A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies.

Autor: Salgueiro-Pereira AR; Université Côte d'Azur (UCA), CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Team Physiopathology of Neuronal Circuits and Behavior, France., Duprat F; Université Côte d'Azur (UCA), INSERM, CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology (IPMC), Team Pathophysiology of Voltage-Gated Na(+) channels and of Neuronal Excitability, France., Pousinha PA; Université Côte d'Azur (UCA), CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Team Physiopathology of Neuronal Circuits and Behavior, France., Loucif A; Université Côte d'Azur (UCA), INSERM, CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology (IPMC), Team Pathophysiology of Voltage-Gated Na(+) channels and of Neuronal Excitability, France., Douchamps V; Université de Strasbourg, CNRS, LNCA, Strasbourg, France., Regondi C; U.O. Clinical and Experimental Epileptology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy., Ayrault M; Université Côte d'Azur (UCA), INSERM, CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology (IPMC), Team Pathophysiology of Voltage-Gated Na(+) channels and of Neuronal Excitability, France., Eugie M; Université Côte d'Azur (UCA), CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Team Physiopathology of Neuronal Circuits and Behavior, France., Stunault MI; Université Côte d'Azur (UCA), CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Team Physiopathology of Neuronal Circuits and Behavior, France., Escayg A; Department of Human Genetics, Emory University, Atlanta, GA, USA., Goutagny R; Université de Strasbourg, CNRS, LNCA, Strasbourg, France., Gnatkovsky V; U.O. Clinical and Experimental Epileptology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy., Frassoni C; U.O. Clinical and Experimental Epileptology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy., Marie H; Université Côte d'Azur (UCA), CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Team Physiopathology of Neuronal Circuits and Behavior, France., Bethus I; Université Côte d'Azur (UCA), CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Team Physiopathology of Neuronal Circuits and Behavior, France. Electronic address: bethus@ipmc.cnrs.fr., Mantegazza M; Université Côte d'Azur (UCA), INSERM, CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology (IPMC), Team Pathophysiology of Voltage-Gated Na(+) channels and of Neuronal Excitability, France. Electronic address: mantegazza@ipmc.cnrs.fr.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2019 May; Vol. 125, pp. 31-44. Date of Electronic Publication: 2019 Jan 17.
DOI: 10.1016/j.nbd.2019.01.006
Abstrakt: SCN1A (Na V 1.1 sodium channel) mutations cause Dravet syndrome (DS) and GEFS+ (which is in general milder), and are risk factors in other epilepsies. Phenotypic variability limits precision medicine in epilepsy, and it is important to identify factors that set phenotype severity and their mechanisms. It is not yet clear whether SCN1A mutations are necessary for the development of severe phenotypes or just for promoting seizures. A relevant example is the pleiotropic R1648H mutation that can cause either mild GEFS+ or severe DS. We used a R1648H knock-in mouse model (Scn1a RH/+ ) with mild/asymptomatic phenotype to dissociate the effects of seizures and of the mutation per se. The induction of short repeated seizures, at the age of disease onset for Scn1a mouse models (P21), had no effect in WT mice, but transformed the mild/asymptomatic phenotype of Scn1a RH/+ mice into a severe DS-like phenotype, including frequent spontaneous seizures and cognitive/behavioral deficits. In these mice, we found no major modifications in cytoarchitecture or neuronal death, but increased excitability of hippocampal granule cells, consistent with a pathological remodeling. Therefore, we demonstrate for our model that an SCN1A mutation is a prerequisite for a long term deleterious effect of seizures on the brain, indicating a clear interaction between seizures and the mutation for the development of a severe phenotype generated by pathological remodeling. Applied to humans, this result suggests that genetic alterations, even if mild per se, may increase the risk of second hits to develop severe phenotypes.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: