The transient receptor potential (TRP) superfamily of non-selective cationic channels are involved in several processes plausibly relevant to migraine pathophysiology, including multimodal sensory and pain perception, central and peripheral sensitization, and regulation of calcium homeostasis. With the aim of identifying single nucleotide polymorphisms (SNPs) in TRP genes that may confer increased genetic susceptibility to migraine, we carried out a case-control genetic association study with replication, including a total of 1,040 cases and 1,037 controls. We genotyped 149 SNPs covering 14 TRP genes with known brain expression. The two-stage study comprised samples of 555 and 485 Spanish, Caucasian patients, selected according to the ICHD-II criteria for the diagnosis of migraine without aura (MO) or migraine with aura (MA). In the discovery sample, 19 SNPs in ten TRP genes showed nominal association (P < 0.05) with MO, MA, or overall migraine. In the replication sample, nominal association was confirmed for TRPV3 rs7217270 in MA and TRPV1 rs222741 in the overall migraine group. Risk haplotypes were identified for seven of the genes showing nominal association in the discovery set, but none of them was replicated. The present findings suggest that members of the vanilloid TRPV subfamily of receptors contribute to the genetic susceptibility to migraine in the Spanish population.

Hemiplegic migraine (HM) is a rare and severe subtype of autosomal dominant migraine, characterized by a complex aura including some degree of motor weakness. Mutations in four genes (CACNA1A, ATP1A2, SCN1A and PRRT2) have been detected in familial and in sporadic cases. This genetically and clinically heterogeneous disorder is often accompanied by permanent ataxia, epileptic seizures, mental retardation, and chronic progressive cerebellar atrophy. Here we report a mutation screening in the CACNA1A and ATP1A2 genes in 18 patients with HM. Furthermore, intragenic copy number variant (CNV) analysis was performed in CACNA1A using quantitative approaches. We identified four previously described missense CACNA1A mutations (p.Ser218Leu, p.Thr501Met, p.Arg583Gln, and p.Thr666Met) and two missense changes in the ATP1A2 gene, the previously described p.Ala606Thr and the novel variant p.Glu825Lys. No structural variants were found. This genetic screening allowed the identification of more than 30% of the disease alleles, all present in a heterozygous state. Functional consequences of the CACNA1A-p.Thr501Met mutation, previously described only in association with episodic ataxia, and ATP1A2-p.Glu825Lys, were investigated by means of electrophysiological studies, cell viability assays or Western blot analysis. Our data suggest that both these variants are disease-causing.

Episodic ataxia is an autosomal dominant ion channel disorder characterized by episodes of imbalance and incoordination. The disease is genetically heterogeneous and is classified as episodic ataxia type 2 (EA2) when it is caused by a mutation in the CACNA1A gene, encoding the α1A subunit of the P/Q-type voltage-gated calcium channel Cav2.1. The vast majority of EA2 disease-causing variants are loss-of-function (LoF) point changes leading to decreased channel currents. CACNA1A exonic deletions have also been reported in EA2 using quantitative approaches. We performed a mutational screening of the CACNA1A gene, including the promoter and 3′UTR regions, in 49 unrelated patients diagnosed with episodic ataxia. When pathogenic variants were not found by sequencing, we performed a copy number variant (CNV) analysis to screen for duplications or deletions. Overall, sequencing screening allowed identification of six different point variants (three nonsense and three missense changes) and two coding indels, one of them found in two unrelated patients. Additionally, CNV analysis identified a deletion in a patient spanning exon 35 as a result of a recombination event between flanking intronic Alu sequences. This study allowed identification of potentially pathogenic alterations in our sample, five of them novel, which cover 20% of the patients (10/49). Our data suggest that most of these variants are disease-causing, although functional studies are required.

Familial hemiplegic migraine (FHM)-causing mutations in the gene encoding the P/Q Ca 2+ channel α 1A subunit (CACNA1A) locate to the pore and voltage sensor regions and normally involve gainof-channel function. We now report on a mutation identified in the first intracellular loop of CACNA1A (α 1A(A454T) ) that does not cause FHM but is associated with the absence of sensorimotor symptoms in a migraine with aura pedigree. α 1A(A454T) channels showed weakened regulation of voltage-dependent steady-state inactivation by Ca V β subunits. More interestingy, A454T mutation suppressed P/Q channel modulation by syntaxin 1A or SNAP-25 and decreased exocytosis. Our findings reveal the importance of I-II loop structural integrity in the functional interaction between P/Q channel and proteins of the vesicle-docking/fusion machinery, and that genetic variation in CACNA1A may be not only a cause but also a modifier of migraine phenotype.CaV 2.1 (P/Q) channels | SNARE proteins | migraine with aura F amilial hemiplegic migraine (FHM) is an autosomal dominantly inherited subtype of migraine with aura that features some degree of hemiparesis during attacks (1, 2). The generally accepted view on migraine pathophysiology points to cortical spreading depression (CSD), an abnormal increase of cortical activity-followed by a long-lasting neuronal suppression wavethat propagates across the cortex, as the cause of the aura and migraine itself (1, 3). FHM-causing mutations have been reported in the CACNA1A gene (encoding the P/Q Ca 2+ channel α 1 subunit) (4), resulting in a gain of P/Q channel function, mainly due to a reduction in the voltage threshold of channel activation favoring CSD initiation and propagation (1, 5-11). Other genetic and environmental factors may also play a role in shaping the phenotype, as identical mutations show different clinical characteristics (2).The P/Q Ca 2+ channel contains a pore-forming α 1A subunit and several regulatory subunits, including intracellular β subunits (Ca V β 1-4 ) that bind to the intracellular loop between transmembrane domains I and II of α 1A (see Fig. 1B for an illustration of the channel complex). The effect of the regulatory subunits is essential for increasing the expression levels and modulating the voltage-dependent activation and inactivation of P/Q channels (12-15).Presynaptic proteins of the vesicle-docking/fusion machinery, including plasma membrane SNARE proteins (syntaxin 1A and SNAP-25) and synaptotagmin, bind to a specific site (synprint) in the large intracellular loop connecting domains II and III of the P/Q channel α 1A subunit (Fig. 1B). This interaction allows secretory vesicles docking to the plasma membrane near the pathway for Ca 2+ entry, optimizing neurotransmitter release.Syntaxin 1A and SNAP-25 also exert an inhibitory effect on P/Q channel activity by left-shifting the voltage dependence of steadystate inactivation (12,16,17). The synprint site serves an important anchoring function that may facilitate SNARE's modulation of channel gating, but the involvem...

We report the case of a 9-year-old girl with early-onset developmental delay, chronic ataxia and prolonged hemiplegic migraine episodes bringing about progressive deterioration. Two days into one episode, diffusion-weighted magnetic resonance imaging disclosed unilateral striatal abnormal signal consistent with cytotoxic edema, which evolved into atrophy on follow-up scans. Mutational screen of CACNA1A gene identified a de novo p.Tyr1387Cys mutation.

No association was found between the assayed SNP and any of the clinical groups considered.

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