Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2
Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2
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DOI：
10.1093/hmg/ddl019
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发表时间：
2006-03-15
影响因子：
3.5
通讯作者：
Frankel, WN
中科院分区：
文献类型：
--
作者：
Kearney, JA;Yang, Y;Frankel, WN
电压门控钠通道Scn 2a突变导致C57 BL/6 J品系背景下的转基因Scn 2a（Q54）小鼠中度癫痫。进行性癫痫的发作始于成年人，起源于海马体的短持续时间部分性癫痫发作。潜在的异常是海马神经元持续钠电流的增加。电压门控钾通道Kcnq 2负责产生M电流（I-KM），该电流被认为控制海马神经元的兴奋性并限制其重复放电。为了确定受损的M电流是否会加剧Scn 2a（Q54）小鼠的癫痫发作表型，我们用Kcnq 2的两个突变等位基因进行了遗传杂交。Szt 1小鼠携带一个自发缺失，去除了Kcnq 2的C-末端结构域。一种新的Kcnq 2错义突变V182 M通过筛选ENU治疗的男性后代降低阈值，以电诱发的最小阵挛性癫痫发作。携带Scn 2a（Q54）转基因与任一Kcnq 2突变的双突变小鼠在3周龄时表现出早期发作的严重癫痫、全身强直-阵挛性癫痫发作和幼年致死性。钠通道突变表型的这种急剧恶化表明，M电流在该动物模型中防止癫痫发作和蔓延中起着关键作用。Scn 2a和Kcnq 2之间的遗传相互作用表明，单基因癫痫基因的轻度等位基因的组合可以导致严重的疾病，并为人类癫痫的复杂遗传提供了一个模型。这些数据表明，这些基因之间的相互作用可能有助于在具有钠通道突变的人类家族中观察到的可变表达性。在对23名SCN 1A错义突变的SMEI患者进行的筛查中，未发现KCNQ 2的第二位点突变。
A mutation in the voltage-gated sodium-channel Scn2a results in moderate epilepsy in transgenic Scn2a(Q54) mice maintained on a C57BL/6J strain background. The onset of progressive epilepsy begins in adults with short-duration partial seizures that originate in the hippocampus. The underlying abnormality is an increase in persistent sodium current in hippocampal neurons. The voltage-gated potassium channel Kcnq2 is responsible for generating M current (I-KM) that is thought to control excitability and limit repetitive firing of hippocampal neurons. To determine whether impaired M current would exacerbate the seizure phenotype of Scn2a(Q54) mice, we carried out genetic crosses with two mutant alleles of Kcnq2. Szt1 mice carry a spontaneous deletion that removes the C-terminal domain of Kcnq2. A novel Kcnq2 missense mutation V182M was identified by screening the offspring of ENU-treated males for reduced threshold to electrically evoked minimal clonic seizures. Double mutant mice carrying the Scn2a(Q54) transgene together with either of the Kcnq2 mutations exhibited severe epilepsy with early onset, generalized tonic-clonic seizures and juvenile lethality by 3 weeks of age. This dramatic exacerbation of the sodium-channel mutant phenotype indicates that M current plays a critical role in preventing seizure initiation and spreading in this animal model. The genetic interaction between Scn2a and Kcnq2 demonstrates that combinations of mild alleles of monogenic epilepsy genes can result in severe disease and provides a model for complex inheritance of human epilepsy. The data suggest that interaction between these genes might contribute to the variable expressivity observed in human families with sodium-channel mutations. In a screen of 23 SMEI patients with missense mutations of SCN1A, no second-site mutations in KCNQ2 were identified.