INVOLVEMENT OF A CA2+ CHANNEL GENE IN FAMILIAL HEMIPLEGIC MIGRAINE AND MIGRAINE WITH AND WITHOUT AURA

A gene for familial hemiplegic migraine, a subtype of migraine with au ra, was assigned to chromosome 19p13. In this region, we identified a brain-specific P/Q-type calcium-channel alpha(1A)-subunit gene, CACNA 1A, with 47 exons covering 300 kb. Sequencing of all exons and their f lanking surroundings revealed polymorphic variations, including a (CA) (n)-repeat and a (CAG)(n)-repeat in the 3' untranslated region. In pat ients with familial hemiplegic migraine, we found four different misse nse mutations in conserved functional domains. One of the mutations ha s occurred on two different haplotypes in unrelated familial hemiplegi c migraine families. Moreover, in episodic ataxia type 2, we found two mutations disrupting the reading frame. Thus, familial hemiplegic mig raine and episodic ataxia type 2 can be considered as allelic channelo pathies. Involvement of this familial hemiplegic migraine locus in mig raine with end without aura was demonstrated by sib-pair analysis. We showed an increase of shared marker alleles of locus D19S394, which is tightly linked to the gene. The association between the alpha(1A) cal cium channel and familial hemiplegic migraine, and the increase of sha red alleles in migraine-affected sib-pairs, have uncovered a new pathw ay for the pathophysiology of migraine. This finding may provide a rat ionale for the development of specific prophylactic therapy for migrai ne and other (peroxysmal) cerebral disorders.