Referenced in: none

Automatically associated channels: Cav2.1

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

Authors: Tracey D Graves, Paola Imbrici, Esther E Kors, Gisela M Terwindt, Louise H Eunson, Rune R Frants, Joost Haan, Michel D Ferrari, Peter J Goadsby, Michael G Hanna, Arn M J M Van Den Maagdenberg, Dimitri M Kullmann

Journal, date & volume: Neurobiol. Dis., 2008 Oct , 32, 10-5

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18606230

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.