The novel p.L1649Q mutation in the SCN1A epilepsy gene is associated with familial hemiplegic migraine: genetic and functional studies. Mutation in brief #957. Online.
Familial hemiplegic migraine (FHM) is a severe subtype of migraine with hemiparesis during attacks. We scanned 10 families with FHM without mutations in the CACNA1A (FHM1) and ATP1A2 (FHM2) genes. We identified the novel p.L1649Q mutation (c.4946T>A) in Na(v)1.1 sodium channel gene SCN1A (FHM3) in a North American kindred with FHM without associated ataxia or epilepsy. Functional analysis of the mutation, introduced in the highly homologous human SCN5A, revealed markedly slowed inactivation and a two-fold faster recovery from fast inactivation predicting enhanced neuronal excitation. Our findings establish the role of neuronal Na(v)1.1 sodium channels in FHM and reinforce the involvement of ion channel dysfunction in the pathogenesis of this episodic brain disorder.
Vanmolkot
Kaate R J
KR
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Babini
Elena
E
de Vries
Boukje
B
Stam
Anine H
AH
Freilinger
Tobias
T
Terwindt
Gisela M
GM
Norris
Lisa
L
Haan
Joost
J
Frants
Rune R
RR
Ramadan
Nabih M
NM
Ferrari
Michel D
MD
Pusch
Michael
M
van den Maagdenberg
Arn M J M
AM
Dichgans
Martin
M
D002478:Cells, Cultured; D004827:Epilepsy / Q000235:genetics*; D006580:Genetic Carrier Screening; D006801:Humans; D008881:Migraine Disorders / Q000235:genetics*; D016296:Mutagenesis; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics*
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels