ArticlesMutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine
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.
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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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