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Novel mutation confirms seizure locus SCN1A is also familial hemiplegic migraine locus FHM3.

ABSTRACT: Although SCN1A, the gene encoding the neuronal voltage-gated sodium channel, type 1A, is a well-recognized target of mutations underlying a spectrum of epilepsy syndromes, and lies within an extended 12-Mb disease-associated haplotype at the familial hemiplegic migraine-3 locus, it remains to be confirmed that mutations within this gene itself cause syndromes that include migraine phenotypes. The novel T1174S missense mutation of this gene was detected segregating in a family with a heterozygous female child who presented with myoclonus and an abnormal electroencephalogram, and in her heterozygous mother, who had an ataxic migraine syndrome similar to that of her own mother. This three-generation family exhibits the broad phenotypic spectrum of the dominant neuronal hyperexcitability syndromes produced by even a given allele of this sodium channel gene. It also exhibits the second allele of this sodium channel gene associated with a migraine syndrome similar to those caused at the two other familial hemiplegic migraine loci, confirming that this gene itself, not some linked gene, is the familial hemiplegic migraine-3 locus.

SUBMITTER: Gargus JJ

PROVIDER: S-EPMC2151385 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Novel mutation confirms seizure locus SCN1A is also familial hemiplegic migraine locus FHM3.

Gargus J Jay JJ Tournay Anne A

Pediatric neurology 20071201 6

Although SCN1A, the gene encoding the neuronal voltage-gated sodium channel, type 1A, is a well-recognized target of mutations underlying a spectrum of epilepsy syndromes, and lies within an extended 12-Mb disease-associated haplotype at the familial hemiplegic migraine-3 locus, it remains to be confirmed that mutations within this gene itself cause syndromes that include migraine phenotypes. The novel T1174S missense mutation of this gene was detected segregating in a family with a heterozygous ...[more]

PMID: 18021921

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Project description:BackgroundFamilial hemiplegic migraine (FHM) is a group of genetic migraine, associated with hemiparesis and aura. Three causative different genes have been identified, all of which are involved in membrane ion transport. Among these, SCN1A encodes the voltage-gated Na+ channel Nav1.1, and FHM caused by mutations of SCN1A is named FHM3. For 7 of the 12 known FHM3-causing SCNA1 mutations functional consequences have been investigated, and even if gain of function effect seems to be a predominant phenotype, for several mutations conflicting results have been obtained and the available data do not reveal a univocal FHM3 pathomechanism.MethodsTo obtain a more complete picture, here, we characterized by patch clamp approach the remaining 5 mutations (Q1489H, I1498M, F1499?L, M1500?V, F1661?L) in heterologous expression systems.ResultsWith the exception of I1498M, all mutants exhibited the same current density as WT and exhibited a shift of the steady state inactivation to more positive voltages, an accelerated recovery from inactivation, and an increase of the persistent current, revealing that most FHM3 mutations induce a gain of function. We also determined the effect of GS967, a late Na+ current blocker, on the above mentioned mutants as well as on previously characterized ones (L1649Q, L1670?W, F1774S). GS967 inhibited persistent currents of all SCNA1 FMH3-related mutants and dramatically slowed the recovery from fast inactivation of WT and mutants, consistent with the hypothesis that GS967 specifically binds to and thereby stabilizes the fast inactivated state. Simulation of neuronal firing showed that enhanced persistent currents cause an increase of ionic fluxes during action potential repolarization and consequent accumulation of K+ and/or exhaustion of neuronal energy resources. In silico application of GS967 largely reduced net ionic currents in neurons without impairing excitability.ConclusionIn conclusion, late Na+ current blockers appear a promising specific pharmacological treatment of FHM3.

Dataset Information

Novel mutation confirms seizure locus SCN1A is also familial hemiplegic migraine locus FHM3.

Publications

Novel mutation confirms seizure locus SCN1A is also familial hemiplegic migraine locus FHM3.

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