Abstract
OBJECTIVE: To search for differences in prevalence of a CACNA1E variant between migraine without aura, various phenotypes of migraine with aura, and healthy controls.
BACKGROUND: Familial hemiplegic migraine type 1 (FHM1) is associated with mutations in the CACNA1A gene coding for the alpha 1A (Cav 2.1) pore-forming subunit of P/Q voltage-dependent Ca2+ channels. These mutations are not found in the common forms of migraine with or without aura. The alpha 1E subunit (Cav 2.3) is the counterpart of Cav 2.1 in R-type Ca2+ channels, has different functional properties, and is encoded by the CACNA1E gene.
METHODS: First, we performed a total exon sequencing of the CACNA1E gene in three probands selected because they had no abnormalities in the three FHM genes. In a patient suffering from basilar-type migraine, we identified a single nucleotide polymorphism (SNP) in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760; Minor Allele Frequency 0.2241) hitherto not studied in migraine. In a second step, we determined its occurrence in four groups by direct sequencing on blood genomic DNA: migraine patients without aura (N = 24), with typical aura (N = 55), complex neurological auras (N = 19; hemiplegic aura: N = 15; brain stem aura: N = 4), and healthy controls (N = 102).
RESULTS: The Asp859Glu - rs35737760 SNP of the CACNA1E gene was present in 12.7% of control subjects and in 20.4% of the total migraine group. In the migraine group it was significantly over-represented in patients with complex neurological auras (42.1%), OR 4.98 (95% CI: 1.69-14.67, uncorrected P = .005, Bonferroni P = .030, 2-tailed Fisher's exact test). There was no significant difference between migraine with typical aura (10.9%) and controls.
CONCLUSIONS: We identified a polymorphism in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760) that is more prevalent in hemiplegic and brain stem aura migraine. This missense variant causes a change from aspartate to glutamate at position 859 of the Cav 2.3 protein and might modulate the function of R-type Ca2+ channels. It could thus be relevant for migraine with complex neurological aura, although this remains to be proven.
| Original language | English |
|---|---|
| Pages (from-to) | 1136-1144 |
| Number of pages | 9 |
| Journal | Headache |
| Volume | 57 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Jul 2017 |
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Keywords
- Aspartic Acid
- Calcium Channels, R-Type
- Case-Control Studies
- Cation Transport Proteins
- Cerebellar Ataxia
- DNA Mutational Analysis
- Exons
- Female
- Gene Frequency
- Genetic Predisposition to Disease
- Glutamic Acid
- Humans
- Male
- Migraine Disorders
- Phenotype
- Polymorphism, Single Nucleotide
- Retrospective Studies
- Statistics, Nonparametric
- Journal Article
Cite this
Possible Involvement of the CACNA1E Gene in Migraine : A Search for Single Nucleotide Polymorphism in Different Clinical Phenotypes. / Ambrosini, Anna; D'Onofrio, Mara; Buzzi, Maria Gabriella; Arisi, Ivan; Grieco, Gaetano S; Pierelli, Francesco; Santorelli, Filippo M; Schoenen, Jean.
In: Headache, Vol. 57, No. 7, 07.2017, p. 1136-1144.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Possible Involvement of the CACNA1E Gene in Migraine
T2 - A Search for Single Nucleotide Polymorphism in Different Clinical Phenotypes
AU - Ambrosini, Anna
AU - D'Onofrio, Mara
AU - Buzzi, Maria Gabriella
AU - Arisi, Ivan
AU - Grieco, Gaetano S
AU - Pierelli, Francesco
AU - Santorelli, Filippo M
AU - Schoenen, Jean
N1 - © 2017 American Headache Society.
