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The Role of Noncoding Genetic Elements in the Transcriptional Regulation of the Voltage‐Gated Sodium Channels SCN1A and SCN8A
Author(s) -
Inglis George Andrew Stanowski,
Escayg Andrew
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.756.10
Subject(s) - dravet syndrome , epilepsy , scn3a , sodium channel , gene , epilepsy syndromes , biology , regulation of gene expression , gene expression , genetics , medicine , bioinformatics , neuroscience , protein subunit , g alpha subunit , chemistry , organic chemistry , sodium
Epilepsy is a common neurological disorder that affects over 50 million people worldwide, and is characterized by recurrent, unprovoked seizures. Altered brain expression of the voltage‐gated sodium channel (VGSC) α subunit gene SCN1A has been shown to directly cause some forms of epilepsy. Heterozygous loss‐of‐function mutations in the VGSC gene SCN1A (encoding the protein Na v 1.1) are responsible for 70–80% of cases of Dravet Syndrome (DS), a severe, treatment‐resistant form of childhood epilepsy. A significant decrease in SCN1A mRNA levels is also associated with temporal lobe epilepsy (TLE), the most common form of treatment‐resistant epilepsy in adults. Restoring SCN1A expression through increased gene expression is predicted to be therapeutic in these cases. Conversely, loss‐of‐function or reduced expression in the VGSC gene SCN8A (encoding the protein Na v 1.6) has been demonstrated to increase seizure resistance and quality of life in mouse models of DS and TLE. However, despite the important role of the VGSC genes in epilepsy, and the clinical potential of modulating SCN1A and SCN8A expression as a therapy for patients with epilepsy, we have limited knowledge about the genetic elements or factors responsible for the transcriptional regulation of these two genes. By analyzing several genomic markers of open or actively transcribed chromatin across neuronal cell types, we identified several genetic elements in both SCN1A and SCN8A with putative transcriptional regulatory ability. We have cloned these elements into a vector upstream of a human SCN1A promoter driving luciferase reporter expression. A number of these constructs resulted in altered luciferase activity relative to empty vectors or constructs with just the SCN1A promoter, suggesting the cloned elements have functional significance. Additional analyses, including identification of proteins responsible for transcription, are being conducted on a subset of these elements. Support or Funding Information This work was supported through funding from the NIH National Institute of Neurological Disorders and Stroke (NINDS) and the Emory University Genetics & Molecular Biology T32 Training Grant.