De novo Y1460C missense variant in Na V 1.1 impedes the pore region and results in epileptic encephalopathy

Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. SCN1A encodes Na V 1.1, a neuronal voltage-gated Na + channel that is highly expressed throughout the central nervous system. Na V 1.1 is localized within the axon initial segment where it plays a critical role in the initiation and propagation of action potentials and neuronal firing, predominantly in γ-amino-butyric-acid (GABA)ergic neurons of the hippocampus. The objective of this study was to characterize a de novo missense variant of uncertain significance in the SCN1A gene of a proband presented with febrile status epilepticus characterized by generalized tonic clonic movements associated with ictal emesis and an abnormal breathing pattern. Screening a gene panel revealed a heterozygous missense variant of uncertain significance in the SCN1A gene, designated c.4379A>G, p.(Tyr1460Cys). The Na V 1.1 wild-type (WT) and mutant channel reproduced in vivo and were transfected in HEK 293 cells. Na + currents were recorded using the whole-cell configuration of the patch-clamp technique. This Na V 1.1 variant (Tyr1460Cys) failed to express functional Na + currents when expressed in HEK293 cells, most probably due to a pore defect of the channel given that the cell surface expression of the channel was normal. Currents generated after co-transfection with functional WT channels exhibited biophysical properties comparable to those of WT channels, which was mainly due to the functional WT channels at the cell surface. The Na V 1.1 variant failed to express functional Na + currents, most probably due to pore impairment and exhibited a well-established loss of function mechanism. The present study highlights the added-value of functional testing for understanding the pathophysiology and potential treatment decisions for patients with undiagnosed developmental epileptic encephalopathy.