title: 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.
abstract: 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.
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, 510260, China.|Department of Epilepsy, Guangzhou General Hospital of Guangzhou Military Command, Liu-hua Road 111, Guangzhou, 510010, China.
authors.forename: Qu-Wen
authors.initials: QW
authors.lastname: Gao
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, 510260, China.
authors.forename: Li-Dong
authors.initials: LD
authors.lastname: Hua
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, 510260, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, 510260, China.
authors.forename: Cui-Xia
authors.initials: CX
authors.lastname: Fan
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, 510260, China.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Deng
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, 510260, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, 510260, China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Bian
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, 510260, China.
authors.forename: Chuan-Xing
authors.initials: CX
authors.lastname: Shao
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, 510260, China.
authors.forename: Na
authors.initials: N
authors.lastname: He
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, 510260, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China. wpliao@163.net.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, 510260, China. wpliao@163.net.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Liao
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China. stoneyiwu@163.com.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, 510260, China. stoneyiwu@163.com.
authors.forename: Yi-Wu
authors.initials: YW
authors.lastname: Shi
mesh_terms: D000293:Adolescent; D000927:Anticonvulsants / Q000009:adverse effects*; D001483:Base Sequence; D005260:Female; D015894:Genome, Human; D006579:Heterozygote; D006801:Humans; D008297:Male; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012640:Seizures / Q000235:genetics*
chemical_list: D000927:Anticonvulsants; D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
keywords: Mutation; Noncoding regions; Partial epilepsy with febrile seizures plus; Promoter; SCN1A