Mapping genetic modifiers of survival in a mouse model of Dravet syndrome

Genes Brain Behav. 2014 Feb;13(2):163-72. doi: 10.1111/gbb.12099. Epub 2013 Nov 14.


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.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chromosomes / genetics
  • Epilepsies, Myoclonic / genetics*
  • Epilepsies, Myoclonic / physiopathology
  • Genes, Modifier*
  • Mice
  • Mice, Inbred C57BL
  • NAV1.1 Voltage-Gated Sodium Channel / genetics
  • Penetrance*
  • Quantitative Trait Loci


  • NAV1.1 Voltage-Gated Sodium Channel
  • Scn1a protein, mouse