期刊
ANNALS OF NEUROLOGY
卷 75, 期 4, 页码 581-590出版社
WILEY
DOI: 10.1002/ana.24128
关键词
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资金
- Victorian Government
- National Health and Medical Research Council of Australia [628952, 1016715, 1005050, 466671, 1006110, 1032603]
- NIH National Institute of Neurological Disorders and Stroke [NINDS] [NS053998]
- NINDS [NS053998, NS077274, NS077303, NS077276]
ObjectiveMutations 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. MethodsHere we use a Xenopus laevis oocyte-based automated 2-electrode voltage clamp assay. The effects of quinidine (100 and 300M) are also tested. Using quantitative reverse transcriptase polymerase chain reaction, the relative levels of mouse brain mKcnt1 mRNA expression are determined. ResultsWe 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. InterpretationThese 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
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