Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy.

Autor:	Berecki G; Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia; geza.berecki@florey.edu.au steve.petrou@unimelb.edu.au., Howell KB; Department of Neurology, Royal Children's Hospital, Parkville, VIC 3052, Australia.; Department of Pediatrics, University of Melbourne, Parkville, VIC 3052, Australia.; Murdoch Children's Research Institute, Parkville, VIC 3052, Australia., Deerasooriya YH; Department of Mechanical Engineering, University of Melbourne, Parkville, VIC 3052, Australia., Cilio MR; Department of Neurology, University of California, San Francisco Benioff Children's Hospital, University of California, San Francisco, CA 94158.; Department of Pediatrics, University of California, San Francisco Benioff Children's Hospital, University of California, San Francisco, CA 94158., Oliva MK; Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia., Kaplan D; Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia., Scheffer IE; Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia.; Department of Neurology, Royal Children's Hospital, Parkville, VIC 3052, Australia.; Department of Pediatrics, University of Melbourne, Parkville, VIC 3052, Australia.; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia., Berkovic SF; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia., Petrou S; Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia; geza.berecki@florey.edu.au steve.petrou@unimelb.edu.au.; Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC 3050, Australia.; Australian Research Council (ARC) Centre of Excellence for Integrated Brain Function, University of Melbourne, Parkville, VIC 3052, Australia.; RogCon, Inc., Cambridge, MA 02142.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Jun 12; Vol. 115 (24), pp. E5516-E5525. Date of Electronic Publication: 2018 May 29.
DOI:	10.1073/pnas.1800077115
Abstrakt:	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. Competing Interests: Conflict of interest statement: G.B. is funded by RogCon, Inc., Miami, Florida, a biotechnology company focused on drug research, discovery, and development for select ion channelopathies, including SCN2A. I.E.S. has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, Biomarin, and Nutricia; editorial boards of the Annals of Neurology, Neurology and Epileptic Disorders; may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has received speaker honoraria from GlaxoSmithKline, Athena Diagnostics, UCB, Eisai, and Transgenomics; has received funding for travel from Athena Diagnostics, UCB, Biocodex, GlaxoSmithKline, Biomarin, and Eisai; and receives/has received research support from the National Health and Medical Research Council of Australia, National Institutes of Health, Australian Research Council, Health Research Council of New Zealand, CURE, The American Epilepsy Society, the US Department of Defense Autism Spectrum Disorder Research Program, March of Dimes, and Perpetual Charitable Trustees. S.P. is cofounder, Chief Scientific Officer, and equity holder of RogCon, Inc., Miami, Florida, a biotech company focused on the delivery of novel therapeutics for SCN2A disorders. RogCon, Inc. provided funding for this project. S.P. is also cofounder and equity holder in Praxis Precision Medicines, Inc., Cambridge, Massachusetts, which develops precision medicines for neurogenetic disorders, including those caused by SCN2A mutations. S.P. is a Scientific Advisor and equity holder in Pairnomix, Inc., Minneaopolis, Minnisota, which is undertaking precision medicine development in epilepsy and related disorders.
Databáze:	MEDLINE
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