期刊
NEUROBIOLOGY OF DISEASE
卷 32, 期 1, 页码 10-15出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2008.06.002
关键词
EA2; ataxia; cerebellum; channelopathy; Ca2+ channel; migraine
资金
- Medical Research Council (UK)
- Netherlands Organization for Scientific Research (NWO)
- Health's NIHR Biomedical Research Centres
- NIH [RU54 RR019482]
- NATIONAL CENTER FOR RESEARCH RESOURCES [U54RR019482] Funding Source: NIH RePORTER
- MRC [G0601943, G0200373, G116/147] Funding Source: UKRI
- Medical Research Council [G116/147, G0200373, G0601943] Funding Source: researchfish
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.
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