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
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.
KeywordsSCN1A Mutation Noncoding regions Promoter Partial epilepsy with febrile seizures plus
We thank all patients, their families, and physicians for participating in this study. We are grateful to the He Shanheng Charity Foundation for contributing to the development of this institute.
Compliance with Ethical Standards
This work was supported by the National Natural Science Foundation of China (grant nos. 81071045, 81271434, 81571273, 81571274, and 81501124), Department of Education of Guang dong Province (grant nos. 2013CXZDA022, 2013KJCX0156, and 2012KJCX009), Foundation for High-level Talents in Higher Education of Guangdong (grant no.2013-167), Yangcheng Scholar Research Project of Guangzhou Municipal College (grant nos.12A016S and 12A017G), Science and Technology Project of Guangzhou (grant nos. 2014 J4100069 and 201508020011), and Collaborative Innovation Center for Neurogenetics and Channelopathies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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