KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine
Carol J. Milligan PhD
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Search for more papers by this authorMelody Li BSc
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Search for more papers by this authorElena V. Gazina PhD
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Search for more papers by this authorSarah E. Heron PhD
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
Sansom Institute for Health Research, University of South Australia, Adelaide, Australia
Search for more papers by this authorUmesh Nair BSc
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Search for more papers by this authorChantel Trager BSc
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Search for more papers by this authorChristopher A. Reid PhD
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Search for more papers by this authorAnu Venkat MD
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorDonald P. Younkin MD
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorDennis J. Dlugos MD
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorSlavé Petrovski PhD
Center for Human Genome Variation, Duke University School of Medicine, Durham, NC
Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Austin Hospital, Heidelberg, Australia
Search for more papers by this authorDavid B. Goldstein PhD
Center for Human Genome Variation, Duke University School of Medicine, Durham, NC
Search for more papers by this authorLeanne M. Dibbens PhD
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
Sansom Institute for Health Research, University of South Australia, Adelaide, Australia
Search for more papers by this authorIngrid E. Scheffer MBBS, PhD
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Australia
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia
Search for more papers by this authorSamuel F. Berkovic MD
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Australia
Search for more papers by this authorCorresponding Author
Steven Petrou PhD
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Australia
Centre for Neural Engineering, University of Melbourne, Melbourne, Australia
Address correspondence to Dr Petrou, Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, 30 Royal Parade, Parkville, Victoria, Australia, 3010. E-mail: [email protected]Search for more papers by this authorCarol J. Milligan PhD
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Search for more papers by this authorMelody Li BSc
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Search for more papers by this authorElena V. Gazina PhD
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Search for more papers by this authorSarah E. Heron PhD
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
Sansom Institute for Health Research, University of South Australia, Adelaide, Australia
Search for more papers by this authorUmesh Nair BSc
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Search for more papers by this authorChantel Trager BSc
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Search for more papers by this authorChristopher A. Reid PhD
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Search for more papers by this authorAnu Venkat MD
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorDonald P. Younkin MD
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorDennis J. Dlugos MD
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorSlavé Petrovski PhD
Center for Human Genome Variation, Duke University School of Medicine, Durham, NC
Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Austin Hospital, Heidelberg, Australia
Search for more papers by this authorDavid B. Goldstein PhD
Center for Human Genome Variation, Duke University School of Medicine, Durham, NC
Search for more papers by this authorLeanne M. Dibbens PhD
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
Sansom Institute for Health Research, University of South Australia, Adelaide, Australia
Search for more papers by this authorIngrid E. Scheffer MBBS, PhD
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Australia
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia
Search for more papers by this authorSamuel F. Berkovic MD
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Australia
Search for more papers by this authorCorresponding Author
Steven Petrou PhD
Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Australia
Centre for Neural Engineering, University of Melbourne, Melbourne, Australia
Address correspondence to Dr Petrou, Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, 30 Royal Parade, Parkville, Victoria, Australia, 3010. E-mail: [email protected]Search for more papers by this authorAbstract
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 300μM) 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. Ann Neurol 2014;75:581–590
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