Vestibular migraine (VM) is one of the most common vestibular disorders, affecting around 1% of the general population (1). It is characterized by recurrent attacks of vestibular symptoms, a current or previous history of migraine, and the existence of one or more migraine features during the vestibular episodes. Recently, VM has been included as a diagnostic category in the latest International Classification of Headache Disorders (ICHD) criteria (2).

Most cases of VM are considered sporadic, but familial aggregation of VM with autosomal-dominant inheritance has been described in several families, supporting a genetic background for the condition (3, 4). Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated

with a genetic predisposition for migraine with or without aura (5, 6). Familial hemiplegic migraine (FHM), which is a subtype of migraine with aura, is caused by mutations in CACNA1A, ATP1A2, and SCN1A (7). However, no candidate gene has been validated in VM, although several genetic loci such as chromosomes 5q35, 9q13-q22, 11q, and 22q12 are known (8–11). Furthermore, previous studies have not detected pathogenic mutations in FHM or episodic ataxia (EA) genes in VM patients (12, 13).

Transient receptor potential (TRP) channels are a family of cation channels expressed mostly on the cell (14, 15). They are divided into seven subfamilies including TRPC, TRPV, TRPM, TRPA, TRPN, TRPP, and TRPML, which mediate sensory transduction such as pain, touch, hearing, and thermal sensation. In addition, TRP channels enable individual cells to respond to changes in their local environment. These ion channels have a relatively non-selective permeability to cations including Ca²⁺ and Mg²⁺, and modulate ion entry driving forces. TRP channels have been linked to neurodegenerative disorders, kidney disease, and cancers by altering intracellular ion homeostasis (15–18). Interestingly, they have been repeatedly hypothesized to contribute to migraine via the activation of meningeal nociceptors or the release of calcitonin gene-related peptide (CGRP) (19–22).

The present study investigated the clinical phenotype of a Korean family with VM showing autosomal-dominant inheritance. Here we report one novel mutation in TRPM7 that may explain the VM phenotype in the family.

This study identified a nonsense mutation in TRPM7 in a Korean family with VM. This variant may cause a premature stop codon and loss-of-function in the protein, thus contributing to the development the VM phenotype by altering the homeostasis of intracellular ions.

Several hypotheses have been proposed for explaining the pathophysiology of VM, which remains unclear. The genetic susceptibility of migraine suggests ionic channelopathy involved in glutamate homeostasis as the underlying pathophysiology of VM (28, 29). Indeed, there is accumulating evidence that Ca²⁺ channels could be involved in migraine and VM pathophysiology. Mutations in CACNA1A, which encodes Cav2.1, the α1A subunit of the P/Q-type voltage-gated Ca²⁺ channel, cause three neurological channelopathies: FHM type 1, EA type 2 (EA2), and spinocerebellar ataxia type 6 (30). Patients with FHM or EA2 often experience paroxysmal vertigo, and more than half of EA2 patients have migraine that meets the ICHD criteria. Some members of the present family also presented with hemiplegia and dysarthria during their episodes. Nevertheless, previous studies failed to detect mutations in patients with VM in the genes causing FHM or EA, such as CACNA1A, ATP1A2, SCN1A, and CACNB4 (12, 13), which is consistent with the present study.

TRPM7 reported here encodes the cation selective ion channel that is highly permeable to Ca²⁺, Mg²⁺, and metal ions such as Zn²⁺ (16). This channel comprises a tetrameric complex, with each subunit containing six-transmembrane segments (S1–S6) and a pore-forming loop between S5 and S6 [Figure 3C; (31)]. Its C-terminus contains a TRP box of highly conserved residues, a coiled-coil (CC) domain, and an atypical serine/threonine protein kinase domain (32). The TRPM7 mutation identified in the present study is located in a long “connecting helix” that links the transmembrane segment and the CC domain in the C-terminus, thus predicting truncation of the C-terminus including the CC and kinase domains (32). These domains play an important role in the tetrameric assembly of the channel or in regulating channel function by Mg²⁺ nucleotides (31–34). Therefore, the mutation identified in the present study seems to affect TRPM7 channel activity via structural instability or functional impairment. This hypothesis is supported by a previous animal study which generated knockout mice with the deletion of TRPM7 kinase domain (35). These mice carried truncated mutation quite similar to the mutation described in this study. Although homozygous knockout mice caused embryonic lethality, heterozygous mice were viable, but showed abnormality in the regulation of Mg²⁺ homeostasis and alterations in TRPM7 channel properties. These mice exhibited abnormal behaviors such as clasping, tremor, seizure, and violent sudden leaps as a reaction to the light and noise, similar to photophobia and phonophobia seen in VM. Furthermore, one of the affected individuals in this family had a history of recurrent seizure.

