Show simple item record

Identification of epilepsy modifier genes in a mouse model

dc.creatorHawkins, Nicole Alise
dc.date.accessioned2020-08-23T15:47:35Z
dc.date.available2015-11-25
dc.date.issued2013-11-25
dc.identifier.urihttps://etd.library.vanderbilt.edu/etd-11192013-102912
dc.identifier.urihttp://hdl.handle.net/1803/14623
dc.description.abstractEpilepsy is a neurological disorder affecting approximately 3 million Americans. Two-thirds of patients diagnosed with epilepsy have no known cause for their disease, however recent evidence suggests most result from complex genetic interactions. Research has identified several genes which contribute to monogenic epilepsy, however identifying genes involved in genetically-complex epilepsies has been less successful. Nearly 900 mutations have been identified in the voltage-gated sodium channel genes SCN1A and SCN2A in human epilepsies, including GEFS+, Dravet and Ohtahara syndromes. Affected family members with the same sodium channel mutation often display variability in the clinical severity of their disease, a common feature of genetic epilepsy. Mouse epilepsy models, including sodium channel mutants, also show significant phenotype variability dependent on genetic background. This suggests that epilepsy phenotypes can be influenced by genetic modifiers. The Scn2aQ54 mouse model has an epilepsy phenotype with strain-dependent variability. Scn2aQ54 mice congenic on strain C57BL/6J exhibit delayed seizure onset and improved survival compared to (C57BL/6J x SJL/J)F1.Scn2aQ54 mice. Two dominant modifier loci that influence Scn2aQ54 seizure susceptibility were mapped and designated Moe1 and Moe2. Fine-mapping of Moe1 using interval-specific congenic lines and RNA-Seq identified Cacna1g and Hlf as candidate modifier genes of the Scn2aQ54 seizure phenotype. Cacna1g transgenic and Hlf targeted knockout mouse models were used for systematic evaluation of Cacna1g and Hlf modifier potential by generation of double mutants with Scn2aQ54 mice. These studies provided evidence that supports Hlf and Cacna1g as genetic modifiers of the Scn2aQ54 phenotype. Additional epilepsy modifier genes were identified using a functional candidate gene approach to evaluate known epilepsy mutations Scn2aQ54 and Kcnq2V182M/+ on the phenotype of the Scn1aR1648H/+ GEFS+ model. Combining the Scn1aR1648H/+ mutation with Scn2aQ54 or Kcnq2V182M/+ resulted in severe, juvenile-onset epilepsy that was not observed in single mutants. Understanding the molecular basis of genetic modifiers in a mouse model can provide insight into human epilepsy. Verification of Cacna1g and Hlf as epilepsy modifier genes will suggest new targets for improved treatment of epilepsy and advance molecular diagnostic capabilities by identifying those patients who are most at-risk for developing severe epilepsy.
dc.format.mimetypeapplication/pdf
dc.subjectvoltage-gated ion channels
dc.subjectvoltage-gated sodium channels
dc.subjectmouse models
dc.subjectEpilepsy
dc.subjectgenetic modifier
dc.subjectseizure
dc.titleIdentification of epilepsy modifier genes in a mouse model
dc.typedissertation
dc.contributor.committeeMemberJennifer Kearney
dc.contributor.committeeMemberMichelle Southard-Smith
dc.contributor.committeeMemberDouglas Mortlock
dc.type.materialtext
thesis.degree.namePHD
thesis.degree.leveldissertation
thesis.degree.disciplineNeuroscience
thesis.degree.grantorVanderbilt University
local.embargo.terms2015-11-25
local.embargo.lift2015-11-25
dc.contributor.committeeChairAlfred George


Files in this item

Icon

This item appears in the following Collection(s)

Show simple item record