Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, France.
Nat Genet. 2012 Nov;44(11):1255-9. doi: 10.1038/ng.2441. Epub 2012 Oct 21.
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.
婴儿恶性游走部分性癫痫发作（MMPSI）是一种罕见的婴儿癫痫性脑病，其特征是对抗癫痫药物耐药性的癫痫发作和发育迟缓。我们对 3 名 MMPSI 先证者进行了外显子组测序，发现了影响 KCNT1 钾通道 C 末端结构域的新生获得性功能突变。我们对 9 名 MMPSI 患儿进行了 KCNT1 测序，其中 4 名患儿发现了突变，总共在 12 名无血缘关系的患儿中发现了 6 名患儿有突变。功能研究表明，这些突变导致通道的组成型激活，模拟了蛋白激酶 C 对 C 末端结构域磷酸化的作用。除了调节离子流外，KCNT1 还具有非传导功能，因为其 C 末端与参与发育信号通路的细胞质蛋白相互作用。这些结果为这种破坏性疾病的未来诊断方法和研究提供了重点。
