New CACNA1A deletions are associated to migraine phenotypes

G S Grieco, S Gagliardi, I Ricca, O Pansarasa, M Neri, F Gualandi, G Nappi, A Ferlini, C Cereda

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Familial hemiplegic migraine type 1 (FHM1) is a form of migraine with aura caused by heterozygous mutations in 4 genes: CACNA1A, ATP1A2, SNC1A and PRRT2, but further heterogeneity is expected. Here have been described clinical and molecular features in patients suffering from migraine with Aura (MA), without (MO) and hemiplegic migraine attacks. Next Generation Sequencing by TruSeq Custom Amplicon for CACNA1A and ATP1A2 gene has been performed. All genetic variants have been confirmed by Sanger sequencing and all samples were also analyzed with MLPA assay for ATP1A2-CACNA1A genes to detect duplication or deletion. All MLPA data were verified by Real Time PCR.

RESULTS: Sequencing analysis showed 3 point mutations, two novel variants and one already described in literature. Moreover, MLPA analysis showed 3 deletions in 9 sporadic hemiplegic migraine (18%), in 3 patients with non-hemiplegic migraine (4.1%) and in 3 patients affected by episodic ataxia (20%). Two sporadic patients showed a deletion in exons 41-43, while the rest of HM patients (5) showed a deletion in the terminal part of the CACNA1A gene. About episodic ataxia, we have identified deletions in exon 12-15 and in exon 47. Finally, in migraine patients, we have found different subjects affected by different phenotypes deleted in exon 47.

CONCLUSION: This work highlights the importance to complement analysis as direct sequencing with quantitative analysis (MLPA). In fact, intragenic CACNA1A rearrangements have been detected. Our work demonstrated that deletions in CACNA1A gene may be associated also to different migraine phenotypes.

Original languageEnglish
Pages (from-to)75
JournalJournal of Headache and Pain
Volume19
Issue number1
DOIs
Publication statusPublished - Aug 30 2018

Fingerprint

Migraine Disorders
Phenotype
Exons
Migraine with Aura
Genes
Point Mutation
Real-Time Polymerase Chain Reaction
Mutation

Keywords

  • Adult
  • Calcium Channels/genetics
  • Chromosome Deletion
  • DNA Mutational Analysis
  • Exons/genetics
  • Female
  • Humans
  • Male
  • Middle Aged
  • Migraine Disorders/genetics
  • Phenotype
  • Point Mutation
  • Sequence Analysis, DNA

Cite this

New CACNA1A deletions are associated to migraine phenotypes. / Grieco, G S; Gagliardi, S; Ricca, I; Pansarasa, O; Neri, M; Gualandi, F; Nappi, G; Ferlini, A; Cereda, C.

In: Journal of Headache and Pain, Vol. 19, No. 1, 30.08.2018, p. 75.

Research output: Contribution to journalArticle

@article{2678c51454e14cdbb75cc1966ca13eeb,
title = "New CACNA1A deletions are associated to migraine phenotypes",
abstract = "BACKGROUND: Familial hemiplegic migraine type 1 (FHM1) is a form of migraine with aura caused by heterozygous mutations in 4 genes: CACNA1A, ATP1A2, SNC1A and PRRT2, but further heterogeneity is expected. Here have been described clinical and molecular features in patients suffering from migraine with Aura (MA), without (MO) and hemiplegic migraine attacks. Next Generation Sequencing by TruSeq Custom Amplicon for CACNA1A and ATP1A2 gene has been performed. All genetic variants have been confirmed by Sanger sequencing and all samples were also analyzed with MLPA assay for ATP1A2-CACNA1A genes to detect duplication or deletion. All MLPA data were verified by Real Time PCR.RESULTS: Sequencing analysis showed 3 point mutations, two novel variants and one already described in literature. Moreover, MLPA analysis showed 3 deletions in 9 sporadic hemiplegic migraine (18{\%}), in 3 patients with non-hemiplegic migraine (4.1{\%}) and in 3 patients affected by episodic ataxia (20{\%}). Two sporadic patients showed a deletion in exons 41-43, while the rest of HM patients (5) showed a deletion in the terminal part of the CACNA1A gene. About episodic ataxia, we have identified deletions in exon 12-15 and in exon 47. Finally, in migraine patients, we have found different subjects affected by different phenotypes deleted in exon 47.CONCLUSION: This work highlights the importance to complement analysis as direct sequencing with quantitative analysis (MLPA). In fact, intragenic CACNA1A rearrangements have been detected. Our work demonstrated that deletions in CACNA1A gene may be associated also to different migraine phenotypes.",
keywords = "Adult, Calcium Channels/genetics, Chromosome Deletion, DNA Mutational Analysis, Exons/genetics, Female, Humans, Male, Middle Aged, Migraine Disorders/genetics, Phenotype, Point Mutation, Sequence Analysis, DNA",
author = "Grieco, {G S} and S Gagliardi and I Ricca and O Pansarasa and M Neri and F Gualandi and G Nappi and A Ferlini and C Cereda",
year = "2018",
month = "8",
day = "30",
doi = "10.1186/s10194-018-0891-x",
language = "English",
volume = "19",
pages = "75",
journal = "Journal of Headache and Pain",
issn = "1129-2369",
publisher = "BioMed Central Ltd.",
number = "1",

