A mouse model of human idiopathic generalized epilepsy

Emory University, Atlanta GA

Investigators

Abstract

DESCRIPTION (provided by applicant): The idiopathic generalized epilepsies (IGEs) encompass several syndromes that are characterized by age- related, recurrent, and unprovoked generalized seizures in the absence of detectable brain lesions or metabolic abnormalities. The most common IGE subtypes are childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic-clonic seizures (EGTCS). The etiology of IGE is genetically determined, and approximately 18 IGE genes have been identified to date. However, these genes are responsible for rare, Mendelian forms of dominant epilepsy and most of the genetic contributions to the IGEs remain unidentified, presenting a bottleneck to the development of more effective treatments. Copy number variants (CNVs) have recently emerged as an important source of both benign and pathogenic genetic variation. Within the last year, at least four CNVs have been identified in patients with common IGE subtypes. In fact, microdeletions on human chromosome 15q11.2 and 15q13.3 are estimated to account for 1% of IGE, making these the most common causes of IGE identified to date. Interestingly, these deletions have also been identified in autism spectrum disorders, schizophrenia and intellectual disability, suggesting a shared, but yet unidentified mechanism. The goal of this R03 proposal is to generate and characterize mouse models of the human 15q11.2 and 15q13.3 deletions. Homologous recombination in mouse embryonic stem cells (ES) will be used to introduce loxP sites flanking the syntenic intervals on mouse chromosome 7. Cre recombinase mediated deletion of the target intervals will recapitulate the human deletion event. In addition to providing the opportunity to study the mechanisms of these important epilepsy susceptibility loci, the mutant mice will also facilitate a better understanding of genetically complex, clinically challenging disorders such as autism and schizophrenia. We will characterize the seizure phenotype of the mice by evaluating seizure thresholds and spontaneous seizure frequency. These mice will provide a unique resource for detailed phenotypic analysis and mechanistic studies. PUBLIC HEALTH RELEVANCE: Genetic mutations are known to play an important role in the etiology of the idiopathic generalized epilepsies (IGEs);however, most currently identified epilepsy genes contribute to rare forms of epilepsy, and the genes responsible for common forms of IGE remain largely unknown. Within the last year, deletions on human chromosome 15q11.2 and 15q13.3 were estimated to be responsible for approximately 1% of cases of common IGE. In order to understand the mechanism by which these deletions lead to seizure generation, we will generate and characterize mouse lines that carry the same deletions that were observed in the patients.