Investigation of the CACNA1A gene as a candidate for typical migraine susceptibility

Typical migraine is a complex neurological disorder comprised of two main s ubtypes: migraine with (MA) and without aura (MO). The disease etiology is still unclear, but family studies provide strong evidence that defective ge nes play an important role. Familial hemiplegic migraine (FHM) is a very ra re and severe subtype of MA. It has been proposed that FHM and MA may have a similar genetic etiology. Therefore, genetic studies on FHM provide a use ful model for investigating the more prevalent types of typical migraine. F HM in some families has been shown to be caused by mutations in a brain-spe cific P/Q-type calcium channel al subunit gene (CACNA1A) on chromosome 19p1 3. There has also been a report of a CACNA1A mutation being associated with MA in a patient from a family with predominant FHM. We have previously dem onstrated suggestive linkage of typical migraine in a large Australian fami ly to the FHM region on chromosome 19p13. These findings suggest that CACNA 1A may also be implicated in the etiology of typical migraine in this pedig ree. To investigate this possibility, we sequenced two patients carrying th e critical susceptibility haplotype surrounding CACNA1A. No disease-causing mutations or polymorphisms were revealed in any of the 47 exons screened. To determine whether the CACNA1A gene was implicated in typical migraine su sceptibility in the general Caucasian population, we also analyzed 82 indep endent pedigrees and a large case control group. We did not detect any link age or association in these groups and conclude that if CACNA1A plays a rol e in typical migraine, it does not confer a major effect on the disease. (C ) 2001 Wiley-Liss, Inc.