Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/18072
Title: Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy.
Authors: Berecki, Géza;Howell, Katherine B;Deerasooriya, Yadeesha H;Cilio, Maria Roberta;Oliva, Megan K;Kaplan, David;Scheffer, Ingrid E;Berkovic, Samuel F;Petrou, Steven
Affiliation: Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC Australia
Department of Neurology, Royal Children's Hospital, Parkville, VIC, Australia
Department of Pediatrics, University of Melbourne, Parkville, VIC, Australia
Murdoch Children's Research Institute, Parkville, VIC, Australia
Department of Mechanical Engineering, University of Melbourne, Parkville, VIC, Australia
Department of Neurology, University of California, San Francisco Benioff Children's Hospital, University of California, San Francisco, CA
Department of Pediatrics, University of California, San Francisco Benioff Children's Hospital, University of California, San Francisco, CA
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia
Australian Research Council (ARC) Centre of Excellence for Integrated Brain Function, University of Melbourne, Parkville, VIC, Australia
RogCon, Inc., Cambridge, MA
Issue Date: 12-Jun-2018
EDate: 2018-05-29
Citation: Proceedings of the National Academy of Sciences of the United States of America 2018; 115(24): E5516-E5525
Abstract: De novo variants in SCN2A developmental and epileptic encephalopathy (DEE) show distinctive genotype-phenotype correlations. The two most recurrent SCN2A variants in DEE, R1882Q and R853Q, are associated with different ages and seizure types at onset. R1882Q presents on day 1 of life with focal seizures, while infantile spasms is the dominant seizure type seen in R853Q cases, presenting at a median age of 8 months. Voltage clamp, which characterizes the functional properties of ion channels, predicted gain-of-function for R1882Q and loss-of-function for R853Q. Dynamic action potential clamp, that we implement here as a method for modeling neurophysiological consequences of a given epilepsy variant, predicted that the R1882Q variant would cause a dramatic increase in firing, whereas the R853Q variant would cause a marked reduction in action potential firing. Dynamic clamp was also able to functionally separate the L1563V variant, seen in benign familial neonatal-infantile seizures from R1882Q, seen in DEE, suggesting a diagnostic potential for this type of analysis. Overall, the study shows a strong correlation between clinical phenotype, SCN2A genotype, and functional modeling. Dynamic clamp is well positioned to impact our understanding of pathomechanisms and for development of disease mechanism-targeted therapies in genetic epilepsy.
URI: http://ahro.austin.org.au/austinjspui/handle/1/18072
DOI: 10.1073/pnas.1800077115
ORCID: 0000-0003-4580-841X
0000-0002-2311-2174
PubMed URL: 29844171
Type: Journal Article
Subjects: de novo SCN2A mutation
dynamic action potential clamp
epilepsy
modeling
voltage clamp
Appears in Collections:Journal articles

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