title: Premature stop codons in a facilitating EF-hand splice variant of CaV2.1 cause episodic ataxia type 2.
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.
authors.affiliation: Institute of Neurology, University College London, Queen Square, London, United Kingdom.
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Graves
authors.forename: Paola
authors.initials: P
authors.lastname: Imbrici
authors.forename: Esther E
authors.initials: EE
authors.lastname: Kors
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Terwindt
authors.forename: Louise H
authors.initials: LH
authors.lastname: Eunson
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Joost
authors.initials: J
authors.lastname: Haan
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Goadsby
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.forename: Dimitri M
authors.initials: DM
authors.lastname: Kullmann
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D020864:Calcium Channels, N-Type / Q000235:genetics*; D002531:Cerebellum / Q000737:chemistry / Q000503:physiopathology; D018389:Codon, Nonsense / Q000737:chemistry / Q000235:genetics*; D020832:EF Hand Motifs / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D010375:Pedigree; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D014982:Xenopus laevis
chemical_list: D020864:Calcium Channels, N-Type; D018389:Codon, Nonsense; D020033:Protein Isoforms