Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse

被引:353
作者
Burgess, DL [1 ]
Jones, JM [1 ]
Meisler, MH [1 ]
Noebels, JL [1 ]
机构
[1] UNIV MICHIGAN,SCH MED,DEPT HUMAN GENET,ANN ARBOR,MI 48109
关键词
D O I
10.1016/S0092-8674(00)81877-2
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Ca2+ channel beta subunits regulate voltage-dependent calcium currents through direct interaction with alpha(1) subunits. The beta- and alpha(1)-binding motifs are conserved, and all beta subunits can stimulate current amplitude, voltage dependence, and kinetics when coexpressed with various alpha(1) subunits. We used a positional candidate approach to determine that the ataxia and seizures in the lethargic (lh) mouse arise from mutation of the beta-subunit gene Cchb4 on mouse chromosome 2. A four-nucleotide insertion into a splice donor site results in exon skipping, translational frameshift, and protein truncation with loss of the alpha(1)-binding site. The lethargic phenotype is the first example of a mammalian neurological disease caused by an inherited defect in a non-pore-forming subunit of a voltage-gated ion channel.
引用
收藏
页码:385 / 392
页数:8
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