10.1371/journal.pgen.1006398
Nicole A. Hawkins
Nicole A.
Hawkins
Nicole J. Zachwieja
Nicole J.
Zachwieja
Alison R. Miller
Alison R.
Miller
Lyndsey L. Anderson
Lyndsey L.
Anderson
Jennifer A. Kearney
Jennifer A.
Kearney
Fine Mapping of a Dravet Syndrome Modifier Locus on Mouse Chromosome 5 and Candidate Gene Analysis by RNA-Seq
Public Library of Science
2016
voltage-gated sodium channel genes
SUDEP
Low resolution mapping
Dravet syndrome modifier
sodium channel mutation
Dravet Syndrome Modifier Locus
57BL
candidate modifier genes
9 Mb region
findings support Gabra 2
Scn
Dravet syndrome
GABA
strain-dependent epilepsy phenotype
mouse strain background
1a
hyperthermia-induced seizures
gene expression differences
GABRA 2 receptor
change disease severity
SCN 1A mutations result
Gabra 2
Candidate Gene Analysis
Dravet syndrome patients experience
Mouse Chromosome 5
model
2016-10-21 17:39:43
Dataset
https://plos.figshare.com/articles/dataset/Fine_Mapping_of_a_Dravet_Syndrome_Modifier_Locus_on_Mouse_Chromosome_5_and_Candidate_Gene_Analysis_by_RNA-Seq/4053531
<div><p>A substantial number of mutations have been identified in voltage-gated sodium channel genes that result in various forms of human epilepsy. <i>SCN1A</i> mutations result in a spectrum of severity ranging from mild febrile seizures to Dravet syndrome, an infant-onset epileptic encephalopathy. Dravet syndrome patients experience multiple seizures types that are often refractory to treatment, developmental delays, and elevated risk for SUDEP. The same sodium channel mutation can produce epilepsy phenotypes of varying clinical severity. This suggests that other factors, including genetic, modify the primary mutation and change disease severity. Mouse models provide a useful tool in studying the genetic basis of epilepsy. The mouse strain background can alter phenotype severity, supporting a contribution of genetic modifiers in epilepsy. The <i>Scn1a</i><sup><i>+/-</i></sup> mouse model has a strain-dependent epilepsy phenotype. <i>Scn1a</i><sup><i>+/-</i></sup> mice on the 129S6/SvEvTac (129) strain have a normal phenotype and lifespan, while [129xC57BL/6J]F1-<i>Scn1a</i><sup><i>+/-</i></sup> mice experience spontaneous seizures, hyperthermia-induced seizures and high rates of premature death. We hypothesize the phenotypic differences are due to strain-specific genetic modifiers that influence expressivity of the <i>Scn1a</i><sup><i>+/-</i></sup> phenotype. Low resolution mapping of <i>Scn1a</i><sup><i>+/-</i></sup> identified several Dravet syndrome modifier (<i>Dsm</i>) loci responsible for the strain-dependent difference in survival. One locus of interest, <i>Dsm1</i> located on chromosome 5, was fine mapped to a 9 Mb region using interval specific congenics. RNA-Seq was then utilized to identify candidate modifier genes within this narrowed region. Three genes with significant total gene expression differences between 129S6/SvEvTac and [129xC57BL/6J]F1 were identified, including the GABA<sub>A</sub> receptor subunit, <i>Gabra2</i>. Further analysis of <i>Gabra2</i> demonstrated allele-specific expression. Pharmological manipulation by clobazam, a common anticonvulsant with preferential affinity for the GABRA2 receptor, revealed dose-dependent protection against hyperthermia-induced seizures in <i>Scn1a</i><sup><i>+/-</i></sup> mice. These findings support <i>Gabra2</i> as a genetic modifier of the <i>Scn1a</i><sup><i>+/-</i></sup> mouse model of Dravet syndrome.</p></div>