TY - DATA T1 - Fine Mapping of a Dravet Syndrome Modifier Locus on Mouse Chromosome 5 and Candidate Gene Analysis by RNA-Seq PY - 2016/10/21 AU - Nicole A. Hawkins AU - Nicole J. Zachwieja AU - Alison R. Miller AU - Lyndsey L. Anderson AU - Jennifer A. Kearney UR - 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 DO - 10.1371/journal.pgen.1006398 L4 - https://ndownloader.figshare.com/files/6525306 L4 - https://ndownloader.figshare.com/files/6525309 KW - voltage-gated sodium channel genes KW - SUDEP KW - Low resolution mapping KW - Dravet syndrome modifier KW - sodium channel mutation KW - Dravet Syndrome Modifier Locus KW - 57BL KW - candidate modifier genes KW - 9 Mb region KW - findings support Gabra 2 KW - Scn KW - Dravet syndrome KW - GABA KW - strain-dependent epilepsy phenotype KW - mouse strain background KW - 1a KW - hyperthermia-induced seizures KW - gene expression differences KW - GABRA 2 receptor KW - change disease severity KW - SCN 1A mutations result KW - Gabra 2 KW - Candidate Gene Analysis KW - Dravet syndrome patients experience KW - Mouse Chromosome 5 KW - model N2 - A substantial number of mutations have been identified in voltage-gated sodium channel genes that result in various forms of human epilepsy. SCN1A 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 Scn1a+/- mouse model has a strain-dependent epilepsy phenotype. Scn1a+/- mice on the 129S6/SvEvTac (129) strain have a normal phenotype and lifespan, while [129xC57BL/6J]F1-Scn1a+/- 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 Scn1a+/- phenotype. Low resolution mapping of Scn1a+/- identified several Dravet syndrome modifier (Dsm) loci responsible for the strain-dependent difference in survival. One locus of interest, Dsm1 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 GABAA receptor subunit, Gabra2. Further analysis of Gabra2 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 Scn1a+/- mice. These findings support Gabra2 as a genetic modifier of the Scn1a+/- mouse model of Dravet syndrome. ER -