KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine

Ann Neurol. 2014 Apr;75(4):581-90. doi: 10.1002/ana.24128. Epub 2014 Apr 14.


Objective: Mutations in KCNT1 have been implicated in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and epilepsy of infancy with migrating focal seizures (EIMFS). More recently, a whole exome sequencing study of epileptic encephalopathies identified an additional de novo mutation in 1 proband with EIMFS. We aim to investigate the electrophysiological and pharmacological characteristics of hKCNT1 mutations and examine developmental expression levels.

Methods: Here we use a Xenopus laevis oocyte-based automated 2-electrode voltage clamp assay. The effects of quinidine (100 and 300 μM) are also tested. Using quantitative reverse transcriptase polymerase chain reaction, the relative levels of mouse brain mKcnt1 mRNA expression are determined.

Results: We demonstrate that KCNT1 mutations implicated in epilepsy cause a marked increase in function. Importantly, there is a significant group difference in gain of function between mutations associated with ADNFLE and EIMFS. Finally, exposure to quinidine significantly reduces this gain of function for all mutations studied.

Interpretation: These results establish direction for a targeted therapy and potentially exemplify a translational paradigm for in vitro studies informing novel therapies in a neuropsychiatric disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / growth & development
  • Brain / metabolism
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Humans
  • Male
  • Membrane Potentials / drug effects*
  • Membrane Potentials / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Microinjections
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics*
  • Oocytes
  • Patch-Clamp Techniques
  • Potassium Channels / genetics*
  • Potassium Channels, Sodium-Activated
  • Quinidine / pharmacology*
  • Tetradecanoylphorbol Acetate / analogs & derivatives
  • Tetradecanoylphorbol Acetate / pharmacology
  • Time Factors
  • Voltage-Gated Sodium Channel Blockers / pharmacology*
  • Xenopus laevis


  • KCNT1 protein, human
  • Nerve Tissue Proteins
  • Potassium Channels
  • Potassium Channels, Sodium-Activated
  • Voltage-Gated Sodium Channel Blockers
  • 4-O-methyl-12-O-tetradecanoylphorbol 13-acetate
  • Quinidine
  • Tetradecanoylphorbol Acetate