A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus -: and prevalence of variants in patients with epilepsy
A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus -: and prevalence of variants in patients with epilepsy
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DOI：
10.1086/319524
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发表时间：
2001-04-01
影响因子：
9.8
通讯作者：
Meisler, MH
中科院分区：
文献类型：
--
作者：
Escayg, A;Heils, A;Meisler, MH
我们最近描述了两个2型全身性癫痫伴热性惊厥加重（GEFS+）家族中染色体2 q24上神经元钠通道α亚基基因SCN 1A的突变。为了评估SCN 1A对其他类型癫痫的贡献，通过构象敏感性凝胶电泳和变体手动测序筛选了226例青少年肌阵挛性癫痫、失神癫痫或热性惊厥患者;样本包括来自多重家族的165名先证者和61例散发病例。在一个GEFS+家系中发现了新的突变W1204 R。观察到其他7个编码变化;其中3个是潜在的致病突变。两种常见的单倍型，频率为0.67和0.33，由跨越14 kb连锁不平衡区域的5个单核苷酸多态性（SNP）定义。在226名患者中的7名中观察到位于外显子3剪接受体位点上游18个碱基对的SNP，但在185名对照中不存在，这表明可能与疾病突变有关。这项工作证实了SCN 1A在GEFS+中的作用，通过鉴定以前未描述的家族中的新突变。虽然确定了一些候选疾病等位基因，但患者调查表明SCN 1A不是特发性全身性癫痫的主要贡献者。这里确定的SCN 1A单倍型和SNP将在未来的关联和连锁研究中是有用的。
We recently described mutations of the neuronal sodium-channel alpha -subunit gene, SCN1A, on chromosome 2q24 in two families with generalized epilepsy with febrile seizures plus (GEFS+) type 2. To assess the contribution that SCN1A makes to other types of epilepsy, 226 patients with either juvenile myoclonic epilepsy, absence epilepsy, or febrile convulsions were screened by conformation-sensitive gel electrophoresis and manual sequencing of variants; the sample included 165 probands from multiplex families and 61 sporadic cases. The novel mutation W1204R was identified in a family with GEFS+. Seven other coding changes were observed; three of these are potential disease-causing mutations. Two common haplotypes, with frequencies of .67 and .33, were defined by five single-nucleotide polymorphisms (SNPs) spanning a 14-kb region of linkage disequilibrium. An SNP located 18 bp upstream of the splice-acceptor site for exon 3 was observed in 7 of the 226 patients but was not present in 185 controls, suggesting possible association with a disease mutation. This work has confirmed the role of SCN1A in GEFS+, by identification of a novel mutation in a previously undescribed family. Although a few candidate disease alleles were identified, the patient survey suggests that SCN1A is not a major contributor to idiopathic generalized epilepsy. The SCN1A haplotypes and SNPs identified here will be useful in future association and linkage studies.