Premature stop codons in a facilitating EF-hand splice variant of CaV2.1 cause episodic ataxia type 2.
Neurobiol Dis
; 32(1): 10-5, 2008 Oct.
Article
em En
| MEDLINE
| ID: mdl-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Mutação da Fase de Leitura
/
Processamento Alternativo
/
Códon sem Sentido
/
Isoformas de Proteínas
/
Ataxias Espinocerebelares
/
Canais de Cálcio Tipo N
/
Motivos EF Hand
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Adult
/
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article