nature-genetic201211-11

来自法国内克尔-儿童疾病医院的Rima Nabbout及其同事在婴儿期部分性癫痫发作的恶性迁移(一类罕见的、伴随有耐药性癫痫和发育迟缓的癫痫性脑病)患者体内鉴定到KCNT1(钾离子通道)基因的新生突变。他们发现这一突变对KCNT1通道蛋白的活性具有功能获得性作用的效应。相关的研究论文于10月21日在线发表在《Nature Genetics》期刊上。

-2012年11月《自然-遗传》

中文翻译


【题目】KCNT1基因的新生功能获得性突变引起婴儿期部分性癫痫发作的恶性迁移

【译文】婴儿期部分性癫痫发作的恶性迁移(MMPSI)是一种罕见的婴儿癫痫性脑病,其结合了耐药性癫痫和发育迟缓特点。我们对三个患MMPSI的先证者进行外显子组测序,鉴定到影响KCNT1钾离子通道的C端结构域的新生功能获得性突变。我们对另外9名MMPSI患者的KCNT1基因进行测序,在其中的4个人里面鉴定到突变,总共在6名受累者(总数为12人)鉴定到突变。功能分析表明这一突变组成性的激活KCNT1通道蛋白,类似蛋白激酶C碳末端结构域的磷酸化作用。除了调控离子流外,KCNT1蛋白还具有不导电的功能,因为它的C末端能与参与发育信号途径的胞质蛋白互作。总之,这些结果增加了人们对未来的诊断方法和对研究这种破坏性疾病的关注。

英文原稿


[Title]: De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy

[Authors]: Giulia Barcia, Matthew R Fleming, Aline Deligniere, Valeswara-Rao Gazula, Maile R Brown, Maeva Langouet, Haijun Chen, Jack Kronengold, Avinash Abhyankar, Roberta Cilio, Patrick Nitschke, Anna Kaminska, Nathalie Boddaert, Jean-Laurent Casanova, Isabelle Desguerre,Arnold Munnich, Olivier Dulac, Leonard K Kaczmarek, Laurence Colleaux & Rima Nabbout

[Abstract]: Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. We performed exome sequencing in three probands with MMPSI and identified de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional individuals with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated affected individuals. Functional studies showed that the mutations led to constitutive activation of the channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C. In addition to regulating ion flux, KCNT1 has a non-conducting function, as its C terminus interacts with cytoplasmic proteins involved in developmental signaling pathways. These results provide a focus for future diagnostic approaches and research for this devastating condition.

原文地址

http://www.nature.com/ng/journal/v44/n11/full/ng.2441.html

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