linked sodium channel gating effects and persistent currents

“…While a lot of the responsible mutations in Na v 1.1 are loss of function mutations, there are also some gain of function mutations described. Different from what was observed here for the IEM mutation, these mutations did not show hyperpolarizing shifts in activation explaining the hyperexcitability, but enlarged persistent currents when increasing the temperature to 37°C or more ( Gorman et al, 2021 ; Jones et al, 2021 ; Peters et al, 2016 ; Volkers et al, 2013 ). An in-depth evaluation and comparison of these mutations could help to understand the structure-function relation during changing temperature.…”

Late sodium current: incomplete inactivation triggers seizures, myotonias, arrhythmias, and pain syndromes

“…Many mutations in SCN1A and SCN2A produce late sodium currents in the channels encoded by these genes: Na v 1.1 and Na v 1.2 (Escayg & Goldin, 2010; Jones et al., 2021; Scalmani et al., 2006). These are the predominant sodium channels in the central nervous system, and mutations that cause late sodium currents underlie a variety of epileptogenic encephalopathies including, perhaps most famously Dravet syndrome (previously known as severe myoclonic epilepsy of infancy).…”

Gastrointestinal and Autonomic Symptoms—How to Improve the Diagnostic Process in Panayiotopoulos Syndrome?

“…In some cases, it is difficult to identify the main effect on the protein activity because mutations can lead to increased, decreased, or even mixed bothloss- and gain-of-function variants. The heterogeneity results in serious challenges in the treatment processand potential implementation of sodium channel blockers [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. According to studies, mutations of the SCN1A gene related to PS lead to moderate alternation of the voltage-gated sodium channel, probably resulting in a decrease inits function; however, various additional factors, including environmental or epigenetic components, could have an impact on phenotype development.…”