title: Early-onset familial hemiplegic migraine due to a novel SCN1A mutation.
abstract: Introduction Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na+channel NaV1.1. The aim of this study was to explore the clinical, genetic and pathogenetic features of a pure FHM3 family. Methods A three-generation family was enrolled in this study for genetic testing and assessment of clinical features. Whole cell patch-clamp was performed to determine the functions of identified mutant NaV1.1 channels, which were transiently expressed in human tsA201 cells together with β1and β2subunits. Results and conclusions We identified a novel SCN1A (p.Leu1624Pro) mutation in a pure FHM family with notably early-onset attacks at mean age of 7. L1624P locates in S3 of domain IV, the same domain as two of four known pure FHM3 mutations. Compared to WT channels, L1624P displayed an increased threshold-near persistent current in addition to other gain-of-function features such as: a slowing of fast inactivation, a positive shift in steady-state inactivation, a faster recovery and higher channel availability during repetitive stimulation. Similar to the known FHM3 mutations, this novel mutation predicts hyperexcitability of GABAergic inhibitory neurons.
authors.affiliation: 1 Division of Neurophysiology, Ulm University, Germany.
authors.forename: Chunxiang
authors.initials: C
authors.lastname: Fan
authors.affiliation: 2 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wolking
authors.affiliation: 1 Division of Neurophysiology, Ulm University, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Lehmann-Horn
authors.affiliation: 2 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.
authors.forename: Ulrike Bs
authors.initials: UB
authors.lastname: Hedrich
authors.affiliation: 2 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Freilinger
authors.affiliation: 2 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.affiliation: 3 Institute of Human Genetics, Ulm University, Germany.
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.affiliation: 4 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.affiliation: 1 Division of Neurophysiology, Ulm University, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Jurkat-Rott
mesh_terms: D000328:Adult; D002648:Child; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020325:Migraine with Aura / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
keywords: FHM3; Familial hemiplegic migraine; NaV1.1; early-onset; gain of function