PY - 2017/7
Y1 - 2017/7
N2 - OBJECTIVE: To search for differences in prevalence of a CACNA1E variant between migraine without aura, various phenotypes of migraine with aura, and healthy controls.BACKGROUND: Familial hemiplegic migraine type 1 (FHM1) is associated with mutations in the CACNA1A gene coding for the alpha 1A (Cav 2.1) pore-forming subunit of P/Q voltage-dependent Ca2+ channels. These mutations are not found in the common forms of migraine with or without aura. The alpha 1E subunit (Cav 2.3) is the counterpart of Cav 2.1 in R-type Ca2+ channels, has different functional properties, and is encoded by the CACNA1E gene.METHODS: First, we performed a total exon sequencing of the CACNA1E gene in three probands selected because they had no abnormalities in the three FHM genes. In a patient suffering from basilar-type migraine, we identified a single nucleotide polymorphism (SNP) in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760; Minor Allele Frequency 0.2241) hitherto not studied in migraine. In a second step, we determined its occurrence in four groups by direct sequencing on blood genomic DNA: migraine patients without aura (N = 24), with typical aura (N = 55), complex neurological auras (N = 19; hemiplegic aura: N = 15; brain stem aura: N = 4), and healthy controls (N = 102).RESULTS: The Asp859Glu - rs35737760 SNP of the CACNA1E gene was present in 12.7% of control subjects and in 20.4% of the total migraine group. In the migraine group it was significantly over-represented in patients with complex neurological auras (42.1%), OR 4.98 (95% CI: 1.69-14.67, uncorrected P = .005, Bonferroni P = .030, 2-tailed Fisher's exact test). There was no significant difference between migraine with typical aura (10.9%) and controls.CONCLUSIONS: We identified a polymorphism in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760) that is more prevalent in hemiplegic and brain stem aura migraine. This missense variant causes a change from aspartate to glutamate at position 859 of the Cav 2.3 protein and might modulate the function of R-type Ca2+ channels. It could thus be relevant for migraine with complex neurological aura, although this remains to be proven.
AB - OBJECTIVE: To search for differences in prevalence of a CACNA1E variant between migraine without aura, various phenotypes of migraine with aura, and healthy controls.BACKGROUND: Familial hemiplegic migraine type 1 (FHM1) is associated with mutations in the CACNA1A gene coding for the alpha 1A (Cav 2.1) pore-forming subunit of P/Q voltage-dependent Ca2+ channels. These mutations are not found in the common forms of migraine with or without aura. The alpha 1E subunit (Cav 2.3) is the counterpart of Cav 2.1 in R-type Ca2+ channels, has different functional properties, and is encoded by the CACNA1E gene.METHODS: First, we performed a total exon sequencing of the CACNA1E gene in three probands selected because they had no abnormalities in the three FHM genes. In a patient suffering from basilar-type migraine, we identified a single nucleotide polymorphism (SNP) in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760; Minor Allele Frequency 0.2241) hitherto not studied in migraine. In a second step, we determined its occurrence in four groups by direct sequencing on blood genomic DNA: migraine patients without aura (N = 24), with typical aura (N = 55), complex neurological auras (N = 19; hemiplegic aura: N = 15; brain stem aura: N = 4), and healthy controls (N = 102).RESULTS: The Asp859Glu - rs35737760 SNP of the CACNA1E gene was present in 12.7% of control subjects and in 20.4% of the total migraine group. In the migraine group it was significantly over-represented in patients with complex neurological auras (42.1%), OR 4.98 (95% CI: 1.69-14.67, uncorrected P = .005, Bonferroni P = .030, 2-tailed Fisher's exact test). There was no significant difference between migraine with typical aura (10.9%) and controls.CONCLUSIONS: We identified a polymorphism in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760) that is more prevalent in hemiplegic and brain stem aura migraine. This missense variant causes a change from aspartate to glutamate at position 859 of the Cav 2.3 protein and might modulate the function of R-type Ca2+ channels. It could thus be relevant for migraine with complex neurological aura, although this remains to be proven.
KW - Aspartic Acid
KW - Calcium Channels, R-Type
KW - Case-Control Studies
KW - Cation Transport Proteins
KW - Cerebellar Ataxia
KW - DNA Mutational Analysis
KW - Exons
KW - Female
KW - Gene Frequency
KW - Genetic Predisposition to Disease
KW - Glutamic Acid
KW - Humans
KW - Male
KW - Migraine Disorders
KW - Phenotype
KW - Polymorphism, Single Nucleotide
KW - Retrospective Studies
KW - Statistics, Nonparametric
KW - Journal Article
U2 - 10.1111/head.13107
DO - 10.1111/head.13107
M3 - Article
C2 - 28573794
VL - 57
SP - 1136
EP - 1144
JO - Headache
JF - Headache
SN - 0017-8748
IS - 7
ER -