KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Issue 4 (14th April 2014)

• Record Type: Journal Article
• Authors: Milligan, Carol J.; Li, Melody; Gazina, Elena V.; Heron, Sarah E.; Nair, Umesh; Trager, Chantel; Reid, Christopher A.; Venkat, Anu; Younkin, Donald P.; Dlugos, Dennis J.; Petrovski, Slavé; Goldstein, David B.; Dibbens, Leanne M.; Scheffer, Ingrid E.; Berkovic, Samuel F.; Petrou, Steven
• Is Part Of: Annals of neurology. Volume 75:Issue 4(2014:Apr.)
• Page Start: 581
• Page End: 590
• Publication Date: 2014-04-14
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24128
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24128-sec-0001" sec-type="section"> <title>Objective</title> <p>Mutations in <italic>KCNT1</italic> 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 h<italic>KCNT1</italic> mutations and examine developmental expression levels.</p> </sec> <sec id="ana24128-sec-0002" sec-type="section"> <title>Methods</title> <p>Here we use a <italic>Xenopus laevis</italic> 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 m<italic>Kcnt1</italic> mRNA expression are determined.</p> </sec> <sec id="ana24128-sec-0003" sec-type="section"> <title>Results</title> <p>We demonstrate that <italic>KCNT1</italic> 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.</p> </sec> <sec id="ana24128-sec-0004" sec-type="section"> <title>Interpretation</title> <p>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</p> </sec> </abstract>