De novo Y1460C missense variant in Na1.1 impedes the pore region and results in epileptic encephalopathy.

Publication Type:

Journal Article


Sci Rep, Volume 12, Issue 1, p.17182 (2022)


Action Potentials, Epilepsy, Epilepsy, Generalized, gamma-Aminobutyric Acid, HEK293 Cells, Humans, NAV1.1 Voltage-Gated Sodium Channel, NAV1.6 Voltage-Gated Sodium Channel, Patch-Clamp Techniques, Seizures


<p>Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. SCN1A encodes Na1.1, a neuronal voltage-gated Na channel that is highly expressed throughout the central nervous system. Na1.1 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 Na1.1 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 Na1.1 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 Na1.1 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.</p>

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