A Point Mutation in SCN1A 5′ Genomic Region Decreases the Promoter Activity and Is Associated with Mild Epilepsy and Seizure Aggravation Induced by Antiepileptic Drug
A Point Mutation in SCN1A 5′ Genomic Region Decreases the Promoter Activity and Is Associated with Mild Epilepsy and Seizure Aggravation Induced by Antiepileptic Drug
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SCN1A 5'基因组区的点突变降低启动子活性，与抗癫痫药物引起的轻度癫痫和癫痫发作加重有关
DOI：
10.1007/s12035-016-9800-y
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发表时间：
2017-05-01
影响因子：
5.1
通讯作者：
Shi, Yi-Wu
中科院分区：
文献类型：
--
作者：
Gao, Qu-Wen;Hua, Li-Dong;Shi, Yi-Wu
编码区有1274个点突变或基因组重排的SCN1A基因是临床相关性最高的癫痫基因。最近的研究表明，非编码区域的变异可能与癫痫有关，但没有明显的突变报道。我们对166例编码区点突变或基因组重排阴性的癫痫和热性癫痫患者的SCN1A 5'上游区域进行了测序。在一例局部癫痫和热性癫痫患者中发现了一种杂合突变h1 -1962 T b> G，奥卡西平加重了这种突变。该突变来自患者无症状的母亲，在110名正常对照中未发现。T > G位于最常使用的非编码外显子上游和启动子序列内。进一步的实验表明，与配对单倍型相比，该突变使启动子活性降低了42.1% （P < 0.001）。与导致单倍不全和严重表型的零表达相反，该突变引起的损伤相对较小，解释了轻度癫痫的不完全外显。该患者抗癫痫药物引起的癫痫发作加重提示临床注意可能影响SCN1A表达的非编码区突变或变异。
The SCN1A gene with 1274 point mutations in the coding regions or genomic rearrangements is the most clinically relevant epilepsy gene. Recent studies have demonstrated that variations in the noncoding regions are potentially associated with epilepsies, but no distinct mutation has been reported. We sequenced the 5' upstream region of SCN1A in 166 patients with epilepsy and febrile seizures who were negative for point mutations in the coding regions or genomic rearrangements. A heterozygous mutation h1u-1962 T > G was identified in a patient with partial epilepsy and febrile seizures, which was aggravated by oxcarbazepine. This mutation was transmitted from the patient's asymptomatic mother and not found in the 110 normal controls. h1u-1962 T > G was located upstream the most frequently used noncoding exon and within the promoter sequences. Further experiments showed that this mutation decreased the promoter activity by 42.1 % compared with that of the paired haplotype (P < 0.001). In contrast to the null expression that results in haploinsufficiency and severe phenotype, this mutation caused relatively less impairment, explaining the mild epilepsy with incomplete penetrance. The antiepileptic drug-induced seizure aggravation in this patient suggests clinical attention for mutations or variations in noncoding regions that may affect SCN1A expression.