KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine
Article first published online: 14 APR 2014
© 2014 American Neurological Association
Annals of Neurology
Volume 75, Issue 4, pages 581–590, April 2014
How to Cite
Milligan, C. J., Li, M., Gazina, E. V., Heron, S. E., Nair, U., Trager, C., Reid, C. A., Venkat, A., Younkin, D. P., Dlugos, D. J., Petrovski, S., Goldstein, D. B., Dibbens, L. M., Scheffer, I. E., Berkovic, S. F. and Petrou, S. (2014), KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol., 75: 581–590. doi: 10.1002/ana.24128
- Issue published online: 5 MAY 2014
- Article first published online: 14 APR 2014
- Accepted manuscript online: 3 MAR 2014 03:55AM EST
- Manuscript Accepted: 24 FEB 2014
- Manuscript Revised: 21 FEB 2014
- Manuscript Received: 2 OCT 2013
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.
Here we use a Xenopus laevis oocyte-based automated 2-electrode voltage clamp assay. The effects of quinidine (100 and 300μM) are also tested. Using quantitative reverse transcriptase polymerase chain reaction, the relative levels of mouse brain mKcnt1 mRNA expression are determined.
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.
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. Ann Neurol 2014;75:581–590