A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline
A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline
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DOI：
10.1523/jneurosci.3089-03.2004
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发表时间：
2004-03-17
影响因子：
5.3
通讯作者：
Yamakawa, K
中科院分区：
文献类型：
--
作者：
Kamiya, K;Kaneda, M;Yamakawa, K
在特发性癫痫患者中报告了电压门控钠通道α亚单位1型（SCN 1A）和2型（SCN 2A）基因的突变（完全错义）：全身性癫痫伴热性惊厥+。相比之下，SCN 1A的无义突变和移码突变在难治性癫痫中被发现：婴儿期严重肌阵挛性癫痫（SMEI）。在这里，我们描述了第一个无义突变的SCN 2A在一个病人与难治性癫痫和严重的精神衰退。表型与SMEI相似，但由于部分癫痫，延迟发作（1年7个月）和缺乏温度敏感性而不同。突变分析显示，该患者存在SCN 2A的杂合从头无义突变R102 X。Na（v）1.2野生型通道和R102 X突变蛋白在人胚肾293细胞中共表达的膜片钳分析表明，截短的突变蛋白在超极化方向上改变了野生型通道失活的电压依赖性。R102 X截短蛋白的亚细胞定位分析表明，其显性负效应可能是由突变蛋白的直接或间接的细胞骨架相互作用引起的。Nav1.2蛋白的单倍不足是该患者病理学的一个合理解释;然而，我们的生物物理学研究结果表明，R102 X截短蛋白发挥主导的负面作用，导致患者的难治性癫痫。
Mutations, exclusively missense, of voltage-gated sodium channel alpha subunit type 1 ( SCN1A) and type 2 (SCN2A) genes were reported in patients with idiopathic epilepsy: generalized epilepsy with febrile seizures plus. Nonsense and frameshift mutations of SCN1A, by contrast, were identified in intractable epilepsy: severe myoclonic epilepsy in infancy (SMEI). Here we describe a first nonsense mutation of SCN2A in a patient with intractable epilepsy and severe mental decline. The phenotype is similar to SMEI but distinct because of partial epilepsy, delayed onset ( 1 year 7 months), and absence of temperature sensitivity. A mutational analysis revealed that the patient had a heterozygous de novo nonsense mutation R102X of SCN2A. Patch-clamp analysis of Na(v)1.2 wild-type channels and the R102X mutant protein coexpressed in human embryonic kidney 293 cells showed that the truncated mutant protein shifted the voltage dependence of inactivation of wild-type channels in the hyperpolarizing direction. Analysis of the subcellular localization of R102X truncated protein suggested that its dominant negative effect could arise from direct or indirect cytoskeletal interactions of the mutant protein. Haploinsufficiency of Nav1.2 protein is one plausible explanation for the pathology of this patient; however, our biophysical findings suggest that the R102X truncated protein exerts a dominant negative effect leading to the patient's intractable epilepsy.