Biophysical characterization of SCN1A and SCN2A variants related to epilepsy

Epilepsy is a common pediatric neurological disorder characterized by recurrent unprovoked seizures. SCN1A and SCN2A encode two neuronal voltage-gated sodium channels, namely NaV1.1 and NaV1.2 respectively, both of them highly expressed throughout the central nervous system (CNS). NaV1.1 localized within the axon initial segment (AIS) plays a critical role in the initiation and propagation of action potentials, predominantly in γ-aminobutyric acid (GABA)ergic neurons of the hippocampus. NaV1.2 is expressed in excitatory neurons with a steady increase and redistribution from AIS to distal axons. The objective of this study is characterized two mutations found in patients with epilepsy Patient #1 was brought to emergency with a temperature of 39.1°C in febrile status epilepticus characterized by generalized tonic movements associated with ictal emesis and abnormal breathing patterns. The gene panel revealed a heterozygous missense variant of uncertain significance in the SCN1A gene, designated c.4379A>G, p.(Tyr1460Cys).. Patient #2 presented with hypotonia and tonic (bilateral independent focal and sequential) seizures on day one of life. Genetic analysis identified a de novo missense variant in SCN2A, c.2635G>A, p.Gly879Arg, in the patient. NaV1.1 variant (Tyr1460Cys) failed to express functional current in HEK293 cells, most probably related to a trafficking defect of the channel to the cells surface. However, functional studies of the NaV1.2 variant (Gly879Arg) expressed in HEK293 cells revealed a mixed of gain and loss of function, characterized by a reduced cell surface current density and a persistent sodium current and an increase of the window current. We concluded that, while NaV1.1 variant exhibited a well-established loss of function mechanisms, NaV1.2 variant shows that our understanding of genotype-phenotype correlations is still limited and highlights the complexity of the underlying electrophysiological effects of SCN2A variants.