title: Electrophysiological Differences between the Same Pore Region Mutation in SCN1A and SCN3A.
abstract: Mutations in the sodium channel gene, SCN1A (NaV1.1), have been linked to a spectrum of epilepsy syndromes, and many of these mutations occur in the pore region of the channel. Electrophysiological characterization has revealed that most SCN1A mutations in the pore region result in complete loss of function. SCN3A mutations have also been identified in patients with epilepsy; however, mutations in this pore region maintain some degree of electrophysiological function. It is thus speculated that compared to SCN3A disruptions, SCN1A mutations have a more pronounced effect on electrophysiological function. In this study, we identified a novel mutation, N302S, in the SCN3A pore region of a child with epilepsy. To investigate if mutations at the pore regions of SCN3A and SCN1A have different impacts on channel function, we studied the electrophysiological properties of N302S in NaV1.3 and its homologous mutation (with the same amino acid substitution) in NaV1.1 (N301S). Functional analysis demonstrated that SCN1A-N301S had no measurable sodium current, indicating a complete loss of function, while SCN3A-N302S slightly reduced channel activity. This observation indicates that the same pore region mutation affects SCN1A more than SCN3A. Our study further revealed a huge difference in electrophysiological function between SCN1A and SCN3A mutations in the pore region; this might explain the more common SCN1A mutations detected in patients with epilepsy and the more severe phenotypes associated with these mutations.
authors.affiliation: Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou, 510260, China.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Chen
authors.forename: Y-W
authors.initials: YW
authors.lastname: Shi
authors.forename: H-Q
authors.initials: HQ
authors.lastname: Xu
authors.forename: M-L
authors.initials: ML
authors.lastname: Chen
authors.forename: M-M
authors.initials: MM
authors.lastname: Gao
authors.forename: W-W
authors.initials: WW
authors.lastname: Sun
authors.forename: B
authors.initials: B
authors.lastname: Tang
authors.forename: Y
authors.initials: Y
authors.lastname: Zeng
authors.forename: W-P
authors.initials: WP
authors.lastname: Liao
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D055724:Electrophysiological Phenomena / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D009154:Mutation / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D062552:NAV1.3 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; C424715:SCN3A protein, human; D015222:Sodium Channels