Mutations in voltage-gated sodium channels are responsible for several human epilepsies with varying degrees of clinical severity. Over 800 mutations in SCN1A, encoding the neuronal voltage-gated sodium channel Nav1.1, have been reported patients. SCN1A mutations are associated with epilepsy phenotypes on the genetic epilepsy with febrile seizures plus (GEFS+) spectrum. The GEFS+ spectrum ranges from simple febrile seizures on the mild end of the spectrum to Dravet syndrome on the severe end. Heterozygous loss-of-function mutations in SCN1A result in Dravet syndrome, an infant-onset epileptic encephalopathy characterized by a variety of seizure types, developmental delay and elevated mortality risk. A common feature of monogenic epilepsies is variable expressivity in individuals carrying the same mutation, suggesting that clinical severity is influenced by genetic modifiers. Mice with heterozygous deletion of Scn1a (Scn1a+/-) model a number of features of Dravet syndrome, including spontaneous seizures and increased mortality risk. Loss of Scn1a results in reduced sodium current in hippocampal GABAergic interneurons, which is predicted to increase excitability due to failure of inhibition. Phenotype severity in Scn1a+/- mice is strongly dependent on strain background. Scn1a+/- mice on the resistant 129 strain background (129.Scn1a+/-) have no overt phenotype and live a normal lifespan. In contrast, Scn1a+/- mice on a (129xB6)F1 strain background (F1.Scn1a+/-) exhibit spontaneous seizures and premature lethality, with 50% dying by 1 month of age. Based on the strain- dependent difference in phenotype, we hypothesize that genetic modifiers influence Scn1a+/- phenotype severity. We recently mapped several modifier loci that influence premature lethality of Scn1a+/- mice. In the current proposal, we will perform fine mapping and candidate gene analysis with the goal of identifying the responsible modifier genes. In addition to the strain-dependent differences in clinical severity, we also observed strain-dependent differences in hippocampal neuron sodium currents (INa). GABAergic interneurons isolated from the F1.Scn1a+/- mice exhibit decreased INa density compared to wildtype littermate controls. In contrast, INa density is preserved in GABAergic interneurons isolated from 129.Scn1a+/- and is no different from wildtype littermates. This suggests that interneurons from strain 129 compensate for the loss of Nav1.1, while F1 interneurons do not. Based on this observation, we hypothesize that there are strain differences in compensatory capacity in the context of Scn1a heterozygous deletion. We propose to perform RNA-seq analysis to characterize hippocampal transcriptome differences during the critical phase of phenotype onset in susceptible F1.Scn1a+/- and resistant 129.Scn1a+/- mice. The results of this analysis will suggest candidate modifier genes and pathways that influence phenotype severity in Scn1a+/- mice. Identification of Dravet syndrome modifier genes will provide insight into the pathophysiology of epilepsy and will suggest novel therapeutic strategies for the improved treatment of human patients.
The major goal of this proposal is to identify modifier genes that influence mortality risk in Dravet syndrome, an infant-onset epileptic encephalopathy that responds poorly to available treatments. Identification of modifier genes that influence disease severity and mortality risk will provide insight into the molecular events underlying epilepsy and suggest novel therapeutic targets for the improved treatment of human patients.
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| Hawkins, Nicole A; Anderson, Lyndsey L; Gertler, Tracy S et al. (2017) Screening of conventional anticonvulsants in a genetic mouse model of epilepsy. Ann Clin Transl Neurol 4:326-339 |
| Anderson, Lyndsey L; Hawkins, Nicole A; Thompson, Christopher H et al. (2017) Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome. Sci Rep 7:1682 |
| Calhoun, Jeffrey D; Hawkins, Nicole A; Zachwieja, Nicole J et al. (2017) Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome. Epilepsia 58:e111-e115 |
| Hawkins, Nicole A; Zachwieja, Nicole J; Miller, Alison R et al. (2016) Fine Mapping of a Dravet Syndrome Modifier Locus on Mouse Chromosome 5 and Candidate Gene Analysis by RNA-Seq. PLoS Genet 12:e1006398 |
| Hawkins, Nicole A; Kearney, Jennifer A (2016) Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations. Epilepsy Res 119:20-3 |
| Calhoun, Jeffrey D; Hawkins, Nicole A; Zachwieja, Nicole J et al. (2016) Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a. Epilepsia 57:e103-7 |
