Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia

Abstract Episodic ataxia is an autosomal dominant ion channel disorder characterized by episodes of imbalance and incoordination. The disease is genetically heterogeneous and is classified as episodic ataxia type 2 (EA2) when it is caused by a mutation in the CACNA1A gene, encoding the α1A subunit o...

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Autores principales: Cèlia Sintas, Oriel Carreño, Noèlia Fernàndez-Castillo, Roser Corominas, Marta Vila-Pueyo, Claudio Toma, Ester Cuenca-León, Isabel Barroeta, Carles Roig, Víctor Volpini, Alfons Macaya, Bru Cormand
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Publicado: Nature Portfolio 2017
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spelling oai:doaj.org-article:9317232c8b7c4a298032aaa4add4d2832021-12-02T16:06:17ZMutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia10.1038/s41598-017-02554-x2045-2322https://doaj.org/article/9317232c8b7c4a298032aaa4add4d2832017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02554-xhttps://doaj.org/toc/2045-2322Abstract Episodic ataxia is an autosomal dominant ion channel disorder characterized by episodes of imbalance and incoordination. The disease is genetically heterogeneous and is classified as episodic ataxia type 2 (EA2) when it is caused by a mutation in the CACNA1A gene, encoding the α1A subunit of the P/Q-type voltage-gated calcium channel Cav2.1. The vast majority of EA2 disease-causing variants are loss-of-function (LoF) point changes leading to decreased channel currents. CACNA1A exonic deletions have also been reported in EA2 using quantitative approaches. We performed a mutational screening of the CACNA1A gene, including the promoter and 3′UTR regions, in 49 unrelated patients diagnosed with episodic ataxia. When pathogenic variants were not found by sequencing, we performed a copy number variant (CNV) analysis to screen for duplications or deletions. Overall, sequencing screening allowed identification of six different point variants (three nonsense and three missense changes) and two coding indels, one of them found in two unrelated patients. Additionally, CNV analysis identified a deletion in a patient spanning exon 35 as a result of a recombination event between flanking intronic Alu sequences. This study allowed identification of potentially pathogenic alterations in our sample, five of them novel, which cover 20% of the patients (10/49). Our data suggest that most of these variants are disease-causing, although functional studies are required.Cèlia SintasOriel CarreñoNoèlia Fernàndez-CastilloRoser CorominasMarta Vila-PueyoClaudio TomaEster Cuenca-LeónIsabel BarroetaCarles RoigVíctor VolpiniAlfons MacayaBru CormandNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Cèlia Sintas
Oriel Carreño
Noèlia Fernàndez-Castillo
Roser Corominas
Marta Vila-Pueyo
Claudio Toma
Ester Cuenca-León
Isabel Barroeta
Carles Roig
Víctor Volpini
Alfons Macaya
Bru Cormand
Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia
description Abstract Episodic ataxia is an autosomal dominant ion channel disorder characterized by episodes of imbalance and incoordination. The disease is genetically heterogeneous and is classified as episodic ataxia type 2 (EA2) when it is caused by a mutation in the CACNA1A gene, encoding the α1A subunit of the P/Q-type voltage-gated calcium channel Cav2.1. The vast majority of EA2 disease-causing variants are loss-of-function (LoF) point changes leading to decreased channel currents. CACNA1A exonic deletions have also been reported in EA2 using quantitative approaches. We performed a mutational screening of the CACNA1A gene, including the promoter and 3′UTR regions, in 49 unrelated patients diagnosed with episodic ataxia. When pathogenic variants were not found by sequencing, we performed a copy number variant (CNV) analysis to screen for duplications or deletions. Overall, sequencing screening allowed identification of six different point variants (three nonsense and three missense changes) and two coding indels, one of them found in two unrelated patients. Additionally, CNV analysis identified a deletion in a patient spanning exon 35 as a result of a recombination event between flanking intronic Alu sequences. This study allowed identification of potentially pathogenic alterations in our sample, five of them novel, which cover 20% of the patients (10/49). Our data suggest that most of these variants are disease-causing, although functional studies are required.
format article
author Cèlia Sintas
Oriel Carreño
Noèlia Fernàndez-Castillo
Roser Corominas
Marta Vila-Pueyo
Claudio Toma
Ester Cuenca-León
Isabel Barroeta
Carles Roig
Víctor Volpini
Alfons Macaya
Bru Cormand
author_facet Cèlia Sintas
Oriel Carreño
Noèlia Fernàndez-Castillo
Roser Corominas
Marta Vila-Pueyo
Claudio Toma
Ester Cuenca-León
Isabel Barroeta
Carles Roig
Víctor Volpini
Alfons Macaya
Bru Cormand
author_sort Cèlia Sintas
title Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia
title_short Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia
title_full Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia
title_fullStr Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia
title_full_unstemmed Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia
title_sort mutation spectrum in the cacna1a gene in 49 patients with episodic ataxia
publisher Nature Portfolio
publishDate 2017
url https://doaj.org/article/9317232c8b7c4a298032aaa4add4d283
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