title: Novel SCN3A variants associated with focal epilepsy in children.
abstract: Voltage-gated sodium (NaV) channels are essential for initiating and propagating action potentials in the brain. More than 800 mutations in genes encoding neuronal NaV channels including SCN1A and SCN2A have been associated with human epilepsy. Only one epilepsy-associated mutation has been identified in SCN3A encoding the NaV1.3 neuronal sodium channel. We performed a genetic screen of pediatric patients with focal epilepsy of unknown cause and identified four novel SCN3A missense variants: R357Q, D766N, E1111K and M1323V. We determined the functional consequences of these variants along with the previously reported K354Q mutation using heterologously expressed human NaV1.3. Functional defects were heterogeneous among the variants. The most severely affected was R357Q, which had a significantly smaller current density and slower activation than the wild-type (WT) channel as well as depolarized voltage dependences of activation and inactivation. Also notable was E1111K, which evoked a significantly greater level of persistent sodium current than WT channels. Interestingly, a common feature shared by all variant channels was increased current activation in response to depolarizing voltage ramps revealing a functional property consistent with conferring neuronal hyper-excitability. Discovery of a common biophysical defect among variants identified in unrelated pediatric epilepsy patients suggests that SCN3A may contribute to neuronal hyperexcitability and epilepsy.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Vanoye
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Gurnett
authors.affiliation: Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Holland
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA. Electronic address: jennifer.kearney@vanderbilt.edu.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kearney
mesh_terms: D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004828:Epilepsies, Partial / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005820:Genetic Testing; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000502:physiology; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology
chemical_list: D062552:NAV1.3 Voltage-Gated Sodium Channel; C424715:SCN3A protein, human; D015222:Sodium Channels
keywords: Epilepsy; Persistent current; Ramp currents; SCN3A; Sodium channel