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

A. R. Miller, N. A. Hawkins, C. E. Mccollom, J. A. Kearney*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)163-172
Number of pages10
JournalGenes, Brain and Behavior
Volume13
Issue number2
DOIs
StatePublished - Feb 1 2014

Keywords

  • Dravet syndrome
  • Epilepsy
  • Epileptic encephalopathy
  • Mouse model
  • RNA-seq
  • Seizures
  • Severe myoclonic epilepsy of infancy
  • Transcriptomics
  • Voltage-gated ion channels
  • Voltage-gated sodium channels

ASJC Scopus subject areas

  • Genetics
  • Neurology
  • Behavioral Neuroscience

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