Premature stop codons in a facilitating EF-hand splice variant of CaV2.1 cause episodic ataxia type 2.
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.
Graves
Tracey D
TD
Institute of Neurology, University College London, Queen Square, London, United Kingdom.
Imbrici
Paola
P
Kors
Esther E
EE
Terwindt
Gisela M
GM
Eunson
Louise H
LH
Frants
Rune R
RR
Haan
Joost
J
Ferrari
Michel D
MD
Goadsby
Peter J
PJ
Hanna
Michael G
MG
van den Maagdenberg
Arn M J M
AM
Kullmann
Dimitri M
DM
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
D020864:Calcium Channels, N-Type; D018389:Codon, Nonsense; D020033:Protein Isoforms