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

Premature stop codons in CACNAIA, which encodes the alpha(1A) subunit of neuronal P/Q-type (Ca(v)2.1) Ca2+ 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 Ca2+ 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 Ca2+-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-rnediated Current. Because these mutations do not affect the alternate excin 37B, these findings reveal unexpected dependence of cerebellar function on intact exon 37A-containing Ca(v)2.1 channels. (C) 2008 Elsevier Inc. All rights reserved