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.

Association between PRDM16, MEF2D, TRPM8, LRP1 gene polymorphisms and migraine susceptibility in the She ethnic population in China

“…Migraine is a multifactorial disorder resulting from complex interactions between multiple predisposing genes, environmental factors and other factors, including hormonal, vascular, neuronal and pain pathways [8][9][10][11][12]. Migraine is characterized by accompanying symptoms such as auras, ataxia and periodic muscle paralysis; however, genetic studies have suggested that migraines with auras and migraine without auras are different clinical manifestations of the same genetic disease [8,12,13]. Moreover, studies have shown that migraines result from interactions between genetic factors and environmental factors and genetic predisposition and family susceptibility have been demonstrated [14].…”

Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders

“…However, others exhibit loss‐of‐function effects in heterologous cell systems, and mutations such as T1174 can act in both a gain‐ and loss‐of‐function manner, although with respect to FHM its gain‐of‐function in GABAergic neurons may be important . As Na V 1.1 is the predominant channel in GABAergic interneurons, FHM3 SCN1A mutations predict increased firing of inhibitory GABAergic neurons, which could lead to higher extracellular potassium concentrations, enhanced glutamate release, and triggering of CSD . FHM3 KI mouse models have yet to be reported, but will help to reveal how FHM3 mutations cause disease when expressed in a natural cellular context in a whole animal model.…”

Involvement of Voltage-Gated Calcium Channels in Inflammation and Inflammatory Pain

“…11) Interestingly, the trigeminal ganglia isolated from Ca v 2.1 α 1 R192Q mutant knock-in mice expressing a human mutation causing FHM-1 show increases in basal and bradykinin-stimulated CGRP release, 13) and are characterized by the enrichment of activated macrophages and constitutive overexpression of mRNAs for IL-1β, IL-6, IL-10 and tumor necrosis factor α (TNFα). 14) Ca v 2.1 thus regulates the release of neurotransmitters including glutamate and CGRP from the peripheral and central endings of trigeminal nerves, thereby participating in the pathogenesis of migraine. 13,15) Transcripts for all L-type VGCC isoforms, Ca v 1.1-Ca v 1.4, are detectable in lymphocytes, although their functions remain largely unclear.…”