Abstract
BackgroundDeleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood.MethodsTo further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling.ResultsThe two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings.ConclusionsOur findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Nav1.2 gating changes. Moreover, structural modeling was able to predict the severity of the variant impact, supporting a potential role of structural modeling as a prognostic tool. Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants.
Highlights
Deleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD)
Causative variants observed in BFNIE and DEE are usually missense variants clustering in the transmembrane segments and short connecting loops (Ben-Shalom et al 2017), while more than half of the ASD-associated SCN2A variants are predicted to introduce a premature stop codon (Ben-Shalom et al 2017)
ID mutants are non-conducting Representative families of whole-cell current traces of wild-type and conducting mutant channels are shown in Fig. 2a, while Fig. 2b depicts the peak current amplitude normalized by cell capacitance for wild-type and mutant Nav1.2
Summary
Deleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). SCN2A (OMIM 182390) encodes the pore-forming α-subunit of the voltage gated sodium channel type 2 (Nav1.2). It is predominantly expressed at the axon initial segment and nodes of Ranvier of excitatory neurons of the central nervous system and plays a crucial role for axon potential initiation and propagation in early development (Kaplan et al 2001, Kole and Stuart 2012).
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