Possible Involvement of the CACNA1E Gene in Migraine: A Search for Single Nucleotide Polymorphism in Different Clinical Phenotypes

Anna Ambrosini, Mara D'Onofrio, Maria Gabriella Buzzi, Ivan Arisi, Gaetano S Grieco, Francesco Pierelli, Filippo M Santorelli, Jean Schoenen

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)1136-1144
Number of pages9
JournalHeadache
Volume57
Issue number7
DOIs
Publication statusPublished - Jul 2017

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Migraine Disorders
Single Nucleotide Polymorphism
Epilepsy
Migraine without Aura
Migraine with Aura
Phenotype
Genes
Exons
Brain Stem
Mutation
Gene Frequency
Aspartic Acid
Glutamic Acid
DNA
Proteins

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 journalArticle

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title = "Possible Involvement of the CACNA1E Gene in Migraine: A Search for Single Nucleotide Polymorphism in Different Clinical Phenotypes",
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.",
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",
author = "Anna Ambrosini and Mara D'Onofrio and Buzzi, {Maria Gabriella} and Ivan Arisi and Grieco, {Gaetano S} and Francesco Pierelli and Santorelli, {Filippo M} and Jean Schoenen",
note = "{\circledC} 2017 American Headache Society.",
year = "2017",
month = "7",
doi = "10.1111/head.13107",
language = "English",
volume = "57",
pages = "1136--1144",
journal = "Headache",
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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 -