Identification of two mutations in cis in the SCN1A gene in a family showing genetic epilepsy with febrile seizures plus (GEFS+) and idiopathic generalized epilepsy (IGE)

•The first case of epilepsy with two missense mutations in cis in the SCN1A gene is reported.•A novel mutation missense mutation is reported.•The functional effect of the coexistence of two mutations on the same chromosome is documented. Mutations in the SCN1A gene causing either loss or gain of fun...

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Bibliographic Details
Published in:Brain research 2017-12, Vol.1677, p.26-32
Main Authors: Binini, N., Sancini, G., Villa, C., Dal Magro, R., Sansoni, V., Rusconi, R., Mantegazza, M., Grioni, D., Talpo, F., Toselli, M., Combi, R.
Format: Article
Language:English
Subjects:
Epilepsy
Epilepsy, Generalized - genetics
Epilepsy, Generalized - physiopathology
Family
Female
GEFS
Gene
HEK293 Cells
Humans
Male
Membrane Potentials - physiology
Mutation
Mutation, Missense
NAV1.1 Voltage-Gated Sodium Channel - genetics
NAV1.1 Voltage-Gated Sodium Channel - metabolism
Patch-Clamp Techniques
SCN1A
Seizures, Febrile - genetics
Seizures, Febrile - physiopathology
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Summary:•The first case of epilepsy with two missense mutations in cis in the SCN1A gene is reported.•A novel mutation missense mutation is reported.•The functional effect of the coexistence of two mutations on the same chromosome is documented. Mutations in the SCN1A gene causing either loss or gain of function have been frequently found in patients affected by genetic epilepsy with febrile seizures plus (GEFS+) or Dravet syndrome (also named severe myoclonic epilepsy in infancy SMEI). By mutation screening of the SCN1A gene, we identified for the first time a case of two missense mutations in cis (p.[Arg1525Gln;Thr297Ile]) in all affected individuals of an Italian family showing GEFS+ and idiopathic generalized epilepsy (IGE). The p.Arg1525Gln mutation was not previously reported yet and was predicted to be pathological by prediction tools, whereas the p.Thr297Ile was already identified in patients showing SMEI. Functional studies revealed that the Nav1.1 channels harboring both mutations were characterized by a significant shift in the activation curve towards more positive potentials. Our data demonstrate that the p.Arg1525Gln represents a novel mutation in the SCN1A gene altering the channel properties in the co-presence of the p.Thr297Ile.
ISSN:0006-8993
1872-6240
DOI:10.1016/j.brainres.2017.09.023