Elsevier

The Lancet

Volume 366, Issue 9483, 30 July–5 August 2005, Pages 371-377
The Lancet

Articles
Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine

https://doi.org/10.1016/S0140-6736(05)66786-4Get rights and content

Summary

Background

Familial hemiplegic migraine is an autosomal dominant severe subtype of migraine with aura characterised by some degree of hemiparesis during the attacks. So far, mutations in two genes regulating ion translocation—CACNA1A and ATP1A2—have been identified in pedigrees with this disease.

Methods

To identify additional genes for familial hemiplegic migraine, we did a genome-wide linkage analysis of two disease pedigrees without mutations in CACNA1A and ATP1A2. Ion channel genes in the candidate interval were analysed for mutations, and the functional consequences of the recorded sequence alteration were determined.

Findings

We identified a novel locus for familial hemiplegic migraine on chromosome 2q24. Sequencing of candidate genes in this region revealed a heterozygous missense mutation (Gln1489Lys) in the neuronal voltage-gated sodium channel gene SCN1A, mutations of which have been associated with epilepsy. This same mutation was present in three families with familial hemiplegic migraine. It results in a charge-altering aminoacid exchange in the so-called hinged-lid domain of the protein, which is critical for fast inactivation of the channel. Whole-cell recordings in transiently transfected tsA201 cells expressing the highly homologous SCN5A sodium channel showed that the mutation induces a two-fold to four-fold accelerated recovery from fast inactivation without altering any of the other channel parameters investigated.

Interpretation

Dysfunction of the neuronal sodium channel SCN1A can cause familial hemiplegic migraine. Our findings have implications for the understanding of migraine aura. Moreover, our study reinforces the molecular links between migraine and epilepsy, two common paroxysmal disorders.

Introduction

Migraine is a common, disabling, multifactorial brain disorder affecting about 12% of the population.1, 2 About 35% of people with migraine have migraine with aura, which, by contrast with migraine without aura, is characterised by focal neurological symptoms preceding the headache.1, 3 Family history and twin studies have provided evidence for a genetic contribution to migraine, especially migraine with aura,4 although the mode of inheritance is likely to be complex.5

Familial hemiplegic migraine is a rare and severe variant of migraine with aura, which follows an autosomal dominant pattern of inheritance. The aura in this form of migraine is characterised by transient motor weakness in addition to visual, somatosensory, or dysphasic symptoms, all of which are fully reversible.3, 6 Most patients who have familial hemiplegic migraine do not have additional neurological symptoms, but a few patients also develop permanent cerebellar signs.5

This disease is genetically heterogeneous. Families with familial hemiplegic migraine type 1 (FHM1; Online Mendelian Inheritance in Man [OMIM] 141500) have missense mutations in CACNA1A, which encodes the pore-forming α1 subunit of voltage-gated neuronal CaV2·1 (P/Q-type) calcium channels.7 FHM1 accounts for families with pure familial hemiplegic migraine and for most, if not all, cases of the disease with cerebellar signs.8 Familial hemiplegic migraine type 2 (FHM2; OMIM 602481) is associated with missense mutations in ATP1A2, which encodes the α2 subunit of the Na+/K+ pump.9 Yet there is evidence for further locus heterogeneity in families.10

The aim of our study was to identify a novel gene for familial hemiplegic migraine, by doing genome-wide linkage analysis of two pedigrees with the disease, followed by sequencing of candidate genes in the newly identified chromosomal region. Electrophysiological studies were undertaken to determine the functional consequences of the recorded sequence alteration.

Section snippets

Participants

Familial hemiplegic migraine was diagnosed according to the criteria of the International Headache Society.3 All probands were personally examined (by MD and TF). They all underwent a detailed semistructured interview (45–90 min duration), which included questions about migraine as well as febrile and afebrile seizures. All participants provided written informed consent, and approval was obtained from the ethics committee of the medical faculty of the Ludwig-Maximilians-Universität, München.

Results

We identified 20 families of European origin with familial hemiplegic migraine and at least two living affected members. Direct sequencing of all exons and splice sites of the CACNA1A gene (FHM1) and ATP1A2 gene (FHM2) in affected probands identified 11 families without mutations in these two genes.

To identify additional loci for familial hemiplegic migraine, we did a genome-wide linkage analysis at 10 cM density in the two largest families (family 15 and family 16). Table 1 shows clinical

Discussion

We identified a novel locus for familial hemiplegic migraine on chromosome 2q24 using linkage analysis in three pedigrees with the disease. Sequencing of candidate genes in the critical linkage interval revealed a missense mutation (Gln1489Lys) in the neuronal sodium channel gene SCN1A in affected individuals from all three families.

This mutation showed complete cosegregation with the disease phenotype in all three families. The three families shared the same extended haplotype. Consequently,

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