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Title page for ETD etd-10292014-130822


Type of Document Dissertation
Author Jorge, Benjamin S.
Author's Email Address benjamin.jorge@vanderbilt.edu
URN etd-10292014-130822
Title Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Alfred L. George, Jr., M.D. Committee Chair
Douglas P. Mortlock, Ph.D. Committee Member
Jennifer A. Kearney, Ph.D. Committee Member
Kevin C. Ess, M.D., Ph.D. Committee Member
Keywords
  • potassium channel
  • epileptic encephalopathy
  • mouse model
  • genetics
  • whole-exome sequencing
  • epilepsy
Date of Defense 2014-09-19
Availability unrestricted
Abstract
Epilepsy is a common neurological disease characterized by an enduring predisposition to generate seizures. Although multiple factors contribute to epilepsy, the majority of cases are genetic in origin. Variable expressivity is commonly observed in families with inherited mutations in epilepsy-associated genes, suggesting that variation in genetic modifiers may contribute to epilepsy phenotypes. We previously identified the modulatory voltage-gated potassium channel subunit, Kcnv2, as a candidate modifier gene in a transgenic mouse model of epilepsy. This dissertation outlines: the validation of Kcnv2 as a quantitative modifier of epilepsy in mice; the identification of KCNV2 variants in pediatric epilepsy patients; the determination of Kcnv2 regulatory regions; and the identification of mutations in a delayed-rectifier potassium channel gene, KCNB1, in individuals with epileptic encephalopathy. These studies highlight the importance of delayed-rectifier potassium current in governing neuronal excitability and demonstrate the utility of identifying and characterizing genetic modifiers to elucidate mechanisms of pathogenesis.
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