Ca²⁺ and Mg²⁺ play important roles in regulating various neuronal functions. In particular, they exert opposite effects in the signaling of the excitatory neurotransmitter glutamate: glutamate release is triggered by an influx of Ca²⁺, whereas Mg²⁺ inhibits glutamate release by antagonizing Ca²⁺ (36). Thus, a tight balance between Ca²⁺ and Mg²⁺ is needed in order to maintain the proper excitability of neurons. Since TRPM7 channels that are abundantly expressed in neuronal cells are highly selective to Ca²⁺ and Mg²⁺ (37, 38), mutation in TRPM7 may cause alterations in Ca²⁺ and Mg²⁺ homeostasis and neuronal excitability. Migrainous headache is the consequence of cortical spreading depression evoked by glutamate release and N-methyl-D-aspartate (NMDA) receptor activation in the brain. These processes have been linked to low Mg²⁺ concentrations, which contribute to the hyperexcitability of the NMDA receptor (36). A beneficial effect of Mg²⁺ supplementation has also been reported in migraine patients (39). In addition, low Mg²⁺ concentrations increase the amount of substance P released, which is a neuroinflammatory mediator (40). Since the TRPM7 channel is an important Mg²⁺ transporter, it may contribute to VM attacks by affecting intracellular Ca²⁺ and Mg²⁺ homeostasis.

Recently, several TRP channels have been linked to migraine pathophysiology, including TRPV1, TRPV4, TRPM8, and TRPA1 (19). These channels are expressed on trigeminal sensory neurons that innervate the meninges (20, 41). The activation of TRP channels promotes the excitation of nociceptive afferent fibers and potentially leads to pain and allodynia (19, 20). In addition, it can elicit the release of CGRP, causing vasodilation and neurogenic inflammation (19, 42, 43). Several SNPs in TRPV1, TRPV3, and TRPM8 were found to be associated with migraine susceptibility in meta-analyses of observational studies and GWAS (5, 25–27). Based on these findings, TRP channels have been proposed as a therapeutic target in migraine (19, 21, 22, 44). More studies are needed to better explore the potential role for these channels including TRPM7 in migraine pathophysiology.

This study was subjective to some potential limitations. We did not perform functional study determining pathogenicity of the candidate variants. Despite the rarity and putative pathogenicity in functional annotations, establishing the pathogenicity of the variants may be difficult without a functional assay. However, previous functional studies demonstrated that the deletion of TRPM7 kinase domain reduced channel activity and increased its sensitivity to Mg²⁺ inhibition (33–35). Another limitation is difficulty in detecting copy number variations (CNVs) through whole-exome sequencing. CNV analysis can aid the detection of large deletions or duplications of causative genes, but whole-genome sequencing may be more suitable than whole-exome sequencing for CNV analysis. Finally, we used the hg19 as the reference genome for the reads mapping instead of hg38.

In summary, we have presented the clinical characteristics of a Korean family with VM. Whole-exome sequencing identified a potential disease-causing variant in TRPM7, which may cause alterations in intracellular Ca²⁺ and Mg²⁺ homeostasis and neuronal excitability. Our results highlight TRPM7 as a novel candidate gene for VM.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Pusan National University Yangsan Hospital. The patients/participants provided their written informed consent to participate in this study.

EO conducted the experiments and interpretation of the data, and wrote the manuscript. J-HS, JC, S-YC, and K-DC contributed to the interpretation and analysis of data. J-HC conducted the design and conceptualization of the study, interpretaion of the data, and revised the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.