The overall goal of this work is to examine digenic interactions between mutations in the Kcna1 and Scn2a ion channel genes in the context of sudden unexpected death in epilepsy (SUDEP). People with epilepsy are 24 times more likely than the general population to die suddenly for unknown pathological reasons;these deaths are classified as SUDEP and represent the leading cause of epilepsy-related mortality. Several genes have been linked anecdotally to SUDEP, but its genetic etiology is largely unknown and likely complex involving the co-inheritance of multiple susceptibility gene variants. This proposal investigates the ability of subclinical Scn2a-null heterozygosity to act as a protective genetic modifier of epilepsy and premature death in the Kcna1 knockout mouse model of SUDEP. Scn2a, a human epilepsy gene, encodes Nav1.2 voltage-gated sodium channel Alpha-subunits but the knockout mutation utilized here has not been found to cause epilepsy. Kcna1, also a human epilepsy gene, encodes Kv1.1 voltage-gated potassium channel Alpha-subunits that normally act to dampen neuronal excitability. Kcna1 knockout mice accurately model human SUDEP by exhibiting severe epilepsy, brain-driven cardiac dysfunction, and premature death. Given the expression overlap and mutually opposing excitability effects of the two genes, the proposed research tests the hypothesis that subclinical Scn2a-null heterozygosity reduces SUDEP incidence in Kcna1-null mice by suppressing neurocardiac dysfunction and neuronal hyperexcitability associated with the absence of Kv1.1 channels. Preliminary data shows that Scn2a-null heterozygosity prevents SUDEP in Kcna1 knockouts increasing their survival threefold.
In Aim 1, video electroencephalography-electrocardiography (EEG-ECG) is used to determine whether Scn2a-null heterozygosity reduces epileptiform discharges and/or cardiac abnormalities in Kcna1-null mice.
Aim 2 seeks to identify neuronal networks exhibiting functional interaction between Scn2a and Kcna1 by analyzing changes in expression of molecular biomarkers associated with abnormal neuronal activation, such as c-Fos. This research utilizes a novel digenic mouse model as an important first step towards understanding the complex genetic interactions underlying SUDEP with the ultimate goal of improving genotype-based risk prediction, prevention, and therapy in epilepsy. The ability of Scn2a-null heterozygosity to suppress the Kcna1 SUDEP phenotype would demonstrate a proof-of-principle that even subclinical gene variants without obvious phenotypes must be considered when evaluating the genetic risk profiles of epilepsy patients since those alleles can also be critical modifiers of disease susceptibility. Furthermore, the examination of molecular biomarker endophenotypes in this digenic model has the potential to identify previously unrecognized brain networks that are important for SUDEP pathophysiology and candidate therapeutic targets for future studies.

Public Health Relevance

People with epilepsy are 24 times more likely than the general population to die suddenly for unexplained pathological reasons;these deaths are classified as sudden unexpected death in epilepsy (SUDEP) and represent the leading cause of epilepsy-related mortality. The genetic etiology of SUDEP is largely unknown and likely complex involving the co-inheritance of multiple susceptibility gene variants. This proposal seeks to better understand the complex genetics underlying SUDEP by analyzing the ability of subclinical Scn2a-null heterozygosity to act as a protective genetic modifier of epilepsy and premature death in the Kcna1 knockout mouse model of SUDEP.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS089397-01
Application #
8765025
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Whittemore, Vicky R
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Shreveport
State
LA
Country
United States
Zip Code
71103