title: Mapping genetic modifiers of survival in a mouse model of Dravet syndrome.
abstract: Epilepsy is a common neurological disorder affecting approximately 1% of the population. Mutations in voltage-gated sodium channels are responsible for several monogenic epilepsy syndromes. More than 800 mutations in the voltage-gated sodium channel SCN1A have been reported in patients with generalized epilepsy with febrile seizures plus and Dravet syndrome. Heterozygous loss-of-function mutations in SCN1A result in Dravet syndrome, a severe infant-onset epileptic encephalopathy characterized by intractable seizures, developmental delays and increased mortality. A common feature of monogenic epilepsies is variable expressivity among individuals with the same mutation, suggesting that genetic modifiers may influence clinical severity. Mice with heterozygous deletion of Scn1a (Scn1a(+/-) ) model a number of Dravet syndrome features, including spontaneous seizures and premature lethality. Phenotype severity in Scn1a(+/-) mice is strongly dependent on strain background. On the 129S6/SvEvTac strain Scn1a(+/-) mice exhibit no overt phenotype, whereas on the (C57BL/6J × 129S6/SvEvTac)F1 strain Scn1a(+/-) mice exhibit spontaneous seizures and early lethality. To systematically identify loci that influence premature lethality in Scn1a(+/-) mice, we performed genome scans on reciprocal backcrosses. Quantitative trait locus mapping revealed modifier loci on mouse chromosomes 5, 7, 8 and 11. RNA-seq analysis of strain-dependent gene expression, regulation and coding sequence variation provided a list of potential functional candidate genes at each locus. Identification of modifier genes that influence survival in Scn1a(+/-) mice will improve our understanding of the pathophysiology of Dravet syndrome and may suggest novel therapeutic strategies for improved treatment of human patients.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Miller
authors.forename: N A
authors.initials: NA
authors.lastname: Hawkins
authors.forename: C E
authors.initials: CE
authors.lastname: McCollom
authors.forename: J A
authors.initials: JA
authors.lastname: Kearney
mesh_terms: D000818:Animals; D002875:Chromosomes / Q000235:genetics; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000503:physiopathology; D060045:Genes, Modifier; D051379:Mice; D008810:Mice, Inbred C57BL; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D019683:Penetrance; D040641:Quantitative Trait Loci
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568249:Scn1a protein, mouse
keywords: Dravet syndrome; RNA-seq; epilepsy; epileptic encephalopathy; mouse model; seizures; severe myoclonic epilepsy of infancy; transcriptomics; voltage-gated ion channels; voltage-gated sodium channels