Mutations in EFHC1 cause juvenile myoclonic epilepsy
Mutations in EFHC1 cause juvenile myoclonic epilepsy
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DOI：
10.1038/ng1393
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发表时间：
2004-08-01
期刊：
影响因子：
30.8
通讯作者：
Yamakawa, K
中科院分区：
文献类型：
--
作者：
Suzuki, T;Delgado-Escueta, AV;Yamakawa, K
青少年肌阵挛癫痫(JME)是遗传性大发作最常见的原因(1，2)。我们先前定位并缩小了染色体6p12-p11(EJM1)(3-5)上与JME相关的区域。在这里，我们描述了该区域的一个新基因EFHC1，它编码一个带有EF-Hand基序的蛋白质。突变分析发现，在6个JME家系中受影响的成员中，EFHC1有5个错义突变与癫痫或EEG多棘波共分离，而在382名对照个体中没有发生。在原代培养的小鼠海马神经元中过表达EFHC1诱导了细胞凋亡，该突变显著降低了该细胞的凋亡率。R型电压依赖性钙通道(Ca(V)2.3)的拮抗剂SNX-482可特异性地抑制细胞凋亡。EFHC1和Ca(V)2.3免疫物质重叠分布于小鼠脑内，EFHC1与Cav2.3C末端共沉淀。在膜片钳分析中，EFHC1特异性地增加了R型钙电流，这种电流被JME相关的突变逆转。
Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures(1,2). We previously mapped and narrowed a region associated with JME on chromosome 6p12-p11 (EJM1)(3-5). Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca2+ channel (Ca(v)2.3). EFHC1 and Ca(v)2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Cav2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca2+ currents that were reversed by the mutations associated with JME.