New CACNA1A Deletions Are Associated to Migraine Phenotypes

Overview

Journal J Headache Pain

Publisher Biomed Central

Date 2018 Sep 1

PMID 30167989

Citations 11

Authors

G S Grieco

S Gagliardi

I Ricca

O Pansarasa

M Neri

F Gualandi

G Nappi

A Ferlini

C Cereda

Affiliations

Soon will be listed here.

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.

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References

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

Silberstein S, Dodick D . Migraine genetics: Part II. Headache. 2013; 53(8):1218-29. DOI: 10.1111/head.12169. View

Pradotto L, Mencarelli M, Bigoni M, Milesi A, Di Blasio A, Mauro A . Episodic ataxia and SCA6 within the same family due to the D302N CACNA1A gene mutation. J Neurol Sci. 2016; 371:81-84. DOI: 10.1016/j.jns.2016.10.029. View

Denier C, Ducros A, Vahedi K, Joutel A, Thierry P, Ritz A . High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Neurology. 1999; 52(9):1816-21. DOI: 10.1212/wnl.52.9.1816. View

Wan J, Mamsa H, Johnston J, Spriggs E, Singer H, Zee D . Large Genomic Deletions in CACNA1A Cause Episodic Ataxia Type 2. Front Neurol. 2011; 2:51. PMC: 3169784. DOI: 10.3389/fneur.2011.00051. View

Nachbauer W, Nocker M, Karner E, Stankovic I, Unterberger I, Eigentler A . Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature. J Neurol. 2014; 261(5):983-91. DOI: 10.1007/s00415-014-7310-2. View

Jodice C, Mantuano E, Veneziano L, Trettel F, Sabbadini G, Calandriello L . Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Hum Mol Genet. 1997; 6(11):1973-8. DOI: 10.1093/hmg/6.11.1973. View

Pelzer N, de Vries B, Kamphorst J, Vijfhuizen L, Ferrari M, Haan J . PRRT2 and hemiplegic migraine: a complex association. Neurology. 2014; 83(3):288-90. DOI: 10.1212/WNL.0000000000000590. View

Zeng A, Liu X, Shen L, Li W, Ding Z, Bai Y . Analysis of mitochondrial DNA variations in a Chinese family with spinocerebellar ataxia. J Clin Neurosci. 2011; 19(1):60-4. DOI: 10.1016/j.jocn.2011.05.011. View

10.

Mantuano E, Veneziano L, Jodice C, Frontali M . Spinocerebellar ataxia type 6 and episodic ataxia type 2: differences and similarities between two allelic disorders. Cytogenet Genome Res. 2003; 100(1-4):147-53. DOI: 10.1159/000072849. View

11.

Graves T, Hanna M . Episodic ataxia: SLC1A3 and CACNB4 do not explain the apparent genetic heterogeneity. J Neurol. 2008; 255(7):1097-9. DOI: 10.1007/s00415-008-0844-4. View

12.

Romaniello R, Zucca C, Tonelli A, Bonato S, Baschirotto C, Zanotta N . A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation. J Neurol Neurosurg Psychiatry. 2010; 81(8):840-3. DOI: 10.1136/jnnp.2008.163402. View

13.

Riant F, Lescoat C, Vahedi K, Kaphan E, Toutain A, Soisson T . Identification of CACNA1A large deletions in four patients with episodic ataxia. Neurogenetics. 2009; 11(1):101-6. DOI: 10.1007/s10048-009-0208-y. View

14.

de Vries B, Frants R, Ferrari M, van den Maagdenberg A . Molecular genetics of migraine. Hum Genet. 2009; 126(1):115-32. DOI: 10.1007/s00439-009-0684-z. View

15.

Labrum R, Rajakulendran S, Graves T, Eunson L, Bevan R, Sweeney M . Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing. J Med Genet. 2009; 46(11):786-91. DOI: 10.1136/jmg.2009.067967. View

16.

Carreno O, Corominas R, Serra S, Sintas C, Fernandez-Castillo N, Vila-Pueyo M . Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies. Mol Genet Genomic Med. 2014; 1(4):206-22. PMC: 3865589. DOI: 10.1002/mgg3.24. View

17.

Mantuano E, Romano S, Veneziano L, Gellera C, Castellotti B, Caimi S . Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2. J Neurol Sci. 2010; 291(1-2):30-6. DOI: 10.1016/j.jns.2010.01.010. View

18.

Condliffe S, Fratangeli A, Munasinghe N, Saba E, Passafaro M, Montrasio C . The E1015K variant in the synprint region of the CaV2.1 channel alters channel function and is associated with different migraine phenotypes. J Biol Chem. 2013; 288(47):33873-33883. PMC: 3837129. DOI: 10.1074/jbc.M113.497701. View

19.

Dichgans M, Schols L, Herzog J, Stevanin G, Weirich-Schwaiger H, Rouleau G . Spinocerebellar ataxia type 6: evidence for a strong founder effect among German families. Neurology. 1999; 52(4):849-51. DOI: 10.1212/wnl.52.4.849. View

20.

Jen J, Kim G, Dudding K, Baloh R . No mutations in CACNA1A and ATP1A2 in probands with common types of migraine. Arch Neurol. 2004; 61(6):926-8. DOI: 10.1001/archneur.61.6.926. View