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Premature stop codons in a facilitating EF-hand splice variant of CaV2.1 cause episodic ataxia type 2

Graves, TD and Imbrici, P and Kors, EE and Terwindt, GM and Eunson, LH and Frants, RR and Haan, J and Ferrari, MD and Goadsby, PJ and Hanna, MG and van den Maagdenberg, AMJM and Kullmann, DM (2008) 'Premature stop codons in a facilitating EF-hand splice variant of CaV2.1 cause episodic ataxia type 2.' Neurobiology of Disease, 32 (1). pp. 10-15. ISSN 0969-9961

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Abstract

Premature stop codons in CACNA1A, which encodes the alpha(1A) subunit of neuronal P/Q-type (Ca(V)2.1) Ca(2+) channels, cause episodic ataxia type 2 (EA2). CACNA1A undergoes extensive alternative splicing, which contributes to the pharmacological and kinetic heterogeneity of Ca(V)2.1-mediated Ca(2+) currents. We identified three novel heterozygous stop codon mutations associated with EA2 in an alternately spliced exon (37A), which encodes part of an EF-hand motif required for Ca(2+)-dependent facilitation. One family had a C to G transversion (Y1854X). A dinucleotide deletion results in the same premature stop codon in a second family, and a further single nucleotide change leads to a different truncation (R1858X) in a de novo case of EA2. Expression studies of the Y1854X mutation revealed loss of Ca(V)2.1-mediated current. Because these mutations do not affect the alternate exon 37B, these findings reveal unexpected dependence of cerebellar function on intact exon 37A-containing Ca(V)2.1 channels.

Item Type: Article
Uncontrolled Keywords: EA2; Ataxia; Cerebellum; Channelopathy; Ca2+ channel; Migraine
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 11 Jan 2013 14:56
Last Modified: 06 Jan 2022 13:40
URI: http://repository.essex.ac.uk/id/eprint/5064

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