Possible Involvement of the CACNA1E Gene in Migraine: A Search for Single Nucleotide Polymorphism in Different Clinical Phenotypes

Abstract

Objective: To search for differences in prevalence of a CACNA1E variant between migraine without aura, various phenotypes of migraine with aura, and healthy controls.

Background: Familial hemiplegic migraine type 1 (FHM1) is associated with mutations in the CACNA1A gene coding for the alpha 1A (Ca_v 2.1) pore-forming subunit of P/Q voltage-dependent Ca²⁺ channels. These mutations are not found in the common forms of migraine with or without aura. The alpha 1E subunit (Ca_v 2.3) is the counterpart of Ca_v 2.1 in R-type Ca²⁺ channels, has different functional properties, and is encoded by the CACNA1E gene.

Methods: First, we performed a total exon sequencing of the CACNA1E gene in three probands selected because they had no abnormalities in the three FHM genes. In a patient suffering from basilar-type migraine, we identified a single nucleotide polymorphism (SNP) in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760; Minor Allele Frequency 0.2241) hitherto not studied in migraine. In a second step, we determined its occurrence in four groups by direct sequencing on blood genomic DNA: migraine patients without aura (N = 24), with typical aura (N = 55), complex neurological auras (N = 19; hemiplegic aura: N = 15; brain stem aura: N = 4), and healthy controls (N = 102).

Results: The Asp859Glu - rs35737760 SNP of the CACNA1E gene was present in 12.7% of control subjects and in 20.4% of the total migraine group. In the migraine group it was significantly over-represented in patients with complex neurological auras (42.1%), OR 4.98 (95% CI: 1.69-14.67, uncorrected P = .005, Bonferroni P = .030, 2-tailed Fisher's exact test). There was no significant difference between migraine with typical aura (10.9%) and controls.

Conclusions: We identified a polymorphism in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760) that is more prevalent in hemiplegic and brain stem aura migraine. This missense variant causes a change from aspartate to glutamate at position 859 of the Ca_v 2.3 protein and might modulate the function of R-type Ca²⁺ channels. It could thus be relevant for migraine with complex neurological aura, although this remains to be proven.

Keywords: Cav2.3 channels; genetics; migraine; migraine aura.