The Revolution in Migraine Genetics: From Aching Channels Disorders to a Next-Generation Medicine

Abstract

Channelopathies are a heterogeneous group of neurological disorders resulting from dysfunction of ion channels located in cell membranes and organelles. The clinical scenario is broad and symptoms such as generalized epilepsy (with or without fever), migraine (with or without aura), episodic ataxia and periodic muscle paralysis are some of the best known consequences of gain- or loss-of-function mutations in ion channels. We review the main clinical effects of ion channel mutations associated with a significant impact on migraine headache. Given the increasing and evolving use of genetic analysis in migraine research-greater emphasis is now placed on genetic markers of dysfunctional biological systems-we also show how novel information in rare monogenic forms of migraine might help to clarify the disease mechanisms in the general population of migraineurs. Next-generation sequencing (NGS) and more accurate and precise phenotyping strategies are expected to further increase understanding of migraine pathophysiology and genetics.

Keywords: astrocyte; calcium channel; glutamate; migraine; sodium channel; tripartite synapse.

Figure 1

Protein pathway driving the migraine process at the tripartite synapse. The illustration depicts different proteins at the tripartite synapse possibly involved in glutamatergic dysfunction in migraine (see text for details). Ca_v2.1 (CACNA1A; red) dysfunction at presynaptic terminals of glutamatergic neurons leads to altered Ca²⁺ influx and enhanced glutamate release by vesicles into the synaptic cleft, favoring the activation and propagation of cortical spreading depression (CSD) in familial hemiplegic migraine 1 (FHM1). Na⁺/K⁺-ATPase (ATP1A2; green) at the astrocyte plasma membrane utilizes ATP hydrolysis to exchange Na⁺ for K⁺ ions, generating a Na⁺ gradient that helps to modulate the glutamate re-uptake by glial excitatory amino acid transporter 1 (EAAT1; SLC1A3; yellow) and EAAT2 (SLC1A2; cyan). Loss-of-function of Na⁺/K⁺-ATPase (FHM2), as well as of EAAT1, slows the clearance of glutamate leading to increased cortical excitability that favors the initiation and propagation of CSD. The activity of EAAT2 also contributes to glutamate clearance, and is downregulated by mutations in astrocyte elevated gene-1 (AEG-1) (MTDH; dashed line), one of the candidate genes emerging from genome-wide association (GWA) studies. Na_V1.1 channels (SCN1A, FHM3; purple) are essential for the generation and propagation of action potentials. FHM3-associated mutations can reduce firing of inhibitory interneurons, or accelerate the recovery of the channel after fast inactivation, causing high-frequency firing of presynaptic glutamatergic neurons. PRRT2 (pink) also affects the glutamate signaling pathway, through defective interaction with SNAP25 (forest green) and the ionotropic glutamate receptor AMPA1 (termed GRIA1; gray with pale pink border), resulting in increased glutamate release. Defective membrane expression of the Na(⁺)-HCO(3)(-) cotransporter NBCe1 (SLC4A4; orange) may affect the uptake of HCO3- into astrocytes leading to altered activity of pH-sensitive NMDA receptors (gray). Both AMPA and NMDA receptors are also directly modulated by LRP1 (dark pink), which is cleaved by a metalloproteinase that is encoded by another migraine-susceptibility gene, MMP16 (fluorescent green). Synaptic activity is also influenced by other proteins thought to contribute to migraine pathophysiology, such as the nuclear transcription factors MEF2D and FHL5, the serine-threonine kinase TGFBR2 (aquamarine), and ASTN2 (fuchsia), a protein related to ASTN1 (pale lilac) and thought to influence neuronal migration. All these mechanisms, when defective, may affect the glutamate signaling pathway, possibly leading to neuronal hyperexcitability predisposing to migraine. The illustration also shows the pathway that starts from the CSD-driven opening of PANX1 channels (lilac) and triggers the inflammatory cascade and subsequent trigeminovascular sensitization. Signaling to PANX1 leads to caspase 1 activation that, in turn, stimulates the release of high-mobility group box 1 (HMGB1) proteins and the activation of the transcription factor nuclear factor κB (NF-κB) in astrocytes. This may lead to local increase in vasoactive inflammatory mediators and sensitization of pain-relevant brainstem regions.

Figure 2

The landscape of past and near future genetic research in migraine headache disorders. The diagram illustrates the relative costs of the molecular methodologies employed in the study of migraine genetics and the timing of the discovery of the major genes involved in FHM and in related disorders. WES, whole-exome sequencing; WGS, whole-genome sequencing; GWAS, genome-wide association studies; NGS, next-generation sequencing.