TY - JOUR
T1 - A two-hit story
T2 - Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies
AU - Salgueiro-Pereira, Ana Rita
AU - Duprat, Fabrice
AU - Pousinha, Paula A.
AU - Loucif, Alexandre
AU - Douchamps, Vincent
AU - Regondi, Cristina
AU - Ayrault, Marion
AU - Eugie, Martine
AU - Stunault, Marion I.
AU - Escayg, Andrew
AU - Goutagny, Romain
AU - Gnatkovsky, Vadym
AU - Frassoni, Carolina
AU - Marie, Hélène
AU - Bethus, Ingrid
AU - Mantegazza, Massimo
PY - 2019/5/1
Y1 - 2019/5/1
N2 - SCN1A (NaV1.1 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 (Scn1aRH/+) 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 Scn1aRH/+ 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.
AB - SCN1A (NaV1.1 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 (Scn1aRH/+) 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 Scn1aRH/+ 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.
KW - Autism
KW - Cognition
KW - Dravet syndrome
KW - Epileptogenesis
KW - GEFS+
KW - Precision medicine
KW - Remodeling
KW - Seizures
UR - http://www.scopus.com/inward/record.url?scp=85060330824&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060330824&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2019.01.006
DO - 10.1016/j.nbd.2019.01.006
M3 - Article
AN - SCOPUS:85060330824
VL - 125
SP - 31
EP - 44
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
ER -