Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse
Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse
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DOI：
10.1016/s0092-8674(00)81877-2
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发表时间：
1997-02-07
期刊：
影响因子：
64.5
通讯作者：
Noebels, JL
中科院分区：
文献类型：
--
作者：
Burgess, DL;Jones, JM;Noebels, JL
Ca 2+通道β亚基通过与α（1）亚基的直接相互作用调节电压依赖性钙电流。β-和α（1）-结合基序是保守的，并且当与各种α（1）亚基共表达时，所有β亚基都可以刺激电流幅度、电压依赖性和动力学。我们使用了一个位置候选人的方法来确定共济失调和癫痫发作的昏睡（1小时）小鼠产生的突变的β-亚基基因Cchb 4小鼠2号染色体上。剪接供体位点中的四个核苷酸插入导致外显子跳跃、翻译移码和蛋白质截短以及α（1）结合位点的丢失。昏睡表型是哺乳动物神经系统疾病的第一个例子，它是由电压门控离子通道的非成孔亚基的遗传缺陷引起的。
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.