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Sci Rep. 2017 May 31;7(1):2514. doi: 10.1038/s41598-017-02554-x.

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

Sintas C1,2,3, Carreño O1,2, Fernàndez-Castillo N1,2,3,4, Corominas R1,2,5,6,7, Vila-Pueyo M5, Toma C1,2,3,8,9, Cuenca-León E5,10,11, Barroeta I12, Roig C12,13, Volpini V14, Macaya A5, Cormand B15,16,17,18.

Author information

1
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain.
2
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
3
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain.
4
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues, Catalonia, Spain.
5
Pediatric Neurology Research Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
6
Department of Health and Experimental Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
7
Hospital del Mar Research Institute (IMIM), Barcelona, Catalonia, Spain.
8
Neuroscience Research Australia, Sydney, New South Wales, Australia.
9
School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
10
Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, Massachusetts, United States of America.
11
Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
12
Department of Neurology, Hospital de la Sta, Creu i St Pau, Barcelona, Catalonia, Spain.
13
Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
14
Centre de Diagnòstic Genètic-Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), l'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
15
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain. bcormand@ub.edu.
16
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. bcormand@ub.edu.
17
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain. bcormand@ub.edu.
18
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues, Catalonia, Spain. bcormand@ub.edu.

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.

PMID:
28566750
PMCID:
PMC5451382
DOI:
10.1038/s41598-017-02554-x
[Indexed for MEDLINE]
Free PMC Article

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