Association analysis of STX1A gene variants in common forms of migraine

Tropeano, Maria; Wöber‐Bingöl, Çiçek; Karwautz, Andreas; Wagner, Gudrun; Vassos, Evangelos; Campos-de-Sousa, Sara; Graggaber, Andrea; Zesch, Heidi Elisabeth; Kienbacher, Christian; Natriashvili, Sofia; Kanbur, Incifer; Wöber, Christian; Collier, David

doi:10.1177/0333102411433300

Cited by 15 publications

(20 citation statements)

References 39 publications

(49 reference statements)

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“…For example, single nucleotide polymorphisms in the transient receptor potential channels TRPV1 and TRPV3, and gene variants in TRESK channel-related genes (STX1A), have been linked to migraine. 66,67 The link between migraine and [Ca 21 ] i dysregulation does not appear to be limited to neurons. In a transgenic mouse model of familial migraine and advanced sleep phase syndrome, casein kinase Id mutations were associated with increased spontaneous and evoked Ca 21 signaling in astrocytes, and an increased susceptibility to CSD.…”

Section: Discussionmentioning

confidence: 99%

Abnormal synaptic Ca²⁺ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

Eikermann-Haerter

Arbel‐Ornath

Yalcin

et al. 2015

Annals of Neurology

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Objective Migraine is one of the most common and debilitating neurological conditions. Familial hemiplegic migraine type 1 (FHM1), a monogenic migraine subtype, is caused by gain-of-function of voltage-gated CaV2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α1A subunit of CaV2.1 channels and are highly susceptible to cortical spreading depression (CSD), the electrophysiologic event underlying migraine aura. To date, however, the mechanism underlying increased CSD/migraine susceptibility remains unclear. Methods We employed in vivo multiphoton microscopy of the genetically encoded Ca2+-indicator yellow cameleon to investigate synaptic morphology and [Ca2+]i in FHM1 mice. In order to study CSD-induced cerebral oligemia, we used in vivo laser speckle flowmetry and multimodal imaging. With electrophysiologic recordings we investigated the effect of the CaV2.1 gating modifier tert-butyl dihydroquinone on CSD in vivo. Results FHM1 mutations elevate neuronal [Ca2+]i and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a CaV2.1 gating modifier, in hyperexcitable FHM1 mice. At the synaptic level, axonal boutons were larger, and dendritic spines were predominantly mushroom type, which both provide a structural correlate for enhanced neuronal excitability. Resting neuronal [Ca2+]i was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium-overloaded neurons was increased. Neuronal [Ca2+]i surge during CSD was faster and larger, and post-CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains. Interpretation Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca2+ homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs.

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Section: Discussionmentioning

confidence: 99%

Abnormal synaptic Ca²⁺ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

Eikermann-Haerter

Arbel‐Ornath

Yalcin

et al. 2015

Annals of Neurology

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“…For STX1A, literature reports have highlighted a significant association of rs4363087 with migraine (Tropeano et al. ). With respect to functionality, VAMP2 is essential for fast Ca 2+ triggered release, because VAMP2 knock‐out mice lacks fast Ca 2+ triggered neurotransmitter release, whereas, slow release phase persists in them (Schoch et al.…”

Section: Discussionmentioning

confidence: 99%

“…VAMP2 also did not reveal any significant role of genetics in the etiology of bipolar disorder; however, no distinct relation could be observed (Abou Jamra et al 2008). For STX1A, literature reports have highlighted a significant association of rs4363087 with migraine (Tropeano et al 2012). With respect to functionality, VAMP2 is essential for fast Ca 2+ triggered release, because VAMP2 knock-out mice lacks fast Ca 2+ triggered neurotransmitter release, whereas, slow release phase persists in them (Schoch et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Synergistic association of STX1A and VAMP2 with cryptogenic epilepsy in North Indian population

et al. 2016

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Introduction“Common epilepsies”, merely explored for genetics are the most frequent, nonfamilial, sporadic cases in hospitals. Because of their much debated molecular pathology, there is a need to focus on other neuronal pathways including the existing ion channels.MethodsFor this study, a total of 214 epilepsy cases of North Indian ethnicity comprising 59.81% generalized, 40.19% focal seizures, and based on epilepsy types, 17.29% idiopathic, 37.38% cryptogenic, and 45.33% symptomatic were enrolled. Additionally, 170 unrelated healthy individuals were also enrolled. Here, we hypothesize the involvement of epilepsy pathophysiology genes, that is, synaptic vesicle cycle, SVC genes (presynapse), ion channels and their functionally related genes (postsynapse). An interactive analysis was initially performed in SVC genes using multifactor dimensionality reduction (MDR). Further, in order to understand the influence of ion channels and their functionally related genes, their interaction analysis with SVC genes was also performed.ResultsA significant interactive two‐locus model of STX1A_rs4363087|VAMP2_rs2278637 (presynaptic genes) was observed among SVC variants in all epilepsy cases (P 1000‐value = 0.054; CVC = 9/10; OR = 2.86, 95%CI = 1.88–4.35). Further, subgroup analysis revealed stronger interaction for the same model in cryptogenic epilepsy patients only (P 1000‐value = 0.012; CVC = 10/10; OR = 4.59, 95%CI = 2.57–8.22). However, interactive analysis of presynaptic and postsynaptic genes did not show any significant association.ConclusionsSignificant synergistic interaction of SVC genes revealed the possible functional relatedness of presynapse with pathophysiology of cryptogenic epilepsy. Further, to establish the clinical utility of the results, replication in a large and similar phenotypic group of patients is warranted.

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“…Syntaxin 1A, encoded by the STX1A gene, is involved in the regulation of neurotransmitters such as GABA by binding to the GABA transporter and inhibiting reuptake of GABA and 5-HT by decreasing the expression and changing subcellular localization of the 5-HT transporter [38]. Various SNPs were investigated to confirm the involvement of the STX1A gene in migraine susceptibility.…”

Section: Gene Polymorphisms and Migrainementioning

confidence: 99%

“…The haplotype analysis demonstrated involvement of the rs6951030 G allele in migraine susceptibility and a protective role for the T allele both for MA and migraine in general. SNP rs2293489 is also connected to migraine; however, no association was found between rs4363087 and rs3793243 variants and the disease [36-38]. All these studies support the role of the STX1A gene as a putative risk factor for migraine.…”

Section: Gene Polymorphisms and Migrainementioning

confidence: 99%

Molecular factors in migraine

et al. 2016

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Migraine is a common neurological disorder that affects 11% of adults worldwide. This disease most likely has a neurovascular origin. Migraine with aura (MA) and more common form - migraine without aura (MO) – are the two main clinical subtypes of disease. The exact pathomechanism of migraine is still unknown, but it is thought that both genetic and environmental factors are involved in this pathological process. The first genetic studies of migraine were focused on the rare subtype of MA: familial hemiplegic migraine (FHM). The genes analysed in familial and sporadic migraine are: MTHFR, KCNK18, HCRTR1, SLC6A4, STX1A, GRIA1 and GRIA3. It is possible that migraine is a multifactorial disease with polygenic influence.Recent studies have shown that the pathomechanisms of migraine involves both factors responsible for immune response and oxidative stress such as: cytokines, tyrosine metabolism, homocysteine; and factors associated with pain transmission and emotions e.g.: serotonin, hypocretin-1, calcitonin gene-related peptide, glutamate. The correlations between genetic variants of the HCRTR1 gene, the polymorphism 5-HTTLPR and hypocretin-1, and serotonin were observed. It is known that serotonin inhibits the activity of hypocretin neurons and may affect the appearance of the aura during migraine attack.The understanding of the molecular mechanisms of migraine, including genotype-phenotype correlations, may contribute to finding markers important for the diagnosis and treatment of this disease.

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Association analysis of STX1A gene variants in common forms of migraine

Abstract: Our results provide support for the hypothesis that STX1A represents a susceptibility gene for migraine.

Cited by 15 publications

References 39 publications

Abnormal synaptic Ca²⁺ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

Abnormal synaptic Ca²⁺ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

Synergistic association of STX1A and VAMP2 with cryptogenic epilepsy in North Indian population

Molecular factors in migraine

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Association analysis of STX1A gene variants in common forms of migraine

Abstract: Our results provide support for the hypothesis that STX1A represents a susceptibility gene for migraine.

Cited by 15 publications

References 39 publications

Abnormal synaptic Ca2+ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

Abnormal synaptic Ca2+ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

Synergistic association of STX1A and VAMP2 with cryptogenic epilepsy in North Indian population

Molecular factors in migraine

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Abnormal synaptic Ca²⁺ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

Abnormal synaptic Ca²⁺ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice