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Divergent effects of the T 1174S SCN1A mutation associated with seizures and hemiplegic migraine
Author(s) -
Cestèle Sandrine,
Labate Angelo,
Rusconi Raffaella,
Tarantino Patrizia,
Mumoli Laura,
Franceschetti Silvana,
Annesi Grazia,
Mantegazza Massimo,
Gambardella Antonio
Publication year - 2013
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12123
Subject(s) - familial hemiplegic migraine , epilepsy , mutation , loss function , proband , phenotype , nap , neuroscience , migraine , ictal , gain of function , medicine , psychology , genetics , biology , migraine with aura , aura , gene
Summary Purpose To report the identification of the T1174S SCN1A (Na V 1.1) mutation in a three‐generation family with both epileptic and familial hemiplegic migraine ( FHM ) phenotypes and clarify the pathomechanism. Methods The five affected individuals underwent detailed clinical analyses. Mutation analyses was performed by direct sequencing of SCN1A ; functional studies by expression in tsA‐201 cells. A computational model was used to compare the effects of T1174S with those of a typical FHM mutation (Q1489K). Key Findings The proband had benign occipital epilepsy (BOE); two relatives had simple febrile seizures ( FS ) and later developed BOE . Two additional relatives had FHM without epilepsy or FS . All affected members and one obliged carrier carried the T1174S mutation. Functional effects were divergent: positive shift of the activation curve and deceleration of recovery from fast inactivation, consistent with loss of function, and increase of persistent current (I NaP ), consistent with gain of function. The I NaP increase was inhibited by dialysis of the cytoplasm, consistent with a modulation. Therefore, as shown by the computational model, T 1174S could in some conditions induce overall loss of function, and in others gain of function; Q1489K induced gain of function in all the conditions. Significance Modulation of the properties of T1174S can lead to a switch between overall gain and loss of function, consistent with a switch between promigraine end epileptogenic effect and, thus, with coexistence of epileptic and FHM phenotypes in the same family. These findings may help to shed light on the complex genotype–phenotype relationship of SCN1A mutations.