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https://hdl.handle.net/2440/92761
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Type: | Journal article |
Title: | KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine |
Author: | Milligan, C. Li, M. Gazina, E. Heron, S. Nair, U. Trager, C. Reid, C. Venkat, A. Younkin, D. Dlugos, D. Petrovski, S. Goldstein, D. Dibbens, L. Scheffer, I. Berkovic, S. Petrou, S. |
Citation: | Annals of Neurology, 2014; 75(4):581-590 |
Publisher: | Wiley |
Issue Date: | 2014 |
ISSN: | 0364-5134 1531-8249 |
Statement of Responsibility: | Carol J. Milligan, Melody Li, Elena V. Gazina, Sarah E. Heron, Umesh Nair, Chantel Trager, Christopher A. Reid, Anu Venkat, Donald P. Younkin, Dennis J. Dlugos, Slavé Petrovski, David B. Goldstein, Leanne M. Dibbens, Ingrid E. Scheffer, Samuel F. Berkovic, and Steven Petrou |
Abstract: | 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. |
Keywords: | Mice, Inbred C57BL Oocytes Tetradecanoylphorbol Acetate Quinidine Nerve Tissue Proteins Potassium Channels Patch-Clamp Techniques Microinjections Electric Stimulation Dose-Response Relationship, Drug Mutation Xenopus laevis Membrane Potentials Time Factors Voltage-Gated Sodium Channel Blockers |
Rights: | © 2014 American Neurological Association |
DOI: | 10.1002/ana.24128 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/628952 http://purl.org/au-research/grants/nhmrc/1016715 http://purl.org/au-research/grants/nhmrc/1005050 http://purl.org/au-research/grants/nhmrc/466671 http://purl.org/au-research/grants/nhmrc/1006110 http://purl.org/au-research/grants/nhmrc/1032603 |
Published version: | http://dx.doi.org/10.1002/ana.24128 |
Appears in Collections: | Aurora harvest 7 Paediatrics publications |
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