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.

MicroRNA-133b is regulated by TAp63 while no gene mutation is present in colorectal cancer

“…A point mutation, or single base modification, is a type of mutation that causes a single nucleotide base substitution, insertion or deletion of genetic material. Point mutations have been proven to influence expression of many genes (17)(18)(19). In addition, miRNA gene point mutations have been reported in almost all types of cancer (20,21).…”

Influence of common SCN1A promoter variants on the severity of SCN1A‐related phenotypes

“…First, it is likely that common variants in the promoter region only have small phenotypic effects, since they otherwise would have been subject to negative selection. This limited effect was also illustrated by Gao et al, (2017); although a pathogenic point mutation in the SCN1A promoter-region led to an in vitro decrease of expression and mild epilepsy in a proband, the same variant was found in the asymptomatic mother of the patient. This indicates that promoter-variants by themselves may only have a limited influence on phenotypes.…”

“…So far, two reports have been published that suggested that pathogenic mutations in the regulatory 5’ region of SCN1A were likely the cause of disease in two Dravet syndrome patients, as no SCN1A coding mutations could be detected. Interestingly, the novel promoter mutations were found to reduce transcription in vitro , increasing the likelihood of their causality (Gao et al, ; Nakayama et al, ). These findings stress the importance of the SCN1A promoter‐regions for correct functioning of the Nav1.1 channel.…”

“…A small decrease in expression of SCN1A could lead to a decreased residual function of Nav1.1 in patients that are already haploinsufficient, and therefore lead to more severe clinical outcomes. Previously, no significant differences in expression were observed for a group of common variants in the first SCN1A promoter region (Gao et al, 2017). We have cloned a new set of haplotypes and used a slightly altered promoter region that includes the first 5' UE in the functional expression analysis.…”

Expanding spectrum of SCN1A-related phenotype with novel mutations

“…It is known that SCN1A mutations are most notably linked to two epilepsy syndromes, severe myoclonic epilepsy of infancy (SMEI), also known as Dravet syndrome (DS; MIM#607208) and the mild familial epilepsy syndrome of genetic epilepsy with febrile seizures (FS) plus (GEFS+; MIM#604233). [1][2][3][4] All of the SCN1A mutations are dominantly inherited and they can result most commonly as observed in either loss of function in DS or altered function in GEFS+. DS is one of the most common and well-defined epileptic encephalopathy.…”