165,166 In 1993 the linkage of the monogenic FHM to chromosome 19p13 was reported by NVP-AUY922 order the Paris group.167 This was soon followed by proof of genetic heterogeneity because approximately only 50% of FHM families appeared to be linked to this locus.168,169 In a subsequent study, including 4 families (3 with migraine with aura and 1 with migraine without aura) with multiple cases, the reported locus of FHM was excluded.170 In contrast, another study from 1995 suggested that the FHM locus on 19p13 was involved in the common

forms of migraine with and without aura.171 In 1996 the protein kinase substrate 80 K-H gene was excluded as a candidate gene for FHM by the Leiden group.172 Then later in 1996 a seminal paper in Cell from the Leiden group reported the first missense mutation in the voltage-gated P/Q Ca2+ channel CACNA1A gene in FHM19 (see Fig. 10). They learn more examined 16 patients with FHM and 50 randomly collected controls with Exon trap experiments, cDNA sequence, and Northern blot analysis. Genomic DNA was used as a template to generate polymerase chain reaction products for single-strand conformational polymorphism analysis and denaturing high-performance liquid chromatography. The authors

concluded that “our findings implicate the P/Q-type channel α1-subunit gene on chromosome 19p13.1 (CACNL1A4) in the pathogenesis both episodic ataxia type 2 and FHM, and most likely also of the more common forms of migraine.”19 A variable

expression of mutations in the P/Q-type calcium channel was observed.173 Since then, 2 other mutations for FHM, the ATP1A2 gene located on chromosome 1q23 (FHM2)173,174 and the SCN1A gene located on chromosome 2q24 (FHM3)175 have been identified.176 Since 1996, several studies have shown linkage to other loci or genes in migraine with and without aura.177-183 In contrast, the D2 receptor Ncol allele did not have an allelic association of migraine with aura.184 In one large genetic study in patients (n = 827) with “typical check details migraine” and controls (n = 765) single-nucleotide polymorphism (SNP) alleles in the insulin receptor gene were associated with migraine.185 A replication study (949 patients and 648 controls) in migraine with aura showed, however, only a nonsignificant trend for an SNP in the insulin gene and migraine (P = .1).186 In a recent comprehensive and large-scale study including 2800 migraine with aura patients from various countries, it was tested whether common variants in ion transport genes could be involved in a common type of migraine.187,188 More than 5000 SNPs in 155 in transport genes (including the 3 FHM genes) were studied, but no significant associations were found.187,188 From this study it seems that common variants in ion transport genes do not play a major role in susceptibility for common types of migraine.