A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family
A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family
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DOI：
10.1038/ng0198-53
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发表时间：
1998-01-01
期刊：
影响因子：
30.8
通讯作者：
Leppert, M
中科院分区：
文献类型：
--
作者：
Charlier, C;Singh, NA;Leppert, M
癫痫疾病影响全世界约2000 - 4000万人，其中40%是特发性全身性癫痫（IGE：参考文献1）。大多数遗传性IGE是复杂的多基因疾病。为了解决癫痫的基本机制，我们集中在一类定义明确的IGE与常染色体显性遗传模式：良性熟悉新生儿惊厥（BFNC：参考文献2，3）。已观察到BFNC的遗传异质性（4）。通过连锁分析，将EBN 1和EBN 2分别定位于染色体20 q13（参考文献5，6）和8 q24（参考文献7，8）。通过定位克隆，我们最近将EBN 1的基因鉴定为KCNQ 2（参考文献9）。该基因是一种基于同源性的电压门控钾通道，是KQT样家族的成员（10）。在这里，我们描述一个额外的成员，KCNQ 3。我们将该新基因定位于第8号染色体，在辐射杂交图谱上的标记D8 S256和D8 S284之间（11）。我们筛选了KCNQ 3中先前在相同标记间隔中与染色体8 q24连锁的大BFNC家族（4，7）中的突变。我们发现一个错义突变的关键孔区在完美的共分离与BFNC表型。在LQT患者的KVLQT 1（KCNQ 1）中也发生了相同的保守氨基酸突变（12）。KCNQ 2、KCNQ 3和同一K+通道家族的未发现基因是其他IGE的强有力候选者。
Epileptic disorders affect about 20-40 million people worldwide, and 40% of these are idiopathic generalized epilepsies (IGEs: ref. 1). Most of the IGEs that are inherited are complex, multigenic diseases. To address basic mechanisms for epilepsies, we have focused on one well-defined class of IGEs with an autosomal-dominant mode of inheritance: the benign familiar neonatal convulsions (BFNC: refs 2,3). Genetic heterogeneity of BFNC has been observed(4). Two loci, EBN1 and EBN2, have been mapped by linkage analysis to chromosome 20q13 (refs 5,6) and chromosome 8q24 (refs 7,8), respectively. By positional cloning, we recently identified the gene for EBN1 as KCNQ2 (ref. 9). This gene, a voltage-gated potassium channel, based on homology, is a member of the KQT-like family(10). Here we describe an additional member, KCNQ3. We mapped this new gene to chromosome 8, between markers D8S256 and D8S284 on a radiation hybrid map(11). We screened KCNQ3 for mutations in the large BFNC family(4,7) previously linked to chromosome 8q24 in the same marker interval. We found a missense mutation in the critical pore region in perfect co-segregation with the BFNC phenotype. The same conserved amino acid is also mutated in KVLQT1 (KCNQ1) in an LQT patient(12). KCNQ2, KCNQ3 and undiscovered genes of the same family of K+ channels are strong candidates for other IGEs.