A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation
A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation
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DOI：
10.1212/01.wnl.0000132979.08394.6d
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发表时间：
2004-07-13
期刊：
影响因子：
9.9
通讯作者：
Bassi, MT
中科院分区：
文献类型：
--
作者：
Borgatti, R;Zucca, C;Bassi, MT
背景：良性家族性新生儿惊厥 (BFNC) 是一种罕见的常染色体显性遗传疾病，由编码 M 电流潜在钾通道亚基的两个基因 KCNQ2 和 KCNQ3 突变引起。该电流通过引起尖峰频率适应来限制神经元过度兴奋。方法：作者描述了一个有 4 名受影响成员的 BFNC 家族：其中两人仅表现出 BFNC，而另外两人，除了 BFNC 之外，还表现出严重的癫痫性脑病或局灶性癫痫发作和智力低下。结果：该家族的所有受影响成员的 KCNQ2 基因 (K526N) 均携带新型错义突变，破坏了参与辅助蛋白结合的通道亚基 C 端区域的三维构象。当在 CHO 细胞中异源表达时，含有与野生型 KCNQ2 和 KCNQ3 亚基同聚或异聚构型的突变亚基的钾通道表现出改变的激活电压依赖性，而细胞内运输和质膜表达没有变化。结论：KCNQ2 K526N 突变可能通过破坏涉及 KCNQ2 C 末端的复杂生化信号传导来影响 M 通道功能。在所述家族中，遗传因素而非后天因素可能参与与 BFNC 相关的神经系统症状表型变异的病理生理学。
Background: Benign familial neonatal convulsion (BFNC) is a rare autosomal dominant disorder caused by mutations in two genes, KCNQ2 and KCNQ3, encoding for potassium channel subunits underlying the M-current. This current limits neuronal hyperexcitability by causing spike-frequency adaptation. Methods: The authors describe a BFNC family with four affected members: two of them exhibit BFNC only while the other two, in addition to BFNC, present either with a severe epileptic encephalopathy or with focal seizures and mental retardation. Results: All affected members of this family carry a novel missense mutation in the KCNQ2 gene (K526N), disrupting the tri-dimensional conformation of a C-terminal region of the channel subunit involved in accessory protein binding. When heterologously expressed in CHO cells, potassium channels containing mutant subunits in homomeric or heteromeric configuration with wild-type KCNQ2 and KCNQ3 subunits exhibit an altered voltage-dependence of activation, without changes in intracellular trafficking and plasma membrane expression. Conclusion: The KCNQ2 K526N mutation may affect M-channel function by disrupting the complex biochemical signaling involving KCNQ2 C-terminus. Genetic rather than acquired factors may be involved in the pathophysiology of the phenotypic variability of the neurologic symptoms associated with BFNC in the described family.