Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia
Sintas, Cèlia (Universitat de Barcelona. Institut de Biomedicina)
Carreño, Oriel (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Fernàndez-Castillo, Noèlia (Institut de Recerca Sant Joan de Déu)
Corominas, Roser (Institut Hospital del Mar d'Investigacions Mèdiques)
Vila-Pueyo, Marta (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Toma, Claudio (University of New South Wales)
Cuenca-León, Ester (Broad Institute of MIT and Harvard)
Barroeta, Isabel (Institut d'Investigació Biomèdica Sant Pau)
Roig, Carles (Universitat Autònoma de Barcelona. Departament de Medicina)
Volpini, Víctor (Institut d'Investigació Biomèdica de Bellvitge)
Macaya Ruiz, Alfons (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Cormand, Bru (Institut de Recerca Sant Joan de Déu)

Date:	2017
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 α subunit of the P/Q-type voltage-gated calcium channel Ca2. 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.
Grants:	Ministerio de Economía, Industria y Competitividad SAF2009-13182-C01 Ministerio de Economía, Industria y Competitividad SAF2009-13182-C03 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-0932 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR-0078 Ministerio de Economía, Industria y Competitividad BES-2007-16450 Ministerio de Economía, Industria y Competitividad BES-2010-033895
Note:	Altres ajuts: Fundació La Marató de TV3 (grant 100731).
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Scientific reports, Vol. 7 (may 2017) , ISSN 2045-2322

DOI: 10.1038/s41598-017-02554-x
PMID: 28566750

9 p, 2.4 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
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