Distinct functional alterations in SCN8A epilepsy mutant channels

Yanling Pan, Theodore R. Cummins

Research output: Contribution to journalArticle

Abstract

Key points: Mutations in the SCN8A gene cause early infantile epileptic encephalopathy. We characterize a new epilepsy-related SCN8A mutation, R850Q, in the human SCN8A channel and present gain-of-function properties of the mutant channel. Systematic comparison of R850Q with three other SCN8A epilepsy mutations, T761I, R1617Q and R1872Q, identifies one common dysfunction in resurgent current, although these mutations alter distinct properties of the channel. Computational simulations in two different neuron models predict an increased excitability of neurons carrying these mutations, which explains the over-excitation that underlies seizure activities in patients. These data provide further insight into the mechanism of SCN8A-related epilepsy and reveal subtle but potentially important distinction of functional characterization performed in the human vs. rodent channels. Abstract: SCN8A is a novel causal gene for early infantile epileptic encephalopathy. It is well accepted that gain-of-function mutations in SCN8A underlie the disorder, although the remarkable heterogeneity of its clinical presentation and poor treatment response demand a better understanding of the disease mechanisms. Here, we characterize a new epilepsy-related SCN8A mutation, R850Q, in human Nav1.6. We show that it is a gain-of-function mutation, with a hyperpolarizing shift in voltage dependence of activation, a two-fold increase of persistent current and a slowed decay of resurgent current. We systematically compare its biophysics with three other SCN8A epilepsy mutations, T767I, R1617Q and R1872Q, in the human Nav1.6 channel. Although all of these mutations are gain-of-function, the mutations affect different aspects of channel properties. One commonality that we discovered is an alteration of resurgent current kinetics, although the mechanisms by which resurgent currents are augmented remain unclear for all of the mutations. Computational simulations predict an increased excitability of neurons carrying these mutations with differential enhancement by open channel blockade.

Original languageEnglish (US)
Pages (from-to)381-401
Number of pages21
JournalJournal of Physiology
Volume598
Issue number2
DOIs
StatePublished - Jan 1 2020

Fingerprint

Epilepsy
Mutation
Brain Diseases
Neurons
Biophysics
Point Mutation
Genes
Rodentia
Seizures

Keywords

  • computational model
  • epilepsy
  • resurgent current
  • SCN8A

ASJC Scopus subject areas

  • Physiology

Cite this

Distinct functional alterations in SCN8A epilepsy mutant channels. / Pan, Yanling; Cummins, Theodore R.

In: Journal of Physiology, Vol. 598, No. 2, 01.01.2020, p. 381-401.

Research output: Contribution to journalArticle

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