title: Divergent sodium channel defects in familial hemiplegic migraine.
abstract: Familial hemiplegic migraine type 3 (FHM3) is a severe autosomal dominant migraine disorder caused by mutations in the voltage-gated sodium channel Na(V)1.1 encoded by SCN1A. We determined the functional consequences of three mutations linked to FHM3 (L263V, Q1489K, and L1649Q) in an effort to identify molecular defects that underlie this inherited migraine disorder. Only L263V and Q1489K generated quantifiable sodium currents when coexpressed in tsA201 cells with the human beta(1) and beta(2) accessory subunits. The third mutant, L1649Q, failed to generate measurable whole-cell current because of markedly reduced cell surface expression. Compared to WT-Na(V)1.1, Q1489K exhibited increased persistent current but also enhanced entry into slow inactivation as well as delayed recovery from fast and slow inactivation, thus resulting in a predominantly loss-of-function phenotype further demonstrated by a greater loss of channel availability during repetitive stimulation. In contrast, L263V exhibited gain-of-function features, including delayed entry into, as well as accelerated recovery from, fast inactivation; depolarizing shifts in the steady-state voltage dependence of fast and slow inactivation; increased persistent current; and delayed entry into slow inactivation. Notably, the two mutations (Q1489K and L1649Q) that exhibited partial or complete loss of function are linked to typical FHM, whereas the gain-of-function mutation L263V occurred in a family having both FHM and a high incidence of generalized epilepsy. We infer from these data that a complex spectrum of Na(V)1.1 defects can cause FHM3. Our results also emphasize the complex relationship between migraine and epilepsy and provide further evidence that both disorders may share common molecular mechanisms.
authors.affiliation: Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN 37240, USA.
authors.forename: Kristopher M
authors.initials: KM
authors.lastname: Kahlig
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rhodes
authors.forename: Michael
authors.initials: M
authors.lastname: Pusch
authors.forename: Tobias
authors.initials: T
authors.lastname: Freilinger
authors.forename: José M
authors.initials: JM
authors.lastname: Pereira-Monteiro
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
mesh_terms: D002460:Cell Line; D004594:Electrophysiology; D004827:Epilepsy / Q000235:genetics; D005190:Family; D006801:Humans; D020325:Migraine with Aura / Q000235:genetics*; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels; D012964:Sodium