}

TY - JOUR

T1 - New CACNA1A deletions are associated to migraine phenotypes

AU - Grieco, G S

AU - Gagliardi, S

AU - Ricca, I

AU - Pansarasa, O

AU - Neri, M

AU - Gualandi, F

AU - Nappi, G

AU - Ferlini, A

AU - Cereda, C

PY - 2018/8/30

Y1 - 2018/8/30

N2 - BACKGROUND: Familial hemiplegic migraine type 1 (FHM1) is a form of migraine with aura caused by heterozygous mutations in 4 genes: CACNA1A, ATP1A2, SNC1A and PRRT2, but further heterogeneity is expected. Here have been described clinical and molecular features in patients suffering from migraine with Aura (MA), without (MO) and hemiplegic migraine attacks. Next Generation Sequencing by TruSeq Custom Amplicon for CACNA1A and ATP1A2 gene has been performed. All genetic variants have been confirmed by Sanger sequencing and all samples were also analyzed with MLPA assay for ATP1A2-CACNA1A genes to detect duplication or deletion. All MLPA data were verified by Real Time PCR.RESULTS: Sequencing analysis showed 3 point mutations, two novel variants and one already described in literature. Moreover, MLPA analysis showed 3 deletions in 9 sporadic hemiplegic migraine (18%), in 3 patients with non-hemiplegic migraine (4.1%) and in 3 patients affected by episodic ataxia (20%). Two sporadic patients showed a deletion in exons 41-43, while the rest of HM patients (5) showed a deletion in the terminal part of the CACNA1A gene. About episodic ataxia, we have identified deletions in exon 12-15 and in exon 47. Finally, in migraine patients, we have found different subjects affected by different phenotypes deleted in exon 47.CONCLUSION: This work highlights the importance to complement analysis as direct sequencing with quantitative analysis (MLPA). In fact, intragenic CACNA1A rearrangements have been detected. Our work demonstrated that deletions in CACNA1A gene may be associated also to different migraine phenotypes.

AB - BACKGROUND: Familial hemiplegic migraine type 1 (FHM1) is a form of migraine with aura caused by heterozygous mutations in 4 genes: CACNA1A, ATP1A2, SNC1A and PRRT2, but further heterogeneity is expected. Here have been described clinical and molecular features in patients suffering from migraine with Aura (MA), without (MO) and hemiplegic migraine attacks. Next Generation Sequencing by TruSeq Custom Amplicon for CACNA1A and ATP1A2 gene has been performed. All genetic variants have been confirmed by Sanger sequencing and all samples were also analyzed with MLPA assay for ATP1A2-CACNA1A genes to detect duplication or deletion. All MLPA data were verified by Real Time PCR.RESULTS: Sequencing analysis showed 3 point mutations, two novel variants and one already described in literature. Moreover, MLPA analysis showed 3 deletions in 9 sporadic hemiplegic migraine (18%), in 3 patients with non-hemiplegic migraine (4.1%) and in 3 patients affected by episodic ataxia (20%). Two sporadic patients showed a deletion in exons 41-43, while the rest of HM patients (5) showed a deletion in the terminal part of the CACNA1A gene. About episodic ataxia, we have identified deletions in exon 12-15 and in exon 47. Finally, in migraine patients, we have found different subjects affected by different phenotypes deleted in exon 47.CONCLUSION: This work highlights the importance to complement analysis as direct sequencing with quantitative analysis (MLPA). In fact, intragenic CACNA1A rearrangements have been detected. Our work demonstrated that deletions in CACNA1A gene may be associated also to different migraine phenotypes.

KW - Adult

KW - Calcium Channels/genetics

KW - Chromosome Deletion

KW - DNA Mutational Analysis

KW - Exons/genetics

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Migraine Disorders/genetics

KW - Phenotype

KW - Point Mutation

KW - Sequence Analysis, DNA

U2 - 10.1186/s10194-018-0891-x

DO - 10.1186/s10194-018-0891-x

M3 - Article

VL - 19

SP - 75

JO - Journal of Headache and Pain

JF - Journal of Headache and Pain

SN - 1129-2369

IS - 1

ER -