Transcriptomic and electrophysiological alterations underlying phenotypic variability in SCN1A-associated febrile seizures

Transcriptomic and electrophysiological alterations underlying phenotypic variability in SCN1A-associated febrile seizures

Abstract Febrile seizures (FS) are a common childhood neurological condition triggered by fever in children without prior neurological disorders. While generally benign, some individuals, particularly those with complex FS or genetic predispositions, may develop epilepsy or other neurological comorb...

Full description

Saved in:
Bibliographic Details
Main Authors: Stefania Scalise, Alessandro Gaeta, Elio Aprigliano, Valeria Lucchino, Raffaele Covello, Mariagrazia Talarico, Barbara Puccio, Pietro Hiram Guzzi, Pierangelo Veltri, Antonio Gambardella, Lilian Juliana Lissner, Alessandra Morano, Pierangelo Cifelli, Veronica Alfano, Eleonora Palma, Gerardo Perozziello, Gabriele Ruffolo, Giovanni Cuda, Elvira Immacolata Parrotta
Format: Article
Language:English
Published: Nature Portfolio 2025-07-01
Series:Scientific Reports
Subjects:
Febrile seizure
Mesial temporal lobe epilepsy
Induced pluripotent stem cell-derived neurons
Voltage-gated sodium channel NaV1.1
SCN1A
GABAergic dysfunction
Online Access:https://doi.org/10.1038/s41598-025-09208-3
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract Febrile seizures (FS) are a common childhood neurological condition triggered by fever in children without prior neurological disorders. While generally benign, some individuals, particularly those with complex FS or genetic predispositions, may develop epilepsy or other neurological comorbidities. The mechanisms underlying this transition remain unclear. Mutations in SCN1A, encoding the NaV1.1 sodium channel α-subunit, have been linked to several epilepsy syndromes associated with FS. This study examines phenotypic variability in individuals carrying the same SCN1A c.434T > C mutation, using induced pluripotent stem cell (iPSC)-derived neurons from two siblings with FS. Despite sharing the mutation, only the older sibling developed temporal lobe epilepsy (TLE). Transcriptomic analysis revealed downregulation of GABAergic pathway genes in both siblings’ neurons, aligning with SCN1A-associated epilepsy. However, neurons from the sibling with TLE exhibited additional abnormalities, including altered AMPA receptor subunit composition, changes in GABAA receptor subunits and chloride cotransporters expression, and reduced brain-derived neurotrophic factor (BDNF) levels, indicative of developmental immaturity. Voltage-clamp recordings confirmed impaired GABAergic and AMPA receptor-mediated synaptic activity. These findings suggest that combined GABAergic dysfunction, aberrant AMPA receptor composition, and reduced BDNF signaling contribute to the more severe phenotype and increased epilepsy susceptibility.
ISSN:2045-2322

Similar Items