Epilepsy is a common disease with significant heritability. For the past two decades a steady stream of gene discovery revealed some human epilepsy variants, and additional seizure-causing genes have been identified in animal models, but together these account for only a fraction of all human disease. In the past few years, rapid improvements in genome sequencing, along with a sophisticated understanding of how to use sequencing to mine variants in human populations, have begun to transform many medical research fields. Very recent individual and community-based sequencing efforts, including the NIH-funded Epi4k consortium, provide a first glimpse into what a discovery boom for epilepsy looks like. These efforts have mostly focused on a subset of disease - childhood epileptic encephalopathy (EE) - defined by intractable, seizures accompanied by cognitive decline, usually very severe. EE is not as common as idiopathic disease, but because of the severity and effect on children, it is a very motivating. Dominant EE variants are not usually heritable in the classical parent-to-child sense, but they can be detected as de novo or somatic mutations. The first wave of Epi4K results was very encouraging. Our conservative estimate suggests that more than 80 EE genes are now on the map from just these first efforts. Some genes were previously known in epilepsy, including ion channels and neurotransmitter receptors, but many are new. Standing between this unqualified success and successful therapies are several key questions, including: How do we know for sure which variants are causal and which are bystanders? Does this group of 80 (or more) genes imply that there are 80 (or more) ways to get disease, or do they instead converge onto a smaller number of pathological mechanisms? What is the relationship between seizures and cognitive decline - is co-dependence the rule or the exception? What neuron types/circuits are rate limiting for disease? Do milder alleles of EE genes also cause the genetically elusive, but more common, IGE? Mutant mice provide powerful models for human disease, and the field of mouse genetics which had also evolved linearly over the years, acquiring sophisticated tools such as conditional gene targeting and strain diversity panels, has also exploded due to both genomic technologies and much more efficient and rapid gene targeting. We think the time has come to aggressively model precise human epilepsy mutations in mice and use them to address key questions. In the next few years we will employ the latest gene targeting approaches along with the diverse toolkit of mouse genetics to make new models, study the etiology seizures and behaviors in these mice, and explore relationships between genes to identify convergent pathological mechanisms.

Public Health Relevance

Epilepsy affects 1% of the US population, and many patients remain therapy-resistant. Recent progress in human genetics has begun to identify a larger number of genes for childhood epileptic encephalopathy, one of the most intractable and devastating forms of disease. The mere identification of new genes will not be enough for development of new therapies, if we cannot determine how they cause disease, or which genes or mechanisms are targetable. The development of new models based directly on these discoveries, and using them to study disease development and molecular mechanisms, is an important, if not critical, step towards translating genetic discoveries into therapies and cures.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
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Genetics of Health and Disease Study Section (GHD)
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Whittemore, Vicky R
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Columbia University (N.Y.)
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New York
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Wolfson, Rachel L; Chantranupong, Lynne; Wyant, Gregory A et al. (2017) KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 543:438-442
Asinof, Samuel; Mahaffey, Connie; Beyer, Barbara et al. (2016) Dynamin 1 isoform roles in a mouse model of severe childhood epileptic encephalopathy. Neurobiol Dis 95:1-11
EpiPM Consortium (2015) A roadmap for precision medicine in the epilepsies. Lancet Neurol 14:1219-28
Dhindsa, Ryan S; Bradrick, Shelton S; Yao, Xiaodi et al. (2015) Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis. Neurol Genet 1:e4
Richard, C D; Tanenbaum, A; Audit, B et al. (2015) SWDreader: a wavelet-based algorithm using spectral phase to characterize spike-wave morphological variation in genetic models of absence epilepsy. J Neurosci Methods 242:127-40
Jackson, Harriet M; Onos, Kristen D; Pepper, Keating W et al. (2015) DBA/2J genetic background exacerbates spontaneous lethal seizures but lessens amyloid deposition in a mouse model of Alzheimer's disease. PLoS One 10:e0125897
Asinof, Samuel K; Sukoff Rizzo, Stacey J; Buckley, Alexandra R et al. (2015) Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy. PLoS Genet 11:e1005347
Tyler, A L; McGarr, T C; Beyer, B J et al. (2014) A genetic interaction network model of a complex neurological disease. Genes Brain Behav 13:831-40
Frankel, Wayne N; Mahaffey, Connie L; McGarr, Tracy C et al. (2014) Unraveling genetic modifiers in the gria4 mouse model of absence epilepsy. PLoS Genet 10:e1004454
Oliva, M K; McGarr, T C; Beyer, B J et al. (2014) Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy. Neurobiol Dis 67:180-90

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