title: Temperature-dependent changes in neuronal dynamics in a patient with an SCN1A mutation and hyperthermia induced seizures.
abstract: Dravet syndrome is the prototype of SCN1A-mutation associated epilepsies. It is characterised by prolonged seizures, typically provoked by fever. We describe the evaluation of an SCN1A mutation in a child with early-onset temperature-sensitive seizures. The patient carries a heterozygous missense variant (c3818C > T; pAla1273Val) in the NaV1.1 brain sodium channel. We compared the functional effects of the variant vs. wild type NaV1.1 using patch clamp recordings from channels expressed in Chinese Hamster Ovary Cells at different temperatures (32, 37, and 40 °C). The variant channels produced a temperature-dependent destabilization of activation and fast inactivation. Implementing these empirical abnormalities in a computational model predicts a higher threshold for depolarization block in the variant, particularly at 40 °C, suggesting a failure to autoregulate at high-input states. These results reveal direct effects of abnormalities in NaV1.1 biophysical properties on neuronal dynamics. They illustrate the value of combining cellular measurements with computational models to integrate different observational scales (gene/channel to patient).
authors: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
authors: C
authors: C
authors: Peters
authors: Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, UK.|Centre for Developmental Cognitive Neuroscience, Institute of Child Health, University College, London, UK.
authors: R E
authors: RE
authors: Rosch
authors: Department of Paediatric Neurology, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors: E
authors: E
authors: Hughes
authors: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
authors: P C
authors: PC
authors: Ruben
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000503:physiopathology; D004827:Epilepsy / Q000235:genetics / Q000503:physiopathology; D005334:Fever / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D009474:Neurons / Q000473:pathology*; D010641:Phenotype; D003294:Seizures, Febrile / Q000235:genetics / Q000503:physiopathology*; D013696:Temperature